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1. Toxicidad en peces de herbicidas formulados con glifosato Toxicity in fishes of herbicides formulated with glyphosate

Author: Maria Alvarez, Isabel T Gimenez, Hugo Saitua, Ricardo D Enriz, and Fernando A Giannini
Subjects: Glifosato, Coadyuvantes, Peces, Toxicidad, Glyphosate, Excipients, Fish, Toxicity, Toxicology. Poisons, RA1190-1270
Abstract: En nuestro país existe una gran extensión de hectáreas cultivadas con soja transgénica, la misma ha sido modificada genéticamente para soportar la acción de un herbicida denominado glifosato. Debido a la gran cantidad de formulaciones comerciales que incluyen glifosato es de importancia analizar el impacto ambiental producido por éstas. La evaluacion de la toxicidad aguda de dos herbicidas comerciales formulados con glifosato y de una solución del mismo; frente a peces de la especie Poecilia reticulata "lebistes" acusa que una de las soluciones produce mortalidad del 100 % de los especimenes a 100 μl/l (equivalente a 48 mg/l de principio activo); la otra a 50 μl/l (equivalente a 24 mg/l de principio activo) y la solución formulada con glifosato puro no produce mortalidad aún a concentraciones de 400 mg/l. Utilizando dosis sub letales en función de los datos obtenidos en el ensayo de toxicidad aguda se determinó que a largo plazo especimenes de Cyprinus carpio haematopterus "carpa koi", manifestaron severas alteraciones hematológicas principalmente frente a una de las formulaciones evaluadas.Nowadays, transgenic soya, modified in order to withstand the impact of the herbicide glyphosate, in one of the main crops grown in Argentina. Due to the large number of commercial formulations that include this drug, is important to analyze both, the acute and chronic environmental impact that they cause. Here the acute toxicity of two commercial herbicides glyphosatebased toward the fish Poecilia reticulate "guppy" was evaluated and compared with pure glyphosate solutions. Interestingly, while commercial herbicides formulations induce a 100% of mortality at concentration ranged between 50 and 100 μl/l, the pure glyphosathe does not present mortality even at doses higher than 400 mg/l. When some long term effects toward Cyprinus carpio haematopterus "koi" were determined by using the sub-lethal doses already calculated it was demonstrated that one of the commercial herbicides induces severe haematological alterations.
Published: 2012

2. Novel Sulfonamide-Based Carbamates as Selective Inhibitors of BChE

Author: Pratibha Magar, Oscar Parravicini, Šárka Štěpánková, Katarina Svrčková, Adriana D. Garro, Izabela Jendrzejewska, Karel Pauk, Jan Hošek, Josef Jampílek, Ricardo D. Enriz, and Aleš Imramovský
Subjects: bioassays, carbamates, cholinesterase inhibitors, molecular modeling, sulfonamides, synthesis, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract: A series of 14 target benzyl [2-(arylsulfamoyl)-1-substituted-ethyl]carbamates was prepared by multi-step synthesis and characterized. All the final compounds were tested for their ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in vitro, and the selectivity index (SI) was determined. Except for three compounds, all compounds showed strong preferential inhibition of BChE, and nine compounds were even more active than the clinically used rivastigmine. Benzyl {(2S)-1-[(2-methoxybenzyl)sulfamoyl]-4-methylpentan-2-yl}carbamate (5k), benzyl {(2S)-1-[(4-chlorobenzyl)sulfamoyl]-4-methylpentan-2-yl}carbamate (5j), and benzyl [(2S)-1-(benzylsulfamoyl)-4-methylpentan-2-yl]carbamate (5c) showed the highest BChE inhibition (IC50 = 4.33, 6.57, and 8.52 µM, respectively), indicating that derivatives 5c and 5j had approximately 5-fold higher inhibitory activity against BChE than rivastigmine, and 5k was even 9-fold more effective than rivastigmine. In addition, the selectivity index of 5c and 5j was approx. 10 and that of 5k was even 34. The process of carbamylation and reactivation of BChE was studied for the most active derivatives 5k, 5j. The detailed information about the mode of binding of these compounds to the active site of both BChE and AChE was obtained in a molecular modeling study. In this study, combined techniques (docking, molecular dynamic simulations, and QTAIM (quantum theory of atoms in molecules) calculations) were employed.
Published: 2021
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3. [Untitled]

Author: Ricardo D. Enriz, Monica L. Freile, Susana Zacchino, María Victoria Rodríguez, Manuel Gonzalez Sierra, Gabriela Egly Feresin, Alejandro Tapia, Beatriz Lima, and Rita R. Kurdelas
Subjects: Baccharis darwinii, Asteraceae, prenylated coumarins, auraptene, antimicrobial activity, Organic chemistry, QD241-441
Abstract: The petroleum ether extract of Baccharis darwinii showed activity against Cryptococcus neoformans and dermatophytes. Bioactivity-guided fractionation of Baccharis darwinii has resulted in the isolation of three coumarins: 5’-hydroxy aurapten (anisocoumarin H, 1), aurapten (7-geranyloxycoumarin, 2) and 5’-oxoaurapten (diversinin, 3). The structures of these compounds were characterized by spectroscopic methods. These compounds were evaluated for their antimicrobialactivity against a panel of each, bacteria and fungi. Compound 3 showed the best activities against Microsporum gypseum, Trichophyton rubrum and Trichophyton mentagrophytes with MICs = 15.6 µg/mL, followed by compound 1 whose MICs against the same fungi were 62.5 µg/mL. In addition they showed fungicidal rather than fungistatic activity. Both compounds showed moderate activity (MICs = 125 µg/mL) against Cryptococcus neoformans. This is the first report of the presence of compound 1 in B. darwinii.
Published: 2010
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4. Nové karbamáty na bázi sulfonamidu jako selektivní inhibitory BChE

Author: Šárka Štěpánková, Jan Hošek, Katarína Svrčková, Ricardo D. Enriz, Josef Jampilek, Adriana Garro, Karel Pauk, Izabela Jendrzejewska, Aleš Imramovský, Oscar Parravicini, and Pratibha Magar
Subjects: Carbamate, cholinesterase inhibitors, Molecular model, synthesis, Stereochemistry, QH301-705.5, medicine.medical_treatment, sulfoamidy, carbamates, inhibitory cholinesteráz, Molecular Dynamics Simulation, Article, Catalysis, Inorganic Chemistry, Structure-Activity Relationship, chemistry.chemical_compound, Catalytic Domain, sulfonamides, BChE, medicine, Humans, Physical and Theoretical Chemistry, Biology (General), bioassays, Molecular Biology, QD1-999, Spectroscopy, Butyrylcholinesterase, Cholinesterase, chemistry.chemical_classification, Binding Sites, biology, Chemistry, molecular modeling, Organic Chemistry, karbamáty, Active site, General Medicine, Acetylcholinesterase, Computer Science Applications, Sulfonamide, Molecular Docking Simulation, Docking (molecular), biology.protein, AChE
Abstract: A series of 14 target benzyl [2-(arylsulfamoyl)-1-substituted-ethyl]carbamates was prepared by multi-step synthesis and characterized. All the final compounds were tested for their ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in vitro, and the selectivity index (SI) was determined. Except for three compounds, all compounds showed strong preferential inhibition of BChE, and nine compounds were even more active than the clinically used rivastigmine. Benzyl {(2S)-1-[(2-methoxybenzyl)sulfamoyl]-4-methylpentan-2-yl}carbamate, benzyl {(2S)-1-[(4-chlorobenzyl)sulfamoyl]-4-methylpentan-2-yl}carbamate, and benzyl [(2S)-1-(benzylsulfamoyl)-4-methylpentan-2-yl]carbamate showed the highest BChE inhibition (IC50 = 4.33, 6.57, and 8.52 mu M, respectively), indicating that the last two derivatives had approximately 5-fold higher inhibitory activity against BChE than rivastigmine, and the first one was even 9-fold more effective than rivastigmine. In addition, the selectivity index was approx. 10 or 34, respectively. The process of carbamylation and reactivation of BChE was studied for the most active derivatives 5k, 5j. The detailed information about the mode of binding of these compounds to the active site of both BChE and AChE was obtained in a molecular modeling study. In this study, combined techniques (docking, molecular dynamic simulations, and QTAIM (quantum theory of atoms in molecules) calculations) were employed. Vícestupňovou syntézou byla připravena a následně charakterizována série 14 cílových benzyl [2-(arylsulfamoyl)-1-substituovaných-ethyl]karbamátů. Všechny finální sloučeniny byly testovány na jejich schopnost inhibovat acetylcholinesterázu (AChE) a butyrylcholinesterázu (BChE) in vitro a byl stanoven index selektivity (SI). Kromě tří sloučenin všechny sloučeniny vykazovaly silnou preferenční inhibici BChE a devět sloučenin bylo dokonce aktivnějších než klinicky používaný rivastigmin. Benzyl {(2S)-1-[(2-methoxybenzyl)sulfamoyl]-4-methylpentan-2-yl}karbamát, benzyl {(2S)-1-[(4-chlorbenzyl)sulfamoyl]-4-methylpentan -2-yl}karbamát a benzyl [(2S)-1-(benzylsulfamoyl)-4-methylpentan-2-yl]karbamát vykazovaly nejvyšší inhibici BChE (IC50 = 4,33, 6,57 a 8,52 mu M), což ukazuje, že poslední dva deriváty měly přibližně 5krát vyšší inhibiční aktivitu proti BChE než rivastigmin a první byl dokonce 9krát účinnější než rivastigmin. Navíc jejich index selektivity byl cca. 10 respektive 34. Proces karbamylace a reaktivace BChE byl studován u nejaktivnějších derivátů. Detailní informace o způsobu vazby těchto sloučenin na aktivní místo BChE i AChE byly získány ve studii molekulárního modelování. V této studii byly použity kombinované techniky (docking, molekulárně dynamické simulace a výpočty QTAIM (kvantová teorie atomů v molekulách)).
Published: 2021

5. Antibacterial Effect of Chitosan–Gold Nanoparticles and Computational Modeling of the Interaction between Chitosan and a Lipid Bilayer Model

Author: Marta G. Fuster, Gloria Víllora, Mercedes G. Montalbán, J J López-Cascales, Juan J. Giner-Casares, María Gloria Villora Cano, Guzmán Carissimi, Gabriela Egly Feresin, Ricardo D. Enriz, and Beatriz Lima
Subjects: General Chemical Engineering, Nanoparticle, Chitosan-gold nanoparticle, macromolecular substances, Antimicrobial activity, Article, lcsh:Chemistry, Chitosan, chemistry.chemical_compound, purl.org/becyt/ford/2.10 [https], CHITOSAN–GOLD NANOPARTICLE, Zeta potential, General Materials Science, Lipid bilayer, antimicrobial activity, Bilayer, Computational model, technology, industry, and agriculture, Combinatorial chemistry, chitosan–gold nanoparticle, computational model, Membrane, lcsh:QD1-999, purl.org/becyt/ford/2 [https], chemistry, Colloidal gold, Antibacterial activity
Abstract: Pathogenic bacteria have the ability to develop antibiotic resistance mechanisms. Their action consists mainly in the production of bacterial enzymes that inactivate antibiotics or the appearance of modifications that prevent the arrival of the drug at the target point or the alteration of the target point itself, becoming a growing problem for health systems. Chitosan&ndash, gold nanoparticles (Cs-AuNPs) have been shown as effective bactericidal materials avoiding damage to human cells. In this work, Cs-AuNPs were synthesized using chitosan as the reducing agent, and a systematic analysis of the influence of the synthesis parameters on the size and zeta potential of the Cs-AuNPs and their UV-vis spectra was carried out. We used a simulation model to characterize the interaction of chitosan with bacterial membranes, using a symmetric charged bilayer and two different chitosan models with different degrees of the chitosan amine protonation as a function of pH, with the aim to elucidate the antibacterial mechanism involving the cell wall disruption. The Cs-AuNP antibacterial activity was evaluated to check the simulation model.
Published: 2020
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6. Targeting defective sphingosine kinase 1 in Niemann–Pick type C disease with an activator mitigates cholesterol accumulation

Author: Josef Jampilek, Michael Maceyka, Sheldon Milstien, Elisa N.D. Palladino, Markus H. Gräler, Pavlina Marvanova, Sarah Spiegel, Can E. Senkal, Ricardo D. Enriz, Jason Newton, Santiago Lima, and Cynthia Weigel
Subjects: 0301 basic medicine, SPHINGOLIPIDS, SPHINGOSINE KINASE (SPHK), Sphingosine kinase, Vesicular Transport Proteins, Biochemistry, purl.org/becyt/ford/1 [https], chemistry.chemical_compound, Mice, Sphingosine, hemic and lymphatic diseases, Lysosomal storage disease, SPHINGOLIPID, LIPID METABOLISM, Membrane Glycoproteins, biology, Chemistry, CHOLESTEROL, Intracellular Signaling Peptides and Proteins, NEURODEGENERATION, Niemann-Pick Disease, Type C, Lipids, Cell biology, Phosphotransferases (Alcohol Group Acceptor), Protein Transport, Cholesterol, Sphingosine kinase 1, lipids (amino acids, peptides, and proteins), Cholesterol Esters, congenital, hereditary, and neonatal diseases and abnormalities, Endosome, Primary Cell Culture, Endosomes, LYSOSOMAL STORAGE DISEASE, NIEMANN–PICK TYPE C, Cell Line, 03 medical and health sciences, Niemann-Pick C1 Protein, Sphingolipidoses, medicine, purl.org/becyt/ford/1.4 [https], Animals, Humans, Molecular Biology, Sphingolipids, GENETIC DISORDER, 030102 biochemistry & molecular biology, nutritional and metabolic diseases, SPHINGOSINE-1-PHOSPHATE (S1P), Cell Biology, Fibroblasts, medicine.disease, Sphingolipid, NPC1, 030104 developmental biology, biology.protein, SPHINGOSINE KINASE, Carrier Proteins, Lysosomes
Abstract: Niemann–Pick type C (NPC) disease is a lysosomal storage disorder arising from mutations in the cholesterol-trafficking protein NPC1 (95%) or NPC2 (5%). These mutations result in accumulation of low-density lipoprotein-derived cholesterol in late endosomes/lysosomes, disruption of endocytic trafficking, and stalled autophagic flux. Additionally, NPC disease results in sphingolipid accumulation, yet it is unique among the sphingolipidoses because of the absence of mutations in the enzymes responsible for sphingolipid degradation. In this work, we examined the cause for sphingosine and sphingolipid accumulation in multiple cellular models of NPC disease and observed that the activity of sphingosine kinase 1 (SphK1), one of the two isoenzymes that phosphorylate sphingoid bases, was markedly reduced in both NPC1 mutant and NPC1 knockout cells. Conversely, SphK1 inhibition with the isotype-specific inhibitor SK1-I in WT cells induced accumulation of cholesterol and reduced cholesterol esterification. Of note, a novel SphK1 activator (SK1-A) that we have characterized decreased sphingoid base and complex sphingolipid accumulation and ameliorated autophagic defects in both NPC1 mutant and NPC1 knockout cells. Remarkably, in these cells, SK1-A also reduced cholesterol accumulation and increased cholesterol ester formation. Our results indicate that a SphK1 activator rescues aberrant cholesterol and sphingolipid storage and trafficking in NPC1 mutant cells. These observations highlight a previously unknown link between SphK1 activity, NPC1, and cholesterol trafficking and metabolism. Fil: Newton, Jason. Virginia Commonwealth University School of Medicine; Estados Unidos Fil: Palladino, Elisa N.D.. Virginia Commonwealth University School of Medicine; Estados Unidos Fil: Weigel, Cynthia. Virginia Commonwealth University School of Medicine; Estados Unidos Fil: Maceyka, Michael. Virginia Commonwealth University School of Medicine; Estados Unidos Fil: Gräler, Markus H.. Universitätsklinikum Jena; Alemania Fil: Senkal, Can E.. Virginia Commonwealth University School of Medicine; Estados Unidos Fil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina Fil: Marvanova, Pavlina. Veterinární univerzita Brno; República Checa Fil: Jampilek, Josef. Univerzita Komenského v Bratislave; Eslovaquia Fil: Lima, Santiago. Virginia Commonwealth University; Estados Unidos Fil: Milstien, Sheldon. Virginia Commonwealth University School of Medicine; Estados Unidos Fil: Spiegel, Sarah. Virginia Commonwealth University School of Medicine; Estados Unidos
Published: 2020

7. Conformational and electronic study of dopamine interacting with the D2 dopamine receptor

Author: Emilio Angelina, Marcela Cristina Vettorazzi, Sebastian A. Andujar, Rodrigo D. Tosso, M. Natalia C. Zarycz, Oscar Parravicini, Ricardo D. Enriz, and Nelida Maria Peruchena
Subjects: 010402 general chemistry, 01 natural sciences, DOPAMINE, Computational chemistry, Dopamine, 0103 physical sciences, medicine, Aqueous solution, 010304 chemical physics, biology, NMR CALCULATIONS, Chemistry, Otras Ciencias Químicas, Atoms in molecules, Ciencias Químicas, Active site, BIOLOGICALLY RELEVANT CONFORMATION, General Chemistry, QTAIM ANALYSIS, Ligand (biochemistry), Potential energy, 0104 chemical sciences, Computational Mathematics, POTENTIAL ENERGY SURFACE, Dopamine receptor, Potential energy surface, MOLECULAR INTERACTIONS, biology.protein, CIENCIAS NATURALES Y EXACTAS, medicine.drug
Abstract: We report an exhaustive conformational and electronic study on dopamine (DA) interacting with the D2 dopamine receptor (D2DR). For the first time, the complete surface of the conformational potential energy of the complex DA/D2DR is reported. Such a surface was obtained through the use of QM/MM calculations. A detailed study of the molecular interactions that stabilize and destabilize the different molecular complexes was carried out using two techniques: Quantum Theory of Atoms in Molecules computations and nuclear magnetic shielding constants calculations. A comparative study of the behavior of DA in the gas phase, aqueous solution, and in the active site of D2DR has allowed us to evaluate the degree of deformation suffered by the ligand and, therefore, analyze how rustic are the lock-key model and the induced fit theory in this case. Our results allow us to propose one of the conformations obtained as the “biologically relevant” conformation of DA when it is interacting with the D2DR. Fil: Tosso, Rodrigo David. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina Fil: Parravicini, Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina Fil: Zarycz, Maria Natalia Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina Fil: Angelina, Emilio Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Química Básica y Aplicada del Nordeste Argentino. Universidad Nacional del Nordeste. Facultad de Ciencias Exactas Naturales y Agrimensura. Instituto de Química Básica y Aplicada del Nordeste Argentino; Argentina Fil: Vettorazzi, Marcela Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina Fil: Peruchena, Nelida Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Química Básica y Aplicada del Nordeste Argentino. Universidad Nacional del Nordeste. Facultad de Ciencias Exactas Naturales y Agrimensura. Instituto de Química Básica y Aplicada del Nordeste Argentino; Argentina Fil: Andujar, Sebastian Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina Fil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina
Published: 2020

8. Synthesis, biological evaluation and molecular modeling studies of substitutedN-benzyl-2-phenylethanamines as cholinesterase inhibitors

Author: Adriana Garro, Gabriela Egly Feresin, Alejandro A. Orden, Florencia Carmona-Viglianco, Daniel Zaragoza-Puchol, Oscar Parravicini, Marcela Kurina-Sanz, and Ricardo D. Enriz
Subjects: Molecular model, Stereochemistry, ACHE AND BCHE INHIBITION, REDUCTIVE AMINATION, 01 natural sciences, Catalysis, purl.org/becyt/ford/1 [https], 03 medical and health sciences, Materials Chemistry, medicine, Galantamine, purl.org/becyt/ford/1.4 [https], MOLECULAR MODELING, Amaryllidaceae Alkaloids, IC50, 030304 developmental biology, Cholinesterase, AMARYLLIDACEAE ALKALOID PRECURSOR, chemistry.chemical_classification, NORBELLADINE ANALOGUES, 0303 health sciences, biology, Chemistry, General Chemistry, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, Enzyme, Mechanism of action, Docking (molecular), biology.protein, medicine.symptom, medicine.drug
Abstract: In this work, we report the synthesis of a series of derivatives of N-benzyl-2-phenylethanamine which is the framework of norbelladine, the natural common precursor of the Amaryllidaceae alkaloids. These compounds were assessed in the inhibition of both AChE and BChE which are the enzymes responsible for the breakdown of acetylcholine and hence they constitute targets in the palliative treatment of Alzheimer's disease. In particular, brominated derivatives exhibited the lowest IC50 values against AChE. Interestingly, the presence of iodine in one of the aromatic rings highly increased the inhibition of BChE compared to its analogues, with an IC50 value similar to that of galantamine, which is the reference compound currently used in the treatment of AD. A possible mechanism of action for these compounds was determined by molecular modeling studies using combined techniques of docking and molecular dynamics simulations. Fil: Carmona Viglianco, Maria Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Investigaciones en Tecnología Química. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto de Investigaciones en Tecnología Química; Argentina Fil: Zaragoza Puchol, José Daniel. Universidad Nacional de San Juan. Facultad de Ingeniería. Instituto de Biotecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan; Argentina Fil: Parravicini, Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina Fil: Garro, Adriana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina Fil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina Fil: Feresin, Gabriela Egly. Universidad Nacional de San Juan. Facultad de Ingeniería. Instituto de Biotecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan; Argentina Fil: Kurina Sanz, Marcela Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Investigaciones en Tecnología Química. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto de Investigaciones en Tecnología Química; Argentina Fil: Orden, Alejandro Agustin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Investigaciones en Tecnología Química. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto de Investigaciones en Tecnología Química; Argentina
Published: 2020

9. Second generation 4,5,6,7-tetrahydrobenzo[d]thiazoles as novel DNA gyrase inhibitors

Author: Lucas J. Gutierrez, Peter Molek, Anamarija Zega, Csaba Pál, Andraž Lamut, Janez Ilaš, Ákos Nyerges, Tihomir Tomašič, Tomaž Bratkovič, Žiga Skok, Ricardo D. Enriz, Nace Zidar, Cristina D. Cruz, Danijel Kikelj, Gábor Draskovits, Päivi Tammela, Michaela Barančoková, Petra Szili, Division of Pharmaceutical Biosciences, Bioactivity Screening Group, Drug Research Program, and University Management
Subjects: MECHANISM, Topoisomerase IV, N-PHENYLINDOLAMIDES, TOPOISOMERASES, medicine.disease_cause, pyrrolamide, 01 natural sciences, DNA gyrase, Enterococcus faecalis, 03 medical and health sciences, Antibiotic resistance, DESIGN, Drug Discovery, BINDING, medicine, ANTIBACTERIALS, OPTIMIZATION, Escherichia coli, 030304 developmental biology, Pharmacology, 0303 health sciences, biology, 010405 organic chemistry, Chemistry, Topoisomerase, biology.organism_classification, N-PHENYL-4,5-DIBROMOPYRROLAMIDES, 0104 chemical sciences, 3. Good health, inhibitor, antibacterial, Biochemistry, QTAIM, 317 Pharmacy, DISCOVERY, biology.protein, Molecular Medicine, Antibacterial activity, thiazole, ATPASE INHIBITORS, Enterococcus faecium
Abstract: Aim: DNA gyrase and topoisomerase IV are essential bacterial enzymes, and in the fight against bacterial resistance, they are important targets for the development of novel antibacterial drugs. Results: Building from our first generation of 4,5,6,7-tetrahydrobenzo[ d]thiazole-based DNA gyrase inhibitors, we designed and prepared an optimized series of analogs that show improved inhibition of DNA gyrase and topoisomerase IV from Staphylococcus aureus and Escherichia coli, with IC50 values in the nanomolar range. Importantly, these inhibitors also show improved antibacterial activity against Gram-positive strains. Conclusion: The most promising inhibitor, 29, is active against Enterococcus faecalis, Enterococcus faecium and S. aureus wild-type and resistant strains, with minimum inhibitory concentrations between 4 and 8 μg/ml, which represents good starting point for development of novel antibacterials.
Published: 2020

10. Design of new quinolin-2-one-pyrimidine hybrids as sphingosine kinases inhibitors

Author: Santiago Lima, Rodrigo Abonia, Sarah Spiegel, Sebastian A. Andujar, Marcela Cristina Vettorazzi, Lucas J. Gutierrez, Justo Cobo, Daniel Insuasty, Manuel Nogueras, Ricardo D. Enriz, and Antonio Marchal
Subjects: Models, Molecular, Sphingosine kinase 1 inhibitors, Pyrimidine, Molecular model, Computational biology, Quinolin-2-one-pyrimidine hybrids, 01 natural sciences, Biochemistry, Bioassays, Article, Synthesis, chemistry.chemical_compound, Drug Discovery, medicine, Humans, Molecular Biology, Inhibitory effect, Molecular interactions, Sphingosine, 010405 organic chemistry, Kinase, Otras Ciencias Químicas, Organic Chemistry, Ciencias Químicas, Cancer, medicine.disease, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, SPHK2, Phosphotransferases (Alcohol Group Acceptor), Pyrimidines, chemistry, Drug Design, Molecular modelling, CIENCIAS NATURALES Y EXACTAS
Abstract: Sphingosine-1-phosphate is now emerging as an important player in cancer, inflammation, autoimmune, neurological and cardiovascular disorders. Abundance evidence in animal and humans cancer models has shown that SphK1 is linked to cancer. Thus, there is a great interest in the development new SphK1 inhibitors as a potential new treatment for cancer. In a search for new SphK1 inhibitors we selected the well-known SKI-II inhibitor as the starting structure and we synthesized a new inhibitor structurally related to SKI-II with a significant but moderate inhibitory effect. In a second approach, based on our molecular modeling results, we designed new structures based on the structure of PF-543, the most potent known SphK1 inhibitor. Using this approach, we report the design, synthesis and biological evaluation of a new series of compounds with inhibitory activity against both SphK1 and SphK2. These new inhibitors were obtained incorporating new connecting chains between their polar heads and hydrophobic tails. On the other hand, the combined techniques of molecular dynamics simulations and QTAIM calculations provided complete and detailed information about the molecular interactions that stabilize the different complexes of these new inhibitors with the active sites of the SphK1. This information will be useful in the design of new SphK inhibitors. Fil: Vettorazzi, Marcela Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina Fil: Insuasty, Daniel. Universidad de Jaén; España Fil: Lima, Santiago. Virginia Commonwealth University School of Medicine; Estados Unidos Fil: Gutierrez, Lucas Joel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina Fil: Nogueras, Manuel. Universidad de Jaén; España Fil: Marchal, Antonio. Universidad de Jaén; España Fil: Abonia, Rodrigo. Universidad del Valle; Colombia Fil: Andujar, Sebastian Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina Fil: Spiegel, Sarah. Virginia Commonwealth University School of Medicine; Estados Unidos Fil: Cobo, Justo. Universidad del Valle; Colombia Fil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina
Published: 2019

11. Searching new structural scaffolds for BRAF inhibitors. An integrative study using theoretical and experimental techniques

Author: Jiri Kos, Pavlina Marvanova, Josef Jampilek, Petr Mokry, Nace Zidar, Danijel Kikelj, Emilio Angelina, Ludmila Estefanía Campos, Tihomir Tomašič, Tomas Gonec, Francisco Matías Garibotto, Sergio E. Alvarez, and Ricardo D. Enriz
Subjects: Proto-Oncogene Proteins B-raf, Molecular model, BRAF INHIBITORS, Antineoplastic Agents, Computational biology, SYNTHESIS, 01 natural sciences, Biochemistry, Cell Line, Tumor, Drug Discovery, medicine, Humans, MOLECULAR MODELING, VIRTUAL SCREENING, Vemurafenib, Protein kinase A, Mutated protein, Protein Kinase Inhibitors, Molecular Biology, Virtual screening, Molecular Structure, 010405 organic chemistry, Chemistry, BIOASSAYS, Melanoma, Otras Ciencias Químicas, Organic Chemistry, Ciencias Químicas, Dabrafenib, medicine.disease, 0104 chemical sciences, Molecular Docking Simulation, 010404 medicinal & biomolecular chemistry, Drug Screening Assays, Antitumor, V600E, CIENCIAS NATURALES Y EXACTAS, Protein Binding, medicine.drug
Abstract: The identification of the V600E activating mutation in the protein kinase BRAF in around 50% of melanoma patients has driven the development of highly potent small inhibitors (BRAFi) of the mutated protein. To date, Dabrafenib and Vemurafenib, two specific BRAFi, have been clinically approved for the treatment of metastatic melanoma. Unfortunately, after the initial response, tumors become resistant and patients develop a progressive and lethal disease, making imperative the development of new therapeutic options. The main objective of this work was to find new BRAF inhibitors with different structural scaffolds than those of the known inhibitors. Our study was carried out in different stages; in the first step we performed a virtual screening that allowed us to identify potential new inhibitors. In the second step, we synthesized and tested the inhibitory activity of the novel compounds founded. Finally, we conducted a molecular modelling study that allowed us to understand interactions at the molecular level that stabilize the formation of the different molecular complexes. Our theoretical and experimental study allowed the identification of four new structural scaffolds, which could be used as starting structures for the design and development of new inhibitors of BRAF. Our experimental data indicate that the most active compounds reduced significantly ERK½ phosphorylation, a measure of BRAF inhibition, and cell viability. Thus, from our theoretical and experimental results, we propose new substituted hydroxynaphthalenecarboxamides, N-(hetero)aryl-piperazinylhydroxyalkylphenylcarbamates, substituted piperazinylethanols and substituted piperazinylpropandiols as initial structures for the development of new inhibitors for BRAF. Moreover, by performing QTAIM analysis, we are able to describe in detail the molecular interactions that stabilize the different Ligand-Receptor complexes. Such analysis indicates which portion of the different molecules must be changed in order to obtain an increase in the binding affinity of these new ligands. Fil: Campos, Ludmila Estefanía. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia; Argentina Fil: Garibotto, Francisco Matías. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia; Argentina Fil: Angelina, Emilio Luis. Universidad Nacional del Nordeste. Facultad de Ciencias Exactas y Naturales y Agrimensura. Departamento de Química. Laboratorio de Estructura Molecular y Propiedades; Argentina Fil: Kos, Jiri. Univerzita Palackého v Olomouci; República Checa Fil: Tomašič, Tihomir. Univerza v Ljubljani; Eslovenia Fil: Zidar, Nace. Univerza v Ljubljani; Eslovenia Fil: Kikelj, Danijel. Univerza v Ljubljani; Eslovenia Fil: Gonec, Tomas. Veterinární a farmaceutická univerzita Brno; República Checa Fil: Marvanova, Pavlina. Veterinární a farmaceutická univerzita Brno; República Checa Fil: Mokry, Petr. Veterinární a farmaceutická univerzita Brno; República Checa Fil: Jampilek, Josef. Univerzita Palackého v Olomouci; República Checa. Univerzita Komenského v Bratislave; Eslovaquia Fil: Alvarez, Sergio Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia; Argentina Fil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia; Argentina
Published: 2019

12. Quinoline analogs of 2-aminoindane as potential central dopaminergic agents

Author: Luis Perdomo, Sebastian Rojas, Simón E. López, Lucia Rodríguez, José Ortega, Katherindel C. Balza, Ligia B. Angel, Jorge E. Ángel, Akram Samear Dabian, María del Rosario Garrido, Anita Israel, Ricardo D. Enriz, María M. Ramírez, Sebastian A. Andujar, Jaime Charris, and Biagina del Carmen Migliore
Subjects: Molecular model, AGONISTS, Central nervous system, 01 natural sciences, chemistry.chemical_compound, Dopamine receptor D2, medicine, 2-Aminoindane, MOLECULAR MODELING, General Pharmacology, Toxicology and Pharmaceutics, Receptor, 010405 organic chemistry, Chemistry, Otras Ciencias Químicas, Organic Chemistry, Quinoline, Dopaminergic, DOPAMINERGIC TRANSMISSION, Ciencias Químicas, HUNTINGTON CHOREA, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, medicine.anatomical_structure, Dopaminergic neurotransmission, PARKINSON, Neuroscience, CIENCIAS NATURALES Y EXACTAS
Abstract: Neurodegenerative disorders such as Parkinson and Huntington Chorea are related with damage to the central dopaminergic system. On the purpose to find new drugs able to re-establish the imbalance on the dopaminergic neurotransmission in the central nervous system and counteract some of the neurodegenerative sicknesses, we have designed, synthesized, pharmacologically evaluated, and studied through molecular modeling,2-aminoindane-quinoline analog derivatives (1–5). Pharmacological studies made on the central nervous system through ICV (intracerebroventricular) and IS (intrastriatal), of compounds (1–5) showed agonistic activity by the activation of dopaminergic mechanisms on the central nervous system. The corresponding molecular modeling study permitted us not only to explain the differential behavior of studied compounds, but also to understand whichmolecular interactions are responsible to stabilize the different complexes formed between those compounds and the D2 receptor. These results validate our medicinal chemical approach in different aspects: the receptor model used, the responsible fragment inserted within the structure of the compounds capable of interacting with the receptor, the complementary functional groups that facilitate the expected response and the pharmacological administration routes. All these aspects are important for the design of this type of compounds as potential anti-Parkinson and/or anti-Huntington agents. Fil: Angel, Jorge E.. Universidad del Zulia. Facultad Experimental de Ciencias; Venezuela Fil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia; Argentina Fil: Balza, Katherindel C.. Universidad del Zulia. Facultad Experimental de Ciencias; Venezuela Fil: Angel, Ligia B.. Universidad del Zulia. Facultad Experimental de Ciencias; Venezuela Fil: Perdomo, Luís E.. Universidad del Zulia. Facultad Experimental de Ciencias; Venezuela Fil: Rodríguez, Lucia Ch.. Universidad del Zulia. Facultad Experimental de Ciencias; Venezuela Fil: Dabian, Akram S.. Universidad del Zulia. Facultad Experimental de Ciencias; Venezuela Fil: Migliore, Biagina del C.. Universidad del Zulia. Facultad Experimental de Ciencias; Venezuela Fil: Ramírez, María M.. Universidad del Zulia. Facultad Experimental de Ciencias; Venezuela Fil: Ortega, José G.. Universidad del Zulia. Facultad Experimental de Ciencias; Venezuela Fil: Charris, Jaime E.. Universidad del Zulia. Facultad Experimental de Ciencias; Venezuela Fil: Israel, Anita. Universidad Central de Venezuela; Venezuela Fil: Garrido, María del R.. Universidad Central de Venezuela; Venezuela Fil: López, Simon E.. University of Florida; Estados Unidos. Universidad Simon Bolivar. Departamento de Quimica.; Venezuela Fil: Rojas, Sebastian. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina Fil: Andujar, Sebastian Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia; Argentina
Published: 2019

13. The nitrone spin trap 5,5-dimethyl-1-pyrroline N-oxide binds to toll-like receptor-2-TIR-BB-loop domain and dampens downstream inflammatory signaling

Author: Marcos D. Muñoz, Ricardo D. Enriz, Jules Russick, Sébastien Lacroix-Desmazes, Sandra E. Gomez Mejiba, Dario C. Ramirez, Sandrine Delignat, Lucas J. Gutierrez, Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Laboratoire des sciences et techniques de l'information, de la communication et de la connaissance (Lab-STICC), École Nationale d'Ingénieurs de Brest (ENIB)-Université de Bretagne Sud (UBS)-Université de Brest (UBO)-École Nationale Supérieure de Techniques Avancées Bretagne (ENSTA Bretagne)-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL)-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)
Subjects: BB-LOOP, In silico, Priming (immunology), Inflammation, Molecular Dynamics Simulation, 01 natural sciences, Nitrone, purl.org/becyt/ford/1 [https], Cyclic N-Oxides, Mice, 03 medical and health sciences, Protein Domains, 0103 physical sciences, TIR DOMAIN, purl.org/becyt/ford/1.4 [https], medicine, Animals, Humans, TLR2, Molecular Biology, 030304 developmental biology, MECHANISM-BASED DRUG, chemistry.chemical_classification, 0303 health sciences, Toll-like receptor, 010304 chemical physics, Functional analysis, DMPO, Otras Ciencias Químicas, SIGNAL TRANSDUCTION, NF-kappa B, Ciencias Químicas, Toll-Like Receptor 2, Cell biology, HEK293 Cells, RAW 264.7 Cells, chemistry, Myeloid Differentiation Factor 88, Molecular Medicine, [SDV.IMM]Life Sciences [q-bio]/Immunology, Nitrogen Oxides, Spin Labels, Signal transduction, medicine.symptom, CIENCIAS NATURALES Y EXACTAS, Protein Binding, Signal Transduction
Abstract: The nitrone spin trap 5,5‑dimethyl‑1‑pyrroline N‑oxide (DMPO) dampens endotoxin-induced and TLR4-driven priming of macrophages, but the mechanism remains unknown. The available information suggests a direct binding of DMPO to the TIR domain, which is shared between TLRs. However, TLR2-TIR domain is the only TLR that have been crystallized. Our in silico data show that DMPO binds to four specific residues in the BB-loop within the TLR2-TIR domain. Our functional analysis using hTLR2.6-expressing HEKs cells showed that DMPO can block zymosan-triggered-TLR2-mediated NF-κB activation. However, DMPO did not affect the overall TLR2-MyD88 protein-protein interaction. DMPO binds to the BB-loop in the TIR-domain and dampens downstream signaling without affecting the overall TIR-MyD88 interaction. These data encourage the use of DMPO-derivatives as potential mechanism-based inhibitors of TLR-triggered inflammation. Fil: Muñoz, Marcos David. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina Fil: Gutierrez, Lucas Joel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Química Básica y Aplicada del Nordeste Argentino. Universidad Nacional del Nordeste. Facultad de Ciencias Exactas Naturales y Agrimensura. Instituto de Química Básica y Aplicada del Nordeste Argentino; Argentina Fil: Delignat, Sandrine. Université Pierre et Marie Curie; Francia. Centre de Recherche des Cordeliers; Francia Fil: Russick, Jules. Université Pierre et Marie Curie; Francia. Centre de Recherche des Cordeliers; Francia Fil: Gomez-Mejiba, Sandra Esther. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina Fil: Lacroix Desmazes, Sebastien. Centre de Recherche des Cordeliers; Francia. Université Pierre et Marie Curie; Francia Fil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina Fil: Ramirez, Dario. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina
Published: 2019

14. Polycerasoidol, a Natural Prenylated Benzopyran with a Dual PPARα/PPARγ Agonist Activity and Anti-inflammatory Effect

Author: Bruno Figadère, Aida Collado, Patrice Marques, Isabel Barrachina, Diego Cortes, Francisco Matías Garibotto, Maria-Jesus Sanz, Nuria Cabedo, Laura Piqueras, Daniel Henri Caignard, Xavier Franck, Almudena Bermejo, Noureddine El Aouad, Ricardo D. Enriz, Fernando D. Suvire, Catherine Dacquet, Universitat de València (UV), Chimie Organique et Bioorganique : Réactivité et Analyse (COBRA), Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie Organique Fine (IRCOF), Université de Rouen Normandie (UNIROUEN), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherches Internationales Servier [Suresnes] (IRIS), Laboratoire d'Excellence en Recherche sur le Médicament et l'Innovation Thérapeutique [Châtenay-Malabry] (LabEx LERMIT), and Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Anti-Inflammatory Agents, RXRα/PPARγ, Pharmaceutical Science, Retinoid X receptor, Pharmacology, 01 natural sciences, Analytical Chemistry, Structure-Activity Relationship, chemistry.chemical_compound, Transactivation, Prenylation, POLYCERASOIDOL, Drug Discovery, Humans, Structure–activity relationship, Glucose homeostasis, Benzopyrans, PPAR alpha, MOLECULAR MODELING, Cytotoxicity, Molecular Structure, 010405 organic chemistry, Chemistry, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Organic Chemistry, Ciencias Químicas, NATARUL PRODUCTS, Peroxisome, 0104 chemical sciences, Benzopyran, PPAR gamma, 010404 medicinal & biomolecular chemistry, Química Orgánica, Complementary and alternative medicine, Molecular Medicine, CIENCIAS NATURALES Y EXACTAS
Abstract: Dual peroxisome proliferator-activated receptor-α/γ (PPARα/γ) agonists regulate both lipid and glucose homeostasis under different metabolic conditions and can exert anti-inflammatory activity. We investigated the potential dual PPARα/γ agonism of prenylated benzopyrans polycerasoidol (1) and polycerasoidin (2) and their derivatives for novel drug development. Nine semisynthetic derivatives were prepared from the natural polycerasoidol (1) and polycerasoidin (2), which were evaluated for PPARα, -γ, -δ and retinoid X receptor-α activity in transactivation assays. Polycerasoidol (1) exhibited potent dual PPARα/γ agonism and low cytotoxicity. Structure–activity relationship studies revealed that a free phenol group at C-6 and a carboxylic acid at C-9′ were key features for dual PPARα/γ agonism activity. Molecular modeling indicated the relevance of these groups for optimal ligand binding to the PPARα and PPARγ domains. In addition, polycerasoidol (1) exhibited a potent anti-inflammatory effect by inhibiting mononuclear leukocyte adhesion to the dysfunctional endothelium in a concentration-dependent manner via RXRα/PPARγ interactions. Therefore, polycerasoidol (1) can be considered a hit-to-lead molecule for the further development of novel dual PPARα/γ agonists capable of preventing cardiovascular events associated with metabolic disorders. Fil: Bermejo, Almudena. Universidad de Valencia; España Fil: Collado, Aida. Universidad de Valencia; España Fil: Barrachina, Isabel. Universidad de Valencia; España Fil: Marqués, Patrice. Universidad de Valencia; España Fil: El Aouad, Noureddine. Universidad de Valencia; España Fil: Franck, Xavier. Université de Rouen; Francia Fil: Garibotto, Francisco Matías. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina Fil: Dacquet, Catherine. Institut de Recherches Servier; Francia Fil: Caignard, Daniel H.. Institut de Recherches Servier; Francia Fil: Suvire, Fernando Daniel. Universidad Nacional de San Luis; Argentina Fil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina Fil: Piqueras, Laura. Universidad de Valencia; España Fil: Figadère, Bruno. Université Paris Sud; Francia Fil: Sanz, María-Jesús. Universidad de Valencia; España Fil: Cabedo, Nuria. Universidad de Valencia; España Fil: Cortes, Diego. Universidad de Valencia; España
Published: 2019

15. Searching for improved mimetic peptides inhibitors preventing conformational transition of amyloid-β 42 monomer

Author: Zsolt Bozsó, Lívia Fülöp, Ernesto G. Mata, Titanilla Szögi, Ana M. Rodríguez, Luciana Méndez, Federica Cioffi, Kerensa Broersen, János Gera, Gábor Paragi, Carina M. L. Delpiccolo, Exequiel Barrera, Ricardo D. Enriz, and Nanobiophysics
Subjects: 0301 basic medicine, 030103 biophysics, Stereochemistry, AMYLOID Β-PEPTIDE, Molecular dynamics, Biochemistry, Mimetic peptides, 03 medical and health sciences, chemistry.chemical_compound, Drug Discovery, MOLECULAR DOCKING, Cytotoxicity, Molecular Biology, Organic Chemistry, Otras Ciencias Naturales y Exactas, Alzheimer's disease, Small molecule, 22/4 OA procedure, Amyloid β peptide, Aβ aggregation, 030104 developmental biology, Monomer, chemistry, ALZHEIMER'S DISEASE, Docking (molecular), Amyloid β-peptide, Molecular docking, MIMETIC PEPTIDES, Thioflavin, MOLECULAR DYNAMICS, AΒ AGGREGATION, CIENCIAS NATURALES Y EXACTAS
Abstract: A series of novel mimetic peptides were designed, synthesised and biologically evaluated as inhibitors of Aβ 42 aggregation. One of the synthesised peptidic compounds, termed compound 7 modulated Aβ 42 aggregation as demonstrated by thioflavin T fluorescence, acting also as an inhibitor of the cytotoxicity exerted by Aβ 42 aggregates. The early stage interaction between compound 7 and the Aβ 42 monomer was investigated by replica exchange molecular dynamics (REMD) simulations and docking studies. Our theoretical results revealed that compound 7 can elongate the helical conformation state of an early stage Aβ 42 monomer and it helps preventing the formation of β-sheet structures by interacting with key residues in the central hydrophobic cluster (CHC). This strategy where early “on-pathway” events are monitored by small molecules will help the development of new therapeutic strategies for Alzheimer's disease. Fil: Gera, János. University of Szeged; Hungría Fil: Szögi, Titanilla. University of Szeged; Hungría Fil: Bozsó, Zsolt. University of Szeged; Hungría Fil: Fülöp, Livia. University of Szeged; Hungría Fil: Barrera Guisasola, Exequiel Ernesto. Instituto Pasteur de Montevideo; Uruguay. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Rodriguez, Ana M.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina Fil: Mendez, Luciana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; Argentina Fil: Delpiccolo, Carina Maria Lujan. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; Argentina Fil: Mata, Ernesto Gabino. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; Argentina Fil: Cioffi, Federica. University of Twente; Países Bajos Fil: Broersen, Kerensa. University of Twente; Países Bajos Fil: Paragi, Gabor. University of Szeged; Hungría Fil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina
Published: 2018

16. The antimicrobial activity of annona emarginata (Schltdl.) H. Rainer and most active isolated compounds against clinically important bacteria

Author: Robert Musiol, Beatriz Lima, Ricardo D. Enriz, Gabriela Egly Feresin, Josef Jampilek, Natividad Herrera Cano, Jiri Kos, Elisa M. Petenatti, Francisco Matías Garibotto, Juan G. Dolab, Ewelina Spaczynska, Alejandro Tapia, and Mónica S. Olivella
Subjects: ANTIBACTERIAL ACTIVITY, (R)-2-(4-METHYLCYCLOHEX-3-EN-1-YL)PROPAN-2-YL (E)-3-(4-HYDROXYPHENYL)-ACRYLATE, Pharmaceutical Science, Decoction, Structure-activity relationships, medicine.disease_cause, 01 natural sciences, Annona, Analytical Chemistry, purl.org/becyt/ford/1 [https], Anti-Infective Agents, Drug Discovery, ANNONA EMARGINATA, Mora, STRUCTURE-ACTIVITY RELATIONSHIPS, (R)-2-(4-methylcyclohex-3-en-1-yl)propan-2-yl (E)-3-(4-hydroxyphenyl)-acrylate, biology, Traditional medicine, Chemistry, Ciencias Químicas, Annona emarginata, Antimicrobial, 3. Good health, Klebsiella pneumoniae, Chemistry (miscellaneous), Staphylococcus aureus, visual_art, Plant Bark, visual_art.visual_art_medium, Molecular Medicine, Bark, Antibacterial activity, CIENCIAS NATURALES Y EXACTAS, Methicillin-Resistant Staphylococcus aureus, Argentina, Flowers, Microbial Sensitivity Tests, Gram-Positive Bacteria, Article, Gram-Negative Bacteria, purl.org/becyt/ford/1.4 [https], medicine, Physical and Theoretical Chemistry, STAPHYLOCOCCUS AUREUS, Plant Extracts, 010405 organic chemistry, Organic Chemistry, antibacterial activity, structure-activity relationships, Pathogenic bacteria, biology.organism_classification, 0104 chemical sciences, Plant Leaves, 010404 medicinal & biomolecular chemistry, Química Orgánica, Medicine, Traditional
Abstract: This research was partially supported by grants from Universidad Nacional de San Luis and PIP 444-CONICET. J.D. thanks a fellowship from CONICET. E.S. and R.M. appreciate National Science Centre grant No 2013/09/B/NZ7/00423. J.K. and J.J. were supported by the grant of the Faculty of Pharmacy of Comenius University in Bratislava No. FaF UK/37/2018 and by SANOFI-AVENTIS Pharma Slovakia, s.r.o. The authors thank Luis A. Del Vitto (UNSL) for his help in the botanical classification and Marcos Maiocchi (UNNE) for the help in the collection of the plant material. B.L., G.E.F. and A.T. thank CICITCA-UNSJ., Annona emarginata (Schltdl.) H. Rainer, commonly known as “arachichú”, “araticú”, “aratigú”, and “yerba mora”, is a plant that grows in Argentina. Infusions and decoctions are used in folk medicine as a gargle against throat pain and for calming toothache; another way to use the plant for these purposes is chewing its leaves. Extracts from bark, flowers, leaves, and fruits from A. emarginata were subjected to antibacterial assays against a panel of Gram (+) and Gram (−) pathogenic bacteria according to Clinical and Laboratory Standards Institute protocols. Extracts from the stem bark and leaves showed moderate activity against the bacteria tested with values between 250–1000 µg/mL. Regarding flower extracts, less polar extracts (hexane, dichloromethane) showed very strong antibacterial activity against methicillin-sensitive Staphylococcus aureus ATCC 25923 and methicillin-resistant S. aureus ATCC 43300 with values between 16–125 µg/mL. Additionally, hexane extract showed activity against Klebsiella pneumoniae (MIC = 250 µg/mL). The global methanolic extract of the fruits (MeOHGEF) was also active against the three strains mentioned above, with MICs values 250–500 µg/mL. Bioassay-guided fractionation of MeOHGEF led to the isolation of a new main compound—(R)-2-(4-methylcyclohex-3-en-1-yl)propan-2-yl (E)-3-(4-hydroxyphenyl)acrylate (1). The structure and relative configurations have been determined by means of 1D and 2D NMR techniques, including COSY, HMQC, HMBC, and NOESY correlations. Compound 1 showed strong antimicrobial activity against all Gram (+) species tested (MICs = 3.12–6.25 µg/mL). In addition, the synthesis and antibacterial activity of some compounds structurally related to compound 1 (including four new compounds) are reported. A SAR study for these compounds was performed based on the results obtained by using molecular calculations., NCN
Published: 2018

17. Cholinesterase-inhibitory effect and in silico analysis of alkaloids from bulbs of Hieronymiella species

Author: Aníbal Alejandro Tapia, Adriana Garro, Jaume Bastida, Gabriela Egly Feresin, Alberto C. Slanis, Natalia B. Pigni, Gustavo Germán Roitman, María Belén Agüero, Javier E. Ortiz, and Ricardo D. Enriz
Subjects: Models, Molecular, HIERONYMIELLA, Aché, AMARYLLIDACEAE, Argentina, Drug Evaluation, Preclinical, Pharmaceutical Science, 01 natural sciences, Plant Roots, Gas Chromatography-Mass Spectrometry, purl.org/becyt/ford/1 [https], chemistry.chemical_compound, Phytomedicine, IN SILICO, Drug Discovery, purl.org/becyt/ford/1.4 [https], Computer Simulation, Amaryllidaceae Alkaloids, Butyrylcholinesterase, Cholinesterase, Pharmacology, chemistry.chemical_classification, ARGENTINA, biology, CHOLINESTERASES, 010405 organic chemistry, Plant Extracts, Amaryllidaceae, Ciencias Químicas, biology.organism_classification, Acetylcholinesterase, language.human_language, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, Enzyme, Química Orgánica, Complementary and alternative medicine, Biochemistry, chemistry, ALKALOIDS, biology.protein, language, Molecular Medicine, Cholinesterase Inhibitors, CIENCIAS NATURALES Y EXACTAS
Abstract: Background In Argentina, the Amaryllidaceae family (59 species) comprises a wide variety of genera, only a few species have been investigated as a potential source of cholinesterases inhibitors to treat Alzheimer disease (AD). Purpose To study the acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities of the basic dichloromethane extracts (E) from Hieronymiella aurea, H. caletensis, H. clidanthoides, H. marginata, and H. speciosa species, as well as the isolated compounds from these plant extracts. Study design and methods AChE and BChE inhibitory activities were evaluated with the Ellman's spectrophotometric method. The alkaloids composition from the E was obtained by gas chromatography-mass spectrometry (GC-MS). The E were successively chromatographed on a silica gel column and permeated on Sephadex LH-20 column to afford the main alkaloids identified by means of spectroscopic data. Additionally, an in silico study was carried out. Results Nine known alkaloids were isolated from the E of five Hieronymiella species. Galanthamine was identified in all the species by GC-MS standing out H. caletensis with a relative abundance of 9.79% of the total ion current. Strong AChE (IC50 = 1.84 - 15.40 µg/ml) and moderate BChE (IC50 = 23.74 - 136.40 µg/ml) inhibitory activities were displayed by the extracts. Among the isolated alkaloids, only sanguinine and chlidanthine (galanthamine-type alkaloids) demonstrated inhibitory activity toward both enzymes. The QTAIM study suggests that sanguinine has the strongest affinity towards AChE, attributed to an additional interaction with Ser200 as well as stronger molecular interactions Glu199 and His440.These results allowed us to differentiate the molecular behavior in the active site among alkaloids possessing different in vitro inhibitory activities. Conclusion Hieronymiella species growing in Argentina represent a rich and widespread source of galanthamine and others AChE and BChE inhibitors alkaloids. Additionally, the new trend towards the use of natural extracts as pharmaceuticals rather than pure drugs opens a pathway for the development of a phytomedicine derived from extracts of Hieronymiella spp. Fil: Ortiz, Javier Esteban. Universidad Nacional de San Juan. Facultad de Ingeniería. Instituto de Biotecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan; Argentina. Universidad Nacional de San Juan. Facultad de Filosofía, Humanidades y Artes. Instituto de Ciencias Básicas; Argentina Fil: Garro, Adriana. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis; Argentina Fil: Pigni, Natalia Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Ciencia y Tecnología de Alimentos Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Ciencia y Tecnología de Alimentos Córdoba; Argentina. Universidad de Barcelona; España Fil: Agüero, María Belén. Universidad Nacional de San Juan. Facultad de Filosofía, Humanidades y Artes. Instituto de Ciencias Básicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan; Argentina. Universidad Nacional de San Juan. Facultad de Ingeniería. Instituto de Biotecnología; Argentina Fil: Roitman, Gustavo Germán. Universidad de Buenos Aires. Facultad de Agronomía. Departamento de Ingeniería Agrícola y Uso de la Tierra. Cátedra de Jardinería; Argentina Fil: Slanis, Alberto Carlos. Universidad Nacional de Tucumán. Facultad de Ciencias Naturales e Instituto Miguel Lillo. Instituto Miguel Lillo; Argentina Fil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis; Argentina. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia; Argentina Fil: Feresin, Gabriela Egly. Universidad Nacional de San Juan. Facultad de Ingeniería. Instituto de Biotecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan; Argentina. Universidad Nacional de San Juan. Facultad de Filosofía, Humanidades y Artes. Instituto de Ciencias Básicas; Argentina Fil: Bastida, Jaume. Universidad de Barcelona; España Fil: Tapia, Aníbal Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan; Argentina. Universidad Nacional de San Juan. Facultad de Filosofía, Humanidades y Artes. Instituto de Ciencias Básicas; Argentina. Universidad Nacional de San Juan. Facultad de Ingeniería. Instituto de Biotecnología; Argentina
Published: 2018

18. The long and winding road to convert an antimicrobial compound into an antimicrobial drug: An overview from a medicinal chemistry point of view

Author: Sebastian A. Andujar, Marcela Cristina Vettorazzi, Maria A. Alvarez, Juan G. Dolab, Sebastian Rojas, Ricardo D. Enriz, and Fernando D. Suvire
Subjects: Antifungal, Traditional medicine, 010405 organic chemistry, Chemistry, medicine.drug_class, Otras Ciencias Químicas, Organic Chemistry, TARGET-BASED SCREENING, Ciencias Químicas, Antimicrobial compound, 010402 general chemistry, Antimicrobial, 01 natural sciences, Combinatorial chemistry, NATURAL PRODUCTS, 0104 chemical sciences, Antimicrobial drug, NEW STRATEGIES, ANTIFUNGAL, NEW DRUGS, medicine, ANTIMICROBIAL, CIENCIAS NATURALES Y EXACTAS
Abstract: Background & Objective: Fungi are responsible for producing infections in humans. While all humans are susceptible to these disorders, immunocompromised people are the most at risk. Although it appears that we have many antifungal drugs in clinical use, unfortunately, most antifungal drugs currently in use have serious limitations or some drawbacks in pharmacokinetic aspects such as they do not possess an adequate solubility. As complement, fungi have developed a significant resistance against them because of their indiscriminate and even irrational use in some cases. Considering such situation, there is an urgent need to develop new and more effective antifungal drugs. Discussion: For such reason, in recent years there has been an incredible increase in the number of studies looking for new compounds with antifungal effects; in particular new structures obtained from natural products. While a large number of compounds with antifungal activities (some of them with novel structures) have been reported, very few have managed to be used therapeutically. In this review article, we have identified and discussed the main reasons for the poor results that have been obtained so far in order to find new antifungal drugs. Also, new strategies which could be under way to improve the search for new antifungal agents for therapeutic use are discussed here, remarking their scope and limitations. Fil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina Fil: Suvire, Fernando Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina Fil: Andujar, Sebastian Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina Fil: Alvarez, María A.. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Departamento de Química; Argentina Fil: Dolab, Juan Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina Fil: Vettorazzi, Marcela Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina Fil: Rojas, Sebastian. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina
Published: 2017

19. An integrative study to identify novel scaffolds for sphingosine kinase 1 inhibitors

Author: Pavel Bobal, Jozef Csöllei, Emilio Angelina, Pavlina Marvanova, Janette Bobalova, Sarah Spiegel, Jan Otevrel, Tomas Gonec, Josef Jampilek, Petr Mokry, Tereza Padrtova, Sergio E. Alvarez, Justo Cobo, Ivan Malík, Alirio Palma, Ricardo D. Enriz, Marcela Cristina Vettorazzi, Lina María Vélez Acosta, and Santiago Lima
Subjects: 0301 basic medicine, Models, Molecular, SPHINGOSINE KINASE 1 INHIBITORS, Stereochemistry, Metabolite, SYNTHESIS, Article, 03 medical and health sciences, chemistry.chemical_compound, Structure-Activity Relationship, Drug Discovery, VIRTUAL SCREENING, Azepine, Protein Kinase Inhibitors, Alkyl, Pharmacology, chemistry.chemical_classification, Virtual screening, biology, Dose-Response Relationship, Drug, Molecular Structure, BIOASSAYS, Otras Ciencias Químicas, Organic Chemistry, Ciencias Químicas, MOLECULAR MODELLING, General Medicine, Sphingolipid, Phosphotransferases (Alcohol Group Acceptor), 030104 developmental biology, Enzyme, chemistry, Sphingosine kinase 1, Molecular targets, biology.protein, Quantum Theory, CIENCIAS NATURALES Y EXACTAS
Abstract: Sphingosine kinase 1 (SphK1), the enzyme that produces the bioactive sphingolipid metabolite, sphingosine-1-phosphate, is a promising new molecular target for therapeutic intervention in cancer and inflammatory diseases. In view of its importance, the main objective of this work was to find new and more potent inhibitors for this enzyme possessing different structural scaffolds than those of the known inhibitors. Our theoretical and experimental study has allowed us to identify two new structural scaffolds (three new compounds), which could be used as starting structures for the design and then the development of new inhibitors of SphK1. Our study was carried out in different steps: virtual screening, synthesis, bioassays and molecular modelling. From our results, we propose a new dihydrobenzo[b]pyrimido[5,4-f]azepine and two alkyl{3-/4-[1-hydroxy-2-(4-arylpiperazin-1-yl)ethyl]phenyl}carbamates as initial structures for the development of new inhibitors. In addition, our molecular modelling study using QTAIM calculations, allowed us to describe in detail the molecular interactions that stabilize the different Ligand-Receptor complexes. Such analyses indicate that the cationic head of the different compounds must be refined in order to obtain an increase in the binding affinity of these ligands. Fil: Vettorazzi, Marcela Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina Fil: Angelina, Emilio Luis. Universidad Nacional del Nordeste. Facultad de Ciencias Exactas y Naturales y Agrimensura. Departamento de Química. Laboratorio de Estructura Molecular y Propiedades; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Lima, Santiago. Virginia Commonwealth University. School of Medicine; Estados Unidos Fil: Gonec, Tomas. Veterinarni A Farmaceuticka Univerzita Brno; República Checa Fil: Otevrel, Jan. Veterinarni A Farmaceuticka Univerzita Brno; República Checa Fil: Marvanova, Pavlina. Veterinarni A Farmaceuticka Univerzita Brno; República Checa Fil: Padrtova, Tereza. Veterinarni A Farmaceuticka Univerzita Brno; República Checa Fil: Mokry, Petr. Veterinarni A Farmaceuticka Univerzita Brno; República Checa Fil: Bobal, Pavel. Veterinarni A Farmaceuticka Univerzita Brno; República Checa Fil: Acosta, Lina M.. Universidad Industrial Santander; Colombia Fil: Palma, Alirio. Universidad Industrial Santander; Colombia Fil: Cobo, Justo. Universidad de Jaén; España Fil: Bobalova, Janette. Institute Of Analytical Chemistry Of The Czech Academy Of Sciences; República Checa Fil: Csollei, Jozef. Comenius University; Eslovaquia Fil: Malik, Ivan. Comenius University; Eslovaquia Fil: Alvarez, Sergio Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina Fil: Spiegel, Sarah. Virginia Commonwealth University. School of Medicine; Estados Unidos Fil: Jampilek, Josef. Comenius University; Eslovaquia Fil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina
Published: 2017

20. The electronic density obtained from a QTAIM analysis used as molecular descriptor. A study performed in a new series of DHFR inhibitors

Author: Rodrigo D. Tosso, Justo Cobo, Emilio Angelina, Lucas J. Gutierrez, Ricaurte Rodríguez, Sebastian A. Andujar, Fernando D. Suvire, Marcela Cristina Vettorazzi, Juan C. Garro, Ricardo D. Enriz, and Manuel Nogueras
Subjects: 0301 basic medicine, 010405 organic chemistry, Chemistry, Stereochemistry, Otras Ciencias Químicas, Organic Chemistry, Ciencias Químicas, 01 natural sciences, MOLECULAR DESCRIPTOR, 0104 chemical sciences, Analytical Chemistry, purl.org/becyt/ford/1 [https], Inorganic Chemistry, 03 medical and health sciences, 030104 developmental biology, QTAIM, Molecular descriptor, purl.org/becyt/ford/1.4 [https], QUANTUM MECHANICS, MOLECULAR DYNAMICS, Spectroscopy, CIENCIAS NATURALES Y EXACTAS, Electronic density
Abstract: The results reported here indicate that the electron density obtained from a QTAIM analysis is an excellent descriptor of molecular interactions that stabilize and destabilize the formation of the ligand-receptor (L-R) complex. The study was conducted on a series of 25 compounds that have inhibitory effects on DHFR. Besides the synthesis and bioassays performed for some of these compounds, various types of molecular calculations were performed. Thus, we performed MD simulations, computations at different levels of theory (ab initio and DFT) using reduced models and a QTAIM study on the different complexes. The resulting model has allowed us to differentiate not only highly active compounds with respect to compounds weakly active, but also among compounds that have similar affinities in this series. The model also showed a high degree of predictability which allows predicting the affinity of non-synthesized compounds. Very important additional information can be obtained through this type of study, it is possible to visualize which amino acids are involved in the interactions determining the different affinities of the ligands. Fil: Tosso, Rodrigo David. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina Fil: Vettorazzi, Marcela Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina Fil: Andujar, Sebastian Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina Fil: Gutierrez, Lucas Joel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina Fil: Garro Martinez, Juan Ceferino. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina Fil: Suvire, Fernando Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina Fil: Angelina, Emilio Luis. Universidad Nacional del Nordeste; Argentina Fil: Rodríguez, Ricaurte. Universidad Nacional de Colombia; Colombia. Universidad de Jaén; España Fil: Nogueras, Manuel. Universidad de Jaén; España Fil: Cobo, Justo. Universidad de Jaén; España Fil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina
Published: 2017

21. Tetrahydroisoquinolines functionalized with carbamates as selective ligands of D2 dopamine receptor

Author: Lucas J. Gutierrez, Sebastian Rojas, M. Pilar López-Gresa, M Jesús Sanz, Diego Cortes, Ricardo D. Enriz, Emilio Angelina, M Lucrecia Bogado, Oscar Parravicini, Nuria Cabedo, and Sebastian A. Andujar
Subjects: Molecular model, QTAIM analysis, Molecular modeling, Molecular Dynamics Simulation, 010402 general chemistry, Ligands, 01 natural sciences, Catalysis, Inorganic Chemistry, Molecular dynamics, THIQs functionalized with carbamates, Dopamine receptor D2, Tetrahydroisoquinolines, BIOQUIMICA Y BIOLOGIA MOLECULAR, Humans, Physical and Theoretical Chemistry, Molecular interactions, 010405 organic chemistry, Chemistry, Receptors, Dopamine D2, Otras Ciencias Químicas, Receptors, Dopamine D1, Organic Chemistry, Ciencias Químicas, Highly selective, Combinatorial chemistry, 0104 chemical sciences, Computer Science Applications, Molecular Docking Simulation, Computational Theory and Mathematics, Docking (molecular), Dopamine receptor, Carbamates, CIENCIAS NATURALES Y EXACTAS, Selective ligands of D2DR
Abstract: [EN] A series of tetrahydroisoquinolines functionalized with carbamates is reported here as highly selective ligands on the dopamine D2 receptor. These compounds were selected by means of a molecular modeling study. The studies were carried out in three stages: first an exploratory study was carried out using combined docking techniques and molecular dynamics simulations. According to these results, the bioassays were performed; these experimental studies corroborated the results obtained by molecular modeling. In the last stage of our study, a QTAIM analysis was performed in order to determine the main molecular interactions that stabilize the different ligand-receptor complexes. Our results show that the adequate use of combined simple techniques is a very useful tool to predict the potential affinity of new ligands at dopamine D1 and D2 receptors. In turn the QTAIM studies show that they are very useful to evaluate in detail the molecular interactions that stabilize the different ligand-receptor complexes; such information is crucial for the design of new ligands., This work was supported by Universidad Nacional de San Luis (UNSL) and CONICET grants 2-1214 and PIP444, respectively. E.L.A, L.J.G, S.A.A and R.D.E are staff members of the National Scientific and Technical Research Council - Argentina ( CONICET, Argentina).
Published: 2017

22. Conformational transition of Aβ42 inhibited by a mimetic peptide. A molecular modeling study using QM/MM calculations and QTAIM analysis

Author: Ricardo D. Enriz, Lucas J. Gutierrez, Francisco Matías Garibotto, Sebastian A. Andujar, Rodrigo Emiliano Salcedo, Ana M. Rodríguez, and Exequiel Ernesto Barrera Guisasola
Subjects: 0301 basic medicine, MIMETIC PEPTIDE INHIBITOR, Amyloid, Molecular model, Stereochemistry, MM-GBSA ANALYSIS, 010402 general chemistry, ONIOM-QTAIM STUDY, 01 natural sciences, Biochemistry, QM/MM, 03 medical and health sciences, chemistry.chemical_compound, Molecular dynamics, MOLECULAR DYNAMICS SIMULATION, AMYLOID β-PEPTIDE, Computational analysis, Physical and Theoretical Chemistry, Transition (genetics), Chemistry, Otras Ciencias Químicas, Ciencias Químicas, Condensed Matter Physics, 0104 chemical sciences, 030104 developmental biology, Monomer, Peptide mimetic, CIENCIAS NATURALES Y EXACTAS
Abstract: The main pathogenic event in Alzheimer's disease is believed to be the aggregation of the amyloid β-peptides into toxic aggregates. In a previous work we designed a mimetic peptide possessing a significant aggregation modulating effect by means of a molecular modeling study, using a pentameric model as a molecular target. Considerable experimental evidence indicates that oligomers as small as dimers have been involved in this disease. Therefore, an alternative therapeutic strategy might be to block the oligomerization at a monomeric level. To this end, using an Aβ42 monomeric model, we explored the capacity and mechanism of our mimetic peptides to stabilize the α-helical conformation while preventing the formation of β-sheet structures. Long time molecular dynamics simulations and MM-GBSA analysis were coupled to investigate this issue. In addition, a combined ONIOM-QTAIM analysis was used to identify at a quantum level the most relevant interactions between Aβ42 and this inhibitor. The computational analysis presented here pointed out six important residues of Aβ42 (Lys16, Val36, Gly37, Gly38, Val39 and Val40) that strongly interact with our mimetic peptide, providing clues about the functional groups that might be modified in order to obtain more potent inhibitors. Fil: Barrera Guisasola, Exequiel Ernesto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina Fil: Gutierrez, Lucas Joel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina Fil: Salcedo, Rodrigo Emiliano. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina Fil: Garibotto, Francisco Matías. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina Fil: Andujar, Sebastian Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina Fil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina Fil: Rodríguez, Ana M.. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia; Argentina
Published: 2016

23. Theoretical study of the conformational energy hypersurface of cyclotrisarcosyl

Author: M.A. Zamora, Ricardo D. Enriz, Maria A. Alvarez, Fernando D. Suvire, Edgardo J. Saavedra, and Mónica S. Olivella
Subjects: POTENTIAL ENERGY HYPERSURFACE, Potential energy hypersurface, Tripeptide, dft calculations, purl.org/becyt/ford/1 [https], conformational study, Computational chemistry, Materials Chemistry, purl.org/becyt/ford/1.4 [https], Conformational energy, Twist, QD1-999, Chemistry, CYCLIC TRIPEPTIDES, CYCLOTRISARCOSYL, General Chemistry, potential energy hypersurface, DFT CALCULATIONS, Relative stability, Crystallography, Hypersurface, CONFORMATIONAL STUDY, cyclotrisarcosyl, Single point, cyclic tripeptides
Abstract: The multidimensional Conformational Potential Energy Hypersurface (PEHS) of cyclotrisarcosyl was comprehensively investigated at the DFT (B3LYP/6-31G(d), B3LYP/6-31G(d,p) and B3LYP/6-311++G(d,p)), levels of theory. The equilibrium structures, their relative stability, and the Transition State (TS) structures involved in the conformational interconversion pathways were analyzed. Aug-cc-pVTZ//B3LYP/6-311++G(d,p) and MP2/6-31G(d)//B3LYP/6-311++G(d,p) single point calculations predict a symmetric cis-cis-cis crown conformation as the energetically preferred form for this compound, which is in agreement with the experimental data. The conformational interconversion between the global minimum and the twist form requires 20.88 kcal mol-1 at the MP2/6-31G(d)//B3LYP/6- 311++G(d,p) level of theory. Our results allow us to form a concise idea about the internal intricacies of the PEHSs of this cyclic tripeptide, describing the conformations as well as the conformational interconversion processes in this hypersurface. In addition, a comparative analysis between the conformational behaviors of cyclotrisarcosyl with that previously reported for cyclotriglycine was carried out. Fil: Alvarez, Maria de Los Angeles. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Departamento de Química; Argentina Fil: Saavedra, Edgardo J.. Universidad Nacional de la Patagonia "San Juan Bosco"; Argentina Fil: Olivella, Mónica Susana. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Departamento de Química; Argentina Fil: Suvire, Fernando Daniel. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Departamento de Química; Argentina Fil: Zamora, Miguel Angel. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Departamento de Química; Argentina Fil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Departamento de Química; Argentina
Published: 2012

24. Synthesis and antifungal activity of N-aryl-N-benzylamines and of their homoallyl analogues

Author: Susana Zacchino, Ricardo D. Enriz, Francisco Matías Garibotto, Vladimir V. Kouznetsov, and Maximiliano Sortino
Subjects: inorganic chemicals, Antifungal, chemistry.chemical_classification, Stereochemistry, medicine.drug_class, organic chemicals, Aryl, Organic Chemistry, food and beverages, lcsh:QD241-441, chemistry.chemical_compound, chemistry, Nitrogen atom, lcsh:Organic chemistry, medicine, Alkyl
Abstract: Ten N-aryl-N-benzylamines were synthesized and evaluated for their antifungal activity, which was compared with their homoallylamine analogues that possessed an allyl group in the carbon next to the nitrogen atom. Results indicated that the absence of the allyl group caused an enhancement of the antifungal activity which could be correlated with the flexibility of the alkyl chain between both aromatic groups. DFT calculations supported these differences in activity.
Published: 2011

25. New small-size peptides possessing antifungal activity

Author: Marcelo F. Masman, Adriana Garro, Susana Zacchino, Ana M. Rodríguez, Csaba Somlai, Botond Penke, Paul G.M. Luiten, Ricardo D. Enriz, Francisco Matías Garibotto, and Marcela Raimondi
Subjects: Models, Molecular, Antifungal Agents, Molecular model, PANCREATIC TRYPSIN-INHIBITOR, Stereochemistry, Small-size peptides, Clinical Biochemistry, Antimicrobial peptides, Pharmaceutical Science, Peptide, Biochemistry, Molecular mechanics, Conformational study, FUNGAL PATHOGENS, Drug Discovery, Candida albicans, Toxicity Tests, Acute, Animals, Amino Acid Sequence, Antifungal activity, Molecular electrostatic potentials, Molecular Biology, Peptide sequence, Cryptococcus neoformans, chemistry.chemical_classification, EMPIRICAL SOLVATION MODELS, Poecilia, biology, Chemistry, POLYPEPTIDES, DRIVEN MONTE-CARLO, Organic Chemistry, Candidiasis, MULTIPLE-MINIMA PROBLEM, Cryptococcosis, biology.organism_classification, ANTIMICROBIAL PEPTIDES, In vitro, Mycoses, INNATE IMMUNITY, Molecular Medicine, MEMBRANE, Peptides, CONFORMATIONAL-ANALYSIS
Abstract: The synthesis, in vitro evaluation, and conformational study of a new series of small-size peptides acting as antifungal agents are reported. In a first step of our study we performed a conformational analysis using Molecular Mechanics calculations. The electronic study was carried out using Molecular electrostatic potentials (MEPs) obtained from RHF/6-31G calculations. On the basis of the theoretical predictions three small-size peptides, RQWKKWWQWRR-NH(2), RQIRRWWQWRR-NH(2), and RQIRRWWQW-NH(2) were synthesized and tested. These peptides displayed a significant antifungal activity against human pathogenic strains including Candida albicans and Cryptococcus neoformans. Our experimental and theoretical results allow the identification of a topographical template which can serve as a guide for the design of new compounds with antifungal properties for potential therapeutic applications against these pathogenic fungi. (C) 2009 Elsevier Ltd. All rights reserved.
Published: 2010

26. New mimetic peptides inhibitors of Aβ aggregation: Molecular guidance for rational drug design

Author: Sebastian A. Andujar, Kerensa Broersen, Ana M. Rodríguez, Carina M. L. Delpiccolo, Ellen Hubin, Luciana Méndez, Exequiel Ernesto Barrera Guisasola, Ivonne M. Kraan, Ricardo D. Enriz, Marcelo F. Masman, Nanobiophysics, and Molecular Dynamics
Subjects: Models, Molecular, LINEAR CONSTRAINT SOLVER, PARTICLE MESH EWALD, Protein Conformation, Amyloid β-protein, BETA-RPOTEIN, MIMETIC, Aggregation modulating effect, chemistry.chemical_compound, Molecular dynamics, MOLECULAR, THERAPEUTIC STRATEGY, Drug Discovery, Cognitive decline, Amyloid beta-protein, SHEET BREAKER PEPTIDES, PROTEIN MISFOLDING DISEASES, Ciencias Químicas, MODELLING, PEPTIDES, General Medicine, SOLID-STATE NMR, ALZHEIMERS-DISEASE, Thioflavin, Molecular modelling, Hydrophobic and Hydrophilic Interactions, CIENCIAS NATURALES Y EXACTAS, Amyloid, Drug design, Molecular Dynamics Simulation, Hydrophobic effect, Mimetic peptides, AMYLOID, Alzheimer Disease, Humans, Molecule, Pharmacology, RAT PRIMARY NEURONS, Amyloid beta-Peptides, DYNAMICS SIMULATIONS, Molecular dynamics simulations, Otras Ciencias Químicas, Organic Chemistry, Water, Peptide Fragments, Crystallography, chemistry, Drug Design, SOLUBLE AMYLOID OLIGOMERS, 2023 OA procedure, Biophysics, Peptidomimetics, Salt bridge
Abstract: A new series of mimetic peptides possessing a significant Aβ aggregation modulating effect was reported here. These compounds were obtained based on a molecular modelling study which allowed us to perform a structural-based virtual selection. Monitoring Aβ aggregation by thioflavin T fluorescence and transmission electron microscopy revealed that fibril formation was significantly decreased upon prolonged incubation in presence of the active compounds. Dot blot analysis suggested a decrease of soluble oligomers strongly associated with cognitive decline in Alzheimer´s disease. For the molecular dynamics simulations, we used an Aβ42 pentameric model where the compounds were docked using a blind docking technique. To analyze the dynamic behaviour of the complexes, extensive molecular dynamics simulations were carried out in explicit water. We also measured parameters or descriptors that allowed us to quantify the effect of these compounds as potential inhibitors of Aβ aggregation. Thus, significant alterations in the structure of our Aβ42 protofibril model were identified. Among others we observed the destruction of the regular helical twist, the loss of a stabilizing salt bridge and the loss of a stabilizing hydrophobic interaction in the β1 region. Our results may be helpful in the structural identification and understanding of the minimum structural requirements for these molecules and might provide a guide in the design of new aggregation modulating ligands. Fil: Barrera Guisasola, Exequiel Ernesto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina. Universidad Nacional de San Luis; Argentina Fil: Andujar, Sebastian Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina. Universidad Nacional de San Luis; Argentina Fil: Hubin, Ellen. University of Twente; Países Bajos. Vrije Universiteit Brussel; Bélgica Fil: Broersen, Kerensa. University of Twente; Países Bajos Fil: Kraan, Ivonne M.. University of Twente; Países Bajos Fil: Mendez, Luciana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Química Rosario; Argentina Fil: Delpiccolo, Carina Maria Lujan. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Química Rosario; Argentina Fil: Masman, Marcelo Fabricio. University Of Groningen; Países Bajos Fil: Rodríguez, Ana M.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina. Universidad Nacional de San Luis; Argentina Fil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina
Published: 2015

27. Molecular Insight into the Interaction Mechanisms of Amino-2H-Imidazole Derivatives With BACE1 Protease: A QM/MM and QTAIM Study

Author: Ricardo D. Enriz, Rodrigo D. Tosso, Esteban Gabriel Vega-Hissi, and Lucas J. Gutierrez
Subjects: Stereochemistry, medicine.medical_treatment, Físico-Química, Ciencia de los Polímeros, Electroquímica, Substituent, Hydrophobic effect, QM/MM, chemistry.chemical_compound, MODELING, Computational chemistry, medicine, Imidazole, Physical and Theoretical Chemistry, ALZHEIMER, Protease, biology, Hydrogen bond, Atoms in molecules, Ciencias Químicas, Active site, INHIBITOR, Condensed Matter Physics, Atomic and Molecular Physics, and Optics, chemistry, QTAIM, biology.protein, CIENCIAS NATURALES Y EXACTAS
Abstract: In this study, we described quantitatively the interactions between two new amino-2H-imidazole inhibitors ((R)-1t and (S)-1m) and BACE1 using a hybrid quantum mechanics-molecular mechanical (QM/MM) method together with a quantum theory of atoms In Molecules (QTAIM) analysis. Our computational calculations revealed that the binding affinity of these compounds is mostly related to the amino-2H-imidazole core, which interact tightly with the aspartate dyad of the active site. The interactions were stronger when the inhibitors presented a bulky substituent with a hydrogen bond acceptor motif pointing toward Trp76, such as the 3,5-dimethyl-4-methoxyphenyl group of compound (S)-1m. Furthermore, the QTAIM analysis revealed that many hydrophobic interactions complement cooperatively the hydrogen bond which is not present when compound (R)-1t is bound to the enzyme. The combined QM/MM-QTAIM analysis allows identifying the interactions that account for the activity difference between compounds, even at a nanomolar range. Fil: Vega Hissi, Esteban Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina. Universidad Nacional de San Luis. Facultad de Quimica, Bioquimica y Farmacia. Departamento de Quimica; Argentina Fil: Tosso, Rodrigo David. Universidad Nacional de San Luis. Facultad de Quimica, Bioquimica y Farmacia. Departamento de Quimica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina Fil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina. Universidad Nacional de San Luis. Facultad de Quimica, Bioquimica y Farmacia. Departamento de Quimica; Argentina Fil: Gutierrez, Lucas Joel. Universidad Nacional del Nordeste. Facultad de Ciencias Exactas y Naturales y Agrimensura. Departamento de Química. Laboratorio de Estructura Molecular y Propiedades; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Published: 2015

28. Structural and functional insights into the anti-BACE1 Fab fragment that recognizes the BACE1 exosite

Author: Sebastian A. Andujar, Héctor A. Baldoni, Ricardo D. Enriz, and Lucas J. Gutierrez
Subjects: Models, Molecular, Molecular model, Stereochemistry, immune complex, Allosteric regulation, Mutagenesis (molecular biology technique), Immune complex formation, Epitopes, Immunoglobulin Fab Fragments, Molecular dynamics, Fragment (logic), Structural Biology, mental disorders, Aspartic Acid Endopeptidases, Humans, Molecular Biology, Chemistry, allosteric control, Otras Ciencias Químicas, Ciencias Químicas, BACE1, General Medicine, Mutagenesis, Site-Directed, Alzheimer, Paratope, Amyloid Precursor Protein Secretases, CIENCIAS NATURALES Y EXACTAS
Abstract: A molecular modeling study giving structural, functional, and mutagenesis insights into the anti-BACE1 Fab fragment that recognizes the BACE1 exosite is reported. Our results allow extending experimental data resulting from X-ray dif- fraction experiments in order to examine unknown aspects for the Fab-BACE1 recognition and its binding mode. Thus, the study performed here allows extending the inherently static nature of crystallographic structures in order to gain a deeper understanding of the structural and dynamical basis at the atomic level. The characteristics and strength of the interatomic interactions involved in the immune complex formation are exhaustively analyzed. The results might explain how the anti-BACE1 Fab fragment and other BACE1 exosite binders are capable to produce an allosteric modulation of the BACE1 activity. Our site-directed mutagenesis study indicated that the functional anti-BACE1 paratope, residues Tyr32 (H1), Trp50 (H2), Arg98 (H3), Phe101 (H3), Trp104 (H3) and Tyr94 (L3), strongly dominates the binding ener- getics with the BACE1 exosite. The mutational studies described in this work might accelerate the development of new BACE1 exosite binders with interesting pharmacological activity. Fil: Gutierrez, Lucas Joel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina. Universidad Nacional de San Luis; Argentina Fil: Andujar, Sebastian Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina. Universidad Nacional de San Luis; Argentina Fil: Enriz, Ricardo Daniel. Universidad Nacional de San Luis; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidiciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Cs.fisico Matemáticas y Naturales. Instituto Multidiciplinario de Investigaciones Biológicas de San Luis; Argentina Fil: Baldoni, Hector Armando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto de Matemática Aplicada de San Luis; Argentina. Universidad Nacional de San Luis; Argentina
Published: 2014

29. 2,3,9- and 2,3,11-Trisubstituted tetrahydroprotoberberines as D2 dopaminergic ligands

Author: Nuria Cabedo, Maria Dolores Ivorra, Sebastian A. Andujar, Ricardo D. Enriz, Maria-Jesus Sanz, Javier Párraga, Laura Piqueras, Emilio Luis Angelina, Abraham Galán, Laura Moreno, and Diego Cortes
Subjects: Models, Molecular, Berberine, Stereochemistry, Cell Survival, MTT and cytofluorometric analysis, Theoretical calculations, Molecular Dynamics Simulation, Ligands, Ciencias Biológicas, Compostos orgànics Síntesi, Drug Discovery, Alcaloides, Dopamina Receptors, Animals, Humans, Tetrahydroprotoberberines, Dopamine receptors, Structure-activity relationships cytotoxicity, Pharmacology, Molecular Structure, Chemistry, Receptors, Dopamine D2, Organic Chemistry, Dopaminergic, General Medicine, Bioquímica y Biología Molecular, Rats, Dopamine receptor, Structureeactivity relationships cytotoxicity, Química orgànica, CIENCIAS NATURALES Y EXACTAS
Abstract: Dopamine-mediated neurotransmission plays an important role in relevant psychiatric and neurological disorders. Nowadays, there is an enormous interest in the development of new dopamine receptors (DR) acting drugs as potential new targets for the treatment of schizophrenia or Parkinson's disease. Previous studies have revealed that isoquinoline compounds such as tetrahydroisoquinolines (THIQs) and tetrahydroprotoberberines (THPBs) can behave as selective D-2 dopaminergic alkaloids since they share structural similarities with dopamine. In the present study we have synthesized eleven 2,3,9- and 2,3,11-trisubstituted THPB compounds (six of them are described for the first time) and evaluated their potential dopaminergic activity. Binding studies on rat striatal membranes were used to evaluate their affinity and selectivity towards D-1 and D-2 DR and establish the structure activity relationship (SAR) as dopaminergic agents. In general, all the tested THPBs with protected phenolic hydroxyls showed a lower affinity for D-1 and D-2 DR than their corresponding homologues with free hydroxyl groups. In previous studies in which dopaminergic affinity of 1-benzyl-THIQs (BTHIQs) was evaluated, the presence of a Cl into the A-ring resulted in increased affinity and selectivity towards D-2 DR. This is in contrast with the current study since the existence of a chlorine atom into the A-ring of the THPBs caused increased affinity for D-1 DR but dramatically reduced the selectivity for D-2 DR. An OH group in position 9 of the THPB (9f) resulted in a higher affinity for DR than its homologue with an OH group in position 11 (9e) (250 fold for D-2 DR). None of the compounds showed any cytotoxicity in freshly isolated human neutrophils. A molecular modelling study of three representative THPBs was carried out. The combination of MD simulations with DFT calculations provided a clear picture of the ligand binding interactions from a structural and energetic point of view. Therefore, it is likely that compound 9d (2,3,9-trihydroxy-THPB) behave as D-2 DR agonist since serine residues cluster are crucial for agonist binding and receptor activation., This study was supported by grants SAF2011-23777, Spanish Ministry of Economy and Competitiveness, RIER RD08/0075/0016, Carlos III Health Institute, Spanish Ministry of Health and the European Regional Development Fund (FEDER). R.D.E. and S.A.A. are staff members of the National Research Council of Argentina (CONICET-Argentina).
Published: 2013

30. Catalytic and molecular properties of rabbit liver carboxylesterase acting on 1,8-cineole derivatives

Author: Paul G.M. Luiten, María del H. Loandos, Margarita B. Villecco, Sebastian A. Andujar, Marcelo F. Masman, Ana C. Muro, Fernando D. Suvire, and Ricardo D. Enriz
Subjects: Pharmacology, Molecular model, Hydrogen bond, Stereochemistry, Chemistry, Enantioselective synthesis, Stereoisomerism, RABBIT LIVER CARBOXYLESTERASE, Plant Science, General Medicine, purl.org/becyt/ford/1 [https], Hydrolysis, Carboxylesterase, Complementary and alternative medicine, Biocatalysis, Docking (molecular), Drug Discovery, purl.org/becyt/ford/1.4 [https], 1,8-CINEOLE, DOCKING, MOLECULAR MODELING
Abstract: Rabbit liver carboxylesterase (rCE) was evaluated as the catalyst for the enantioselective hydrolysis of (±)-3-endo-acetyloxy-1,8-cineole [(±)-4], which yields (1S,3S,4R)-(+)-3-acetyloxy-1,8-cineole [(+)-4] and (1R,3R,4S)-(-)-3-hydroxy-1,8-cineole [(-)-3]. Enantioselective asymmetrization of meso-3,5-diacetoxy- 1,8-cineol (5) gives (1S,3S,4R,5R)-(-)-3-acetyloxy-5- hydroxy-1,8-cineole (6), with high enantioselectivity. rCE has been chosen to perform both experiments and molecular modeling simulations. Docking simulations combined with molecular dynamics calculations were used to study rCE-catalyzed enantioselective hydrolysis of cineol derivatives. Both compounds were found to bind with their acetyl groups stabilized by hydrogen bond interactions between their oxygen atoms and Ser221. Fil: Loandos, Maria del Huerto. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia. Instituto de Química Orgánica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Muro, Ana Carolina. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia. Instituto de Química Orgánica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Villecco, Margarita Beatriz. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia. Instituto de Química Orgánica; Argentina Fil: Masman, Marcelo Fabricio. University of Groningen; Países Bajos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de San Luis; Argentina Fil: Luiten, Paul G. M.. University of Groningen; Países Bajos Fil: Andujar, Sebastian Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina Fil: Suvire, Fernando Daniel. Universidad Nacional de San Luis; Argentina Fil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina
Published: 2012

31. Essential Dynamics on Different Biological Systems: Fis Protein, tvMyb1 Transcriptional Factor and BACE1 Enzyme

Author: Héctor A. Baldoni, Ricardo D. Enriz, and Lucas J. Gutierrez
Subjects: chemistry.chemical_classification, Flexibility (engineering), Enzyme, Transcriptional factor, Chemistry, Dynamics (mechanics), Biophysics, Conformational isomerism, Molecular biology
Abstract: Proteins and enzymes poses a non-covalent 3D structure and therefore their intrinsic flexibility allows the existence of an ensemble of different conformers which are separated by low-energy barriers. These ranges of available conformers for proteins in solution are due to the relative movements among the different domains. Domain motions are important for a variety of protein functions, including catalysis, regulation of activity, transport of metabolites, formation of protein assemblies, and cellular locomotion.
Published: 2012

32. Antifungal Activity of Extracts and Prenylated Coumarins Isolated from Baccharis darwinii Hook & Arn. (Asteraceae)

Author: Susana Zacchino, Manuel Gonzalez Sierra, Ricardo D. Enriz, Alejandro Tapia, Beatriz Lima, Monica L. Freile, María Victoria Rodriguez, Gabriela Egly Feresin, and Rita R. Kurdelas
Subjects: Antifungal Agents, ASTERACEAE, Pharmaceutical Science, Microsporum gypseum, Trichophyton rubrum, Microbial Sensitivity Tests, Asteraceae, Article, Analytical Chemistry, Microbiology, purl.org/becyt/ford/1 [https], chemistry.chemical_compound, Coumarins, auraptene, Drug Discovery, Baccharis darwinii, prenylated coumarins, antimicrobial activity, Petroleum ether, Trichophyton, Physical and Theoretical Chemistry, AURAPTENE, purl.org/becyt/ford/1.6 [https], BACCHARIS DARWINII, ANTIMICROBIAL ACTIVITY, Cryptococcus neoformans, Prenylation, biology, Bacteria, Molecular Structure, Baccharis, Plant Extracts, Spectrum Analysis, Organic Chemistry, Fungi, biology.organism_classification, Fungicide, chemistry, Chemistry (miscellaneous), PRENYLATED COUMARINS, Molecular Medicine
Abstract: The petroleum ether extract of Baccharis darwinii showed activity against Cryptococcus neoformans and dermatophytes. Bioactivity-guided fractionation of Baccharis darwinii has resulted in the isolation of three coumarins: 5'-hydroxy aurapten (anisocoumarin H, 1), aurapten (7-geranyloxycoumarin, 2) and 5'-oxoaurapten (diversinin, 3). The structures of these compounds were characterized by spectroscopic methods. These compounds were evaluated for their antimicrobial activity against a panel of each, bacteria and fungi. Compound 3 showed the best activities against Microsporum gypseum, Trichophyton rubrum and Trichophyton mentagrophytes with MICs = 15.6 μg/mL, followed by compound 1 whose MICs against the same fungi were 62.5 μg/mL. In addition they showed fungicidal rather than fungistatic activity. Both compounds showed moderate activity (MICs = 125 μg/mL) against Cryptococcus neoformans. This is the first report of the presence of compound 1 in B. darwinii. Fil: Kurdelas, Rita Rosa. Universidad Nacional de la Patagonia "San Juan Bosco"; Argentina Fil: Lima, Beatriz Viviana. Universidad Nacional de San Juan. Facultad de Ingeniería. Instituto de Biotecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan; Argentina Fil: Tapia, Aníbal Alejandro. Universidad Nacional de San Juan. Facultad de Ingeniería. Instituto de Biotecnología; Argentina Fil: Feresin, Gabriela Egly. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan; Argentina. Universidad Nacional de San Juan. Facultad de Ingeniería. Instituto de Biotecnología; Argentina Fil: Gonzalez Sierra, Manuel. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; Argentina Fil: Rodriguez, María Victoria. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentina Fil: Zacchino, Susana Alicia Stella. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentina Fil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina Fil: Freile, Monica Liliana. Universidad Nacional de la Patagonia "San Juan Bosco"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Published: 2010
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33. Structure of isolated tyrosyl-glycyl-glycine tripeptide. A comparative conformational study with peptides containing an aromatic ring

Author: Ana M. Rodríguez, Marcelo F. Masman, Exequiel Ernesto Barrera Guisasola, and Ricardo D. Enriz
Subjects: AB INITIO CALCULATIONS, GAS-PHASE CHEMISTRY, Stereochemistry, Chemistry, ab initio calculations, Ab initio, purl.org/becyt/ford/1.7 [https], General Chemistry, Tripeptide, Ring (chemistry), Glycyl-Glycine, purl.org/becyt/ford/1 [https], Residue (chemistry), Ab initio quantum chemistry methods, ygg, YGG, Potential energy surface, Materials Chemistry, gas-phase chemistry, Conformational isomerism, QD1-999, edmc calculations, EDMC CALCULATIONS
Abstract: The potential energy surface (PES) of tyrosyl-glycyl-glycine (YGG) tripeptide in solution was explored using EDMC (Electrostatically Driven Monte Carlo) and in the gas-phase by means of ab initio quantum chemical calculations. The theoretical computational analysis revealed that this tripeptide possesses a significant molecular flexibility. A C7 backbone conformation was the most energetically preferred for the central Gly residue, using both methodologies. Some new stable conformers that have not been previously reported were identified in the gas phase as well. This study points out the interplay of backbone and side-chain contributions in determining the relative stabilities of energy minima. In addition, the peptide backbone of YGG was compared with other small peptides containing aromatic side-chains (Phe-Gly-Gly and Trp-Gly-Gly). The comparison with experimental X-ray results was also satisfactory. Fil: Barrera Guisasola, Exequiel Ernesto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis; Argentina. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia; Argentina Fil: Masman, Marcelo Fabricio. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis; Argentina Fil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina Fil: Rodríguez, Ana M.. Universidad Nacional de San Luis; Argentina
Published: 2010

34. Structure-activity relationship of dopaminergic halogenated 1-benzyl-tetrahydroisoquinoline derivatives

Author: Almudena Bermejo, Ricardo D. Enriz, Sebastian A. Andujar, Vanessa Romero, Noureddine El Aouad, Diego Cortes, M. Dolores Ivorra, Nuria Cabedo, Fernando D. Suvire, Angel Serrano, Paloma Marín, and Inmaculada Berenguer
Subjects: inorganic chemicals, Halogenation, Stereochemistry, Chemical synthesis, Receptors, Dopamine, Structure-Activity Relationship, chemistry.chemical_compound, Structure–activity relationships, Dopamine, Tetrahydroisoquinolines, Biogenic amine, Drug Discovery, medicine, Animals, Structure–activity relationship, Rats, Wistar, Neurotransmitter, Dopamine receptors, STRUCTURE-ACTIVITY RELATIONSHIPS, Pharmacology, chemistry.chemical_classification, 1-Halogenated benzyl-7-chloro-6-hydroxy-tetrahydroisoquinolines, Dopamine uptak, Receptors, Dopamine D2, Receptors, Dopamine D1, Otras Ciencias Químicas, Organic Chemistry, Dopaminergic, Ciencias Químicas, General Medicine, Binding, 1-Halogenated benzyl-7-chloro-6-hydroxytetrahydroisoquinolines, Rats, chemistry, Dopamine receptor, DOPAMINE UPTAKE, Catecholamine, Female, CIENCIAS NATURALES Y EXACTAS, Protein Binding, medicine.drug
Abstract: Two series of halogenated 1-benzyl-7-chloro-6-hydroxy-tetrahydroisoquinolines were prepared to explore the influence of each series on the affinity for dopamine receptors. All the compounds displayed a high affinity for D(1)-like and/or D(2)-like dopamine receptors in striatal membranes, although they were unable to inhibit [(3)H]-dopamine uptake in striatal synaptosomes. The halogen placed on the benzylic ring in 1-benzyl-THIQs, compounds of the series 1, 2'-bromobenzyl derivatives with K(i) values into the nanomolar range, and the series 2, 2',4'-dichlorobenzyl-THIQ homologues, proves to be an important factor to modulate affinity at dopamine receptor. (C) 2009 Elsevier Masson SAS. All rights reserved., This research was supported by the Spanish "Ministerio de Educacion y Ciencia" grant SAF 2007-63142. I. Berenguer acknowledges the fellowship of Generalitat Valenciana. S. Andujar acknowledges the fellowship of CONICET-Argentina.
Published: 2009

35. Ab Initio and DFT Study of the conformational Energy Hypersurface of cyclic Gly-Gly-Gly

Author: Rodrigo D. Tosso, M.A. Zamora, Ricardo D. Enriz, and Fernando D. Suvire
Subjects: Models, Molecular, Protein Conformation, AB INITIO, Ab initio, CYCLIC-TRIGLYCINE, Tripeptide, Peptides, Cyclic, purl.org/becyt/ford/1 [https], Crown form, CYCLIC-TRIPEPTIDES, Computational chemistry, purl.org/becyt/ford/1.4 [https], Conformational energy, Physical and Theoretical Chemistry, Conformational isomerism, Chemistry, Computational Biology, Stereoisomerism, DFT CALCULATIONS, Relative stability, Crystallography, Hypersurface, Models, Chemical, Gly-Gly-Gly, Thermodynamics, CONFORMATIONAL STUDY, Oligopeptides
Abstract: The multidimensional conformational potential energy hypersurface (PEHS) of cyclic Gly-Gly-Gly (1,4,7triazonane-2,5,8-trione) was comprehensively investigated at the Hartree-Fock (RHF/6-31G(d)) level of theory. The equilibrium structures, their relative stability, and the transition state (TS) structures involved in the conformational interconversion pathways were analyzed. aug-cc-pVTZ//B3LYP/6-311++G** single point calculations predict a trans-cis-cis conformation as the energetically preferred form for this compound. However, all of the levels of theory employed here predicted that two forms, a trans-cis-cis and a cis-cis-cis (crown), of conformers contribute significantly to the equilibrium mixture at room temperature. The conformational interconversion between the global minimum and the symmetric cis-cis-cis crown form requires 12.49 kcal/mol at the RHF 6-31G(d) level of theory, whereas the conformational interconversion between the cis-cis-cis crown and cis-cis-cis boat form requires 18.70 kcal/mol. An exploratory topological analysis of the PEHS was also carried out. Our results allow us to form a concise idea about the internal intricacies of the PEHSs of these cyclic tripeptides, describing the conformations as well as the conformational interconversion processes in these hypersurfaces. Fil: Tosso, Rodrigo David. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Área Química General e Inorgánica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis; Argentina Fil: Zamora, Miguel Angel. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Área Química General e Inorgánica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina Fil: Suvire, Fernando Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Área Química General e Inorgánica; Argentina Fil: Enriz, Ricardo Daniel. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Área Química General e Inorgánica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina
Published: 2009

36. Tetrahydroisoquinolines as dopaminergic ligands: 1-Butyl-7-chloro-6-hydroxy-tetrahydroisoquinoline, a new compound with antidepressant-like activity in mice

Author: Maria Dolores Ivorra, Almudena Bermejo, Ricardo D. Enriz, Thomas Freret, Nuria Cabedo, Noureddine El Aouad, Diego Cortes, Sebastian A. Andujar, Vanessa Romero, Inmaculada Berenguer, Fernando D. Suvire, Michel Boulouard, Groupe Mémoire et Plasticité comportementale (GMPc), Université de Caen Normandie (UNICAEN), and Normandie Université (NU)-Normandie Université (NU)
Subjects: Male, Models, Molecular, Stereochemistry, Dopamine, Clinical Biochemistry, Pharmaceutical Science, Motor Activity, 010402 general chemistry, Ligands, 01 natural sciences, Biochemistry, Receptors, Dopamine, chemistry.chemical_compound, Mice, Structure-Activity Relationship, Tetrahydroisoquinolines, Drug Discovery, medicine, Structure–activity relationship, Animals, Receptor, Molecular Biology, 010405 organic chemistry, Tetrahydroisoquinoline, Receptors, Dopamine D2, Receptors, Dopamine D1, [SCCO.NEUR]Cognitive science/Neuroscience, Organic Chemistry, Dopaminergic, Antagonist, Antidepressive Agents, Corpus Striatum, 3. Good health, 0104 chemical sciences, Rats, chemistry, Dopamine receptor, Hydroxyquinolines, Molecular Medicine, Lead compound, medicine.drug, Protein Binding
Abstract: International audience; Three series of 1-substituted-7-chloro-6-hydroxy-tetrahydroisoquinolines (1-butyl-, 1-phenyl- and 1-benzyl derivatives) were prepared to explore the influence of each of these groups at the 1-position on the affinity for dopamine receptors. All the compounds displayed affinity for D(1)-like and/or D(2)-like dopamine receptors in striatal membranes, and were unable to inhibit [(3)H]-dopamine uptake in striatal synaptosomes. Different structure requirements have been observed for adequate D(1) or D(2) affinities. This paper details the synthesis, structural elucidation, dopaminergic binding assays, structure-activity relationships (SAR) of these three series of isoquinolines. Moreover, 1-butyl-7-chloro-6-hydroxy-tetrahydroisoquinoline (1e) with the highest affinity towards D(2)-like receptors (K(i) value of 66nM) and the highest selectivity (49-fold D(2) vs D(1)) by in vitro binding experiments was then evaluated in behavioral assays (spontaneous activity and forced swimming test) in mice. Compound 1e increased locomotor activity in a large dose range (0.04-25mg/kg). Furthermore, this lead compound produced reduction in immobility time in the forced swimming test at a dose (0.01mg/kg) that did not modify locomotor activity. The haloperidol (0.03mg/kg), a D(2) receptor preferred antagonist, blocked the antidepressant-like effect of compound 1e.
Published: 2009

37. Conformational and electronic study of N-acetyl-L-isoleucine-N-methylamide using DFT and IPCM calculations

Author: Ana M. Rodríguez, Joseph C.P Koo, Dante E. Rojas, Ricardo D. Enriz, and Nelida Maria Peruchena
Subjects: Farmacología y Farmacia, Chloroform, CIENCIAS MÉDICAS Y DE LA SALUD, Ipcm Calculations, L-Isoleucine, Methylamide, Condensed Matter Physics, Conformational Study, Polarizable continuum model, Dft, Atomic and Molecular Physics, and Optics, chemistry.chemical_compound, Medicina Básica, chemistry, Computational chemistry, Physical and Theoretical Chemistry, Isoleucine, Acetonitrile
Abstract: A conformational and electronic study on N-acetyl-L-isoleucine-N- methylamide was carried out. All side-chain as well as backbone conformations were explored for this compound. Multidimensional conformational analysis predicts 81 structures in the case of N-acetyl-L-isoleucine-N-methylamide, 53 relaxed structures were determined at the DFT (B3LYP/6-31G(d)) level of theory. An exhaustive electronic study employing the atoms-in-molecules (AIM) method was carried out. In addition, the effects of three solvents (water, acetonitrile, and chloroform) were included in the calculations using the isodensity polarizable continuum model (IPCM) method. Fil: Rodriguez, Ana Maria. Universidad Nacional de San Luis; Argentina Fil: Koo, Joseph C. P.. University of Toronto; Canadá Fil: Rojas, Dante E.. Universidad Nacional del Nordeste. Facultad de Ciencias Exactas y Naturales y Agrimensura; Argentina Fil: Peruchena, Nelida Maria. Universidad Nacional del Nordeste. Facultad de Ciencias Exactas y Naturales y Agrimensura; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste; Argentina Fil: Enriz, Ricardo Daniel. Universidad Nacional de San Luis; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Published: 2006

38. Synthesis of 3-amino-2-ethoxycarbonyl pyrido[1,2-a]thieno-[2,3-d]-4-pyrimidone derivatives and their antimalarial and cytotoxic activities in vitro

Author: Simón E. López, Mary Cordero, Luz Orfila, José N. Domínguez, Jaime Charris, Flavia Riggione, Ricardo D. Enriz, and Fernando Suviere
Subjects: purl.org/becyt/ford/1 [https], chemistry.chemical_compound, Synthesis, Stereochemistry, Chemistry, Cytotoxic activities, Organic Chemistry, purl.org/becyt/ford/1.4 [https], Cytotoxic T cell, Pyrimidone, Pyrido pyrimidines, In vitro
Abstract: A series of 3-amino-2-ethoxycarbonyl pyrido[1,2-a]thieno[2,3-d]-4-pyrimidone 10-13 were prepared in order to investigate their cytotoxicity and antimalarial activities. Some of the them showed a promising activity. The detailed synthesis, spectroscopic, computational and biological data are described. Fil: Charris, Jaime. Universidad Central de Venezuela; Venezuela Fil: Domínguez, José. Universidad Central de Venezuela; Venezuela Fil: Cordero, Mary. Universidad Central de Venezuela; Venezuela Fil: Orfila, Luz. Universidad Central de Venezuela; Venezuela Fil: Riggione, Flavia. Universidad Central de Venezuela; Venezuela Fil: López, Simón E.. Universidad Simon Bolivar. Departamento de Quimica.; Venezuela Fil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina Fil: Suviere, Fernando. Universidad Nacional de San Luis. Facultad de Ciencias Físico- Matemáticas y Naturales; Argentina
Published: 2000

39. An analytic ring closure condition for geometrical algorithm to search the conformational space

Author: Fernando D. Suvire, Ricardo D. Enriz, and L.N. Santagata
Subjects: Ring (mathematics), CONFORMATIONAL SPACE SEARCH, Chemistry, Closure (topology), Extension (predicate logic), Condensed Matter Physics, Space (mathematics), ANALYTIC RING CLOSURE CONDITION, Biochemistry, Set (abstract data type), purl.org/becyt/ford/1 [https], Tree (descriptive set theory), CYCLIC COMPOUNDS, SYSTEMATIC CONFORMATIONAL SEARCH, purl.org/becyt/ford/1.4 [https], Molecular orbital, Physical and Theoretical Chemistry, Algorithm
Abstract: The recently reported geometrical algorithm to search the conformational space (GASCOS) scans conformational space exhaustively using an internal coordinate tree search. Using only geometrical operations and a set of criteria for eliminating chemically unreasonable atomic arrangements, the algorithm generates starting geometries for optimizations by molecular mechanics or by molecular orbital procedures. Up until now GASCOS has been used for linear structures, but an extension to cyclic structures is reported here. Fil: Santagata, Luis Nicolás. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia; Argentina Fil: Suvire, Fernando Daniel. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia; Argentina Fil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina
Published: 2000

40. Study of the Cytotoxic and Antifungal Activities of Neolignans 8.O.4Ã‚Â´ and Structurally Related Compounds

Author: Estela Raquel Correché, Fernando Giannini, P. Matyus, Mirta Carrasco, Ricardo D. Enriz, and S. Zacchino
Subjects: Antifungal, medicine.drug_class, Chemistry, Organic Chemistry, Pharmaceutical Science, Pharmacology, Analytical Chemistry, lcsh:QD241-441, n/a, lcsh:Organic chemistry, Chemistry (miscellaneous), Drug Discovery, medicine, Molecular Medicine, Cytotoxic T cell, Physical and Theoretical Chemistry
Abstract: In the present work we report the antifungal and cytotoxic activities of a neolignan 8.O.4Ã‚Â´series. The most active antifungal compounds show a significant cytotoxic effect which might be related.
Published: 2000

41. A Conformational Study of Flexible Cyclic Compounds (Hydrocarbon Rings of 9-12 Members)

Author: Ricardo D. Enriz, Fernando D. Suvire, Alfredo Armando Morales Rodríguez, S. Rodríguez, and L.N. Santagata
Subjects: chemistry.chemical_classification, Stereochemistry, Organic Chemistry, Pharmaceutical Science, Analytical Chemistry, lcsh:QD241-441, Hydrocarbon, n/a, chemistry, lcsh:Organic chemistry, Chemistry (miscellaneous), Drug Discovery, Molecular Medicine, Physical and Theoretical Chemistry, Systematic search
Abstract: We report here a conformational study of cyclic flexible compounds (rings with 9-12 members). Two methods of systematic search for the minima were used. The results were compared with those obtained using other exploratory methods.
Published: 2000

42. Structural and Thermodynamic Characteristics of the Exosite Binding Pocket on the Human BACE1: A Molecular Modeling Approach.

Author: Lucas J. Gutierrez, Ricardo D. Enriz, and HeÌctor A. Baldoni
Subjects: *THERMODYNAMICS, *CHEMICAL structure, *MOLECULAR models, *SIMULATION methods & models, *MOLECULAR dynamics, *PEPTIDES
Abstract: We report a molecular modeling study aimed to locate and provide the full structural characteristics of the exosite binding site of the BACE1. A three-step procedure was followed. In the first stage, we performed blind docking studies on the whole target surface. In a second stage, the mode of binding was further refined by molecular dynamics (MD) simulation. Finally, binding free energy calculations, through the MM-PBSA protocol, were carried out to gain insight into the stability and thermodynamics of the inhibitor located at the selected binding pockets. Twelve binding pockets were identified on the surface of BACE1 by blind docking studies. The calculations of binding free energies for the 12 complexes show that van der Waals interactions dominate the mode of binding of these complexes. The best ranked complex shows that residues Glu255-Pro258, Phe261, Gly264-Ala272, Asp311-Ala313, Ser315, and Asp317-Tyr320 are located within â¼6 Ã from the INH located at the exosite. The hydrogen bonds formed between the INH peptide, residues Tyr1, Tyr3, and Leu7 with the BACE1 residues Leu267, Cys269, Trp270, Asp311, and Asp 317 can strengthen the binding of the BACE1âINH complex. [ABSTRACT FROM AUTHOR]
Published: 2010
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43. Structure of isolated tyrosyl-glycyl-glycine tripeptide. A comparative conformational study with peptides containing an aromatic ring.

Author: Exequiel E. Barrera Guisasola, Marcelo F. Masman, Ricardo D. Enriz, and Ana M. Rodríguez
Abstract: The potential energy surface (PES) of tyrosyl-glycyl-glycine (YGG) tripeptide in solution was explored using EDMC (Electrostatically Driven Monte Carlo) and in the gas-phase by means of ab initio quantum chemical calculations. The theoretical computational analysis revealed that this tripeptide possesses a significant molecular flexibility. A C7 backbone conformation was the most energetically preferred for the central Gly residue, using both methodologies. Some new stable conformers that have not been previously reported were identified in the gas phase as well. This study points out the interplay of backbone and side-chain contributions in determining the relative stabilities of energy minima. In addition, the peptide backbone of YGG was compared with other small peptides containing aromatic side-chains (Phe-Gly-Gly and Trp-Gly-Gly). The comparison with experimental X-ray results was also satisfactory. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]
Published: 2010
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44. Ab Initio and DFT Study of the Conformational Energy Hypersurface of Cyclic Gly-Gly-Gly.

Author: Rodrigo D. Tosso, Miguel A. Zamora, Fernando D. Suvire, and Ricardo D. Enriz
Published: 2009
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45. In SilicoStudy of Full-Length Amyloid β 1−42 Tri- and Penta-Oligomers in Solution.

Author: Marcelo F. Masman, Ulrich L. M. Eisel, Imre G. Csizmadia, Botond Penke, Ricardo D. Enriz, Siewert Jan Marrink, and Paul G. M. Luiten
Published: 2009
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46. A Comprehensive Conformational Analysis of Bullacin B, a Potent Inhibitor of Complex I. Molecular Dynamics Simulations and Ab InitioCalculations.

Author: José A. Bombasaro, Marcelo F. Masman, Luis N. Santágata, Mónica L. Freile, Ana M. Rodríguez, and Ricardo D. Enriz
Published: 2008
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47. Conformational Preferences of N-Acetyl-l-leucine-N‘-methylamide. Gas-Phase and Solution Calculations on the Model Dipeptide.

Author: Marcelo F. Masman, Sándor Lovas, Richard F. Murphy, Ricardo D. Enriz, and Ana M. Rodríguez
Published: 2007
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48. Arylated analogues of cypronazole: fungicidal effect and activity on human fibroblasts. Docking analysis and molecular dynamics simulations

Author: Natividad Herrera Cano, Sebastian A. Andujar, Cristina Theoduloz, Daniel A. Wunderlin, Ana N. Santiago, Guillermo Schmeda-Hirschmann, Ricardo D. Enriz, and Gabriela E. Feresin
Subjects: Azoles, Antifungal cytotoxicity, Conformational and electronic analysis, Botany, QK1-989
Abstract: Abstract Triadimefon (TDM) and cyproconazole (CPZ) are two triazoles widely used as fungicides. Several azoles were synthesised starting from commercial TDM and CPZ. The compounds were evaluated against phytopathogenic filamentous fungi, including Aspergillus fumigatus (AF), A. niger (AN), A. ustus (AU), A. japonicus (AJ), A. terreus (AT), Fusarium oxysporum and Botrytis cinerea isolated from grapevine in the province of San Juan, Argentina. Three of the synthesised compounds (1-(Biphenyl-4-yloxy)-3,3-dimethyl-1-(1H-1,2,4-triazol-1-yl)butan-2-one, 1; 2-(Biphenyl-4-yl)-3-cyclopropyl-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, 3; 3-Cyclopropyl-2-(4’-fluorobiphenyl-4-yl)-1-(1H-1,2,4-triazol1-yl)butan-2-ol, 4) presented remarkable in vitro fungicidal properties, with better effects than TDM and CPZ on some of the target fungi. Cytotoxicity was assessed using human lung fibroblasts MRC5. Derivative 1, with IC50 values of 389.4 µM, was less toxic towards MRC-5 human lung fibroblasts than commercial TDM (248.5 µM) and CPZ (267.4 µM). Docking analysis and molecular dynamics simulations suggest that the compounds present the same interaction in the binding pocket of the CYP51B enzyme and with the same amino acids as CPZ. The derivatives investigated could be considered broad-spectrum but with some selectivity towards imperfect fungi. Graphical abstract
Published: 2022
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49. Easy synthesis of new series of pteridine analogs: di- and tetra-hydropyrimido[4,5-d]pyrimidines via 5-pyrimidinecarbaldehydes

Author: José M. de la Torre, Manuel Nogueras, Eduardo J. Borkowski, Fernando D. Suvire, Ricardo D. Enriz, and Justo Cobo
Subjects: Organic chemistry, QD241-441
Published: 2014
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50. Structural Requirements for the Antifungal Activities of Natural Drimane Sesquiterpenes and Analogues, Supported by Conformational and Electronic Studies

Author: Susana A. Zacchino, Mauricio Cuellar Fritis, Ricardo D. Enriz, Francisco Garibotto, Marcos Derita, and Iván Montenegro
Subjects: antifungal agents, drimanes, structure-activity relationships, stereo-electronic studies, Organic chemistry, QD241-441
Abstract: Seventeen drimanes including polygodial (1), isopolygodial (2), drimenol (3) and confertifolin (4) obtained from natural sources and the semi-synthetic derivatives 5–17 obtained from 1–3, were evaluated in vitro for antifungal properties against a unique panel of fungi with standardized procedures by using two end-points, MIC100 and MIC50. A SAR analysis of the whole series, supported by conformational and electronic studies, allowed us to show that the Δ7,8 -double bond would be one of the key structural features related to the antifungal activity. The MEPs obtained for active compounds exhibit a clear negative minimum value (deep red zone) in the vicinity of the Δ7,8 -double bond, which is not present in the inactive ones. Apart of this negative zone, a positive region (deep blue) appears in 1, which is not observed either in its epimer 2 nor in the rest of the active compounds. The LogP of active compounds varies between 2.33 and 3.84, but differences in MICs are not correlated with concomitant variations in LogP values.
Published: 2013
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