110 results on '"Enriz RD"'
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2. Studies of Acute and Chronic Toxicity of Commercial Herbicides with Glyphosate against Danio rerio
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Diego Martín Jofré, Juri Ayub M, Jerez Mb, Maria A. Alvarez, Enriz Rd, Fernando Giannini, Perez E, and Mohamed F
- Subjects
0106 biological sciences ,Aché ,Danio ,GLYPHOSATE ,Biology ,Pharmacology ,01 natural sciences ,purl.org/becyt/ford/1 [https] ,Toxicology ,chemistry.chemical_compound ,FISH ,ACUTE TOXICITY ,purl.org/becyt/ford/1.4 [https] ,Isopropylamine ,Chronic toxicity ,010604 marine biology & hydrobiology ,DANIO ,Otras Ciencias Químicas ,0402 animal and dairy science ,Ciencias Químicas ,04 agricultural and veterinary sciences ,biology.organism_classification ,040201 dairy & animal science ,Acetylcholinesterase ,Acute toxicity ,language.human_language ,chemistry ,CHRONIC TOXICITY ,Glyphosate ,Glycine ,language ,CIENCIAS NATURALES Y EXACTAS - Abstract
Glyphosate or N-(phosphonomethyl) glycine is a broad spectrum non-selective systemic herbicide, used to kill weeds, mainly in soybean crops. Nowadays there are many controversies about the intensive use of these herbicides due to the potential environmental impact and the effects on human health. The environmental impacts of commercial Glyphosate formulation Roundup were assessed by evaluation of acute and chronic toxicity of Danio rerio fish.The effects of glyphosate commercial formulations and glyphosate isopropylamine salt solutions were evaluated in different steps. First the lethal doses of Roundup herbicide toward the experimental models were determined. Subsequently the specie was exposed to sublethal concentrations of both, the commercial preparations and pure glyphosate salt in order to evaluate the chronic toxicity.Acute toxicity was assessed by calculating the mortality indexes and chronic toxicity by measuring several biochemical parameters such as the activity of marker enzymes like aspartate aminotransferase (AST), alanine aminotransferase (ALT) and acetylcholinesterase (AchE). The registers of histological alterations in liver tissue sections were also considered in this study.Commercial herbicides produce mortality of D. rerio and sublethal doses of these herbicides and the salt of the pure compound produce effects of chronic toxicity at the liver and muscle level; such are enough causes to limit the potential survival of these organisms in the medium. Fil: Jofré, Diego Martín. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Área Química General e Inorgánica; Argentina Fil: Alvarez, Maria de Fatima. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Área Química General e Inorgánica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Perez, E.. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia; Argentina Fil: Mohamed, F.. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia; Argentina Fil: Jeréz, María Belén. 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: Juri Ayub, Maximiliano. 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. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Área Química General e Inorgánica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Giannini, Fernando Angel. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Área Química General e Inorgánica; Argentina
- Published
- 2015
3. 3-Chlorotyramine Acting as Ligand of the D-2 Dopamine Receptor. Molecular Modeling, Synthesis and D-2 Receptor Affinity
- Author
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Angelina E, Andujar S, Moreno L, Garibotto F, Párraga J, Peruchena N, Cabedo N, Villecco M, Cortes D, and Enriz RD
- Subjects
MD simulations ,QTAIM analysis ,3-Chlorotyramine ,D-2 dopamine receptor - Abstract
We synthesized and tested 3-chlorotyramine as a ligand of the D2 dopamine receptor. This compound displayed a similar affinity by this receptor to that previously reported for dopamine. In order to understand further the experimental results we performed a molecular modeling study of 3-chlorotyramine and structurally related compounds. By combining molecular dynamics simulations with semiempirical (PM6), ab initio and density functional theory calculations, a simple and generally applicable procedure to evaluate the binding energies of these ligands interacting with the D-2 dopamine receptors is reported here. These results provided a clear picture of the binding interactions of these compounds from both structural and energetic view points. A reduced model for the binding pocket was used. This approach allowed us to perform more accurate quantum mechanical calculations as well as to obtain a detailed electronic analysis using the Quantum Theory of Atoms in Molecules (QTAIM) technique. Molecular aspects of the binding interactions between ligands and the D-2 dopamine receptor are discussed in detail. A good correlation between the relative binding energies obtained from theoretical calculations and experimental IC50 values was obtained. These results allowed us to predict that 3-chlorotyramine possesses a significant affinity by the D-2-DR. Our theoretical predictions were experimentally corroborated when we synthesized and tested 3-chlorotyramine which displayed a similar affinity by the D-2-DR to that reported for DA.
- Published
- 2015
4. Synthesis and cytotoxic activity of 4-N-carboxybutyl-5-fluorocytosyl-Arg-Gln-Trp-Arg-Arg-Trp-Trp-Gln-Arg-NH2
- Author
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Somlai C, Correche E, Olivella M, Tolosa L, Lechon MJ, Dombi G, Tóth GK, Penke B, and Enriz RD
- Abstract
The chemical synthesis of 4-N-carboxybutyl-5-fluorocytosine (II) in solution phase starting from 5-fluorocytosine and the solid phase synthesis of Arg-Gln-Trp-Arg-Arg-Trp-Trp-Gln-Arg-NH(2) attached to the 4-N-carboxybutyl-5-fluorocytosine residue at the N-terminus of the peptide (III) via peptide bond formation is reported. The target compound exhibited a significant cytotoxic activity against a culture of HepG2 cells. In addition our results demonstrated that this new compound affect cell viability, produce mitochondrial dysfunction as well as interfere with intracellular calcium homeostasis control; leading to cell malfunction and death.
- Published
- 2012
5. New ATP-competitive inhibitors of E. coli GyrB obtained from the mapping of the hydrophobic floor at the binding site: synthesis and biological evaluation.
- Author
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Gutierrez L, Peršolja P, Tosso R, Zidar N, Kikelj D, and Enriz RD
- Abstract
We mapped the hydrophobic floor, an interesting subsite at the active site of DNA gyrase B (GyrB) from E. coli . We synthesized three new compounds with pendant groups targeting the hydrophobic floor and evaluated their inhibitory activities on DNA gyrase. A new benzothiazole derivative with a benzyl substituent at position 3 of the benzothiazole ring exhibited strong inhibitory activity against E. coli DNA gyrase (IC
50 = 19 ± 3 nM). An exhaustive conformational study using potential energy surfaces (PESs) allowed us to map the new subsite evaluating all critical points on the surface and conformational interconversion pathways. We analyzed the molecular interactions using QTAIM calculations. Our data provide insights into the mechanism of action of these new ligands at the molecular level. Theoretical and experimental data suggest that new ligand optimization strategies should focus on strengthening interactions at the hydrophobic floor while preserving the binding mode of the main scaffold., Competing Interests: The authors declare no conflicts of interest., (This journal is © The Royal Society of Chemistry.)- Published
- 2024
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6. Exploring the interaction of N-(benzothiazol-2-yl)pyrrolamide DNA gyrase inhibitors with the GyrB ATP-binding site lipophilic floor: A medicinal chemistry and QTAIM study.
- Author
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Zidar N, Emanuel Cotman A, Sinnige W, Benek O, Barančokova M, Zega A, Peterlin Mašič L, Tomašič T, Ilaš J, Henderson SR, Mundy JEA, Maxwell A, Stevenson CEM, Lawson DM, Jan Sterk G, Tosso R, Gutierrez L, Enriz RD, and Kikelj D
- Subjects
- Binding Sites, Structure-Activity Relationship, Benzothiazoles chemistry, Benzothiazoles pharmacology, Benzothiazoles chemical synthesis, Adenosine Triphosphate metabolism, Adenosine Triphosphate chemistry, Molecular Structure, Quantum Theory, Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents chemistry, Anti-Bacterial Agents chemical synthesis, Models, Molecular, Topoisomerase II Inhibitors pharmacology, Topoisomerase II Inhibitors chemistry, Topoisomerase II Inhibitors chemical synthesis, DNA Gyrase metabolism, DNA Gyrase chemistry, Escherichia coli enzymology, Escherichia coli drug effects
- Abstract
N-(Benzothiazole-2-yl)pyrrolamide DNA gyrase inhibitors with benzyl or phenethyl substituents attached to position 3 of the benzothiazole ring or to the carboxamide nitrogen atom were prepared and studied for their inhibition of Escherichia coli DNA gyrase by supercoiling assay. Compared to inhibitors bearing the substituents at position 4 of the benzothiazole ring, the inhibition was attenuated by moving the substituent to position 3 and further to the carboxamide nitrogen atom. A co-crystal structure of (Z)-3-benzyl-2-((4,5-dibromo-1H-pyrrole-2-carbonyl)imino)-2,3-dihydrobenzo[d]-thiazole-6-carboxylic acid (I) in complex with E. coli GyrB24 (ATPase subdomain) was solved, revealing the binding mode of this type of inhibitor to the ATP-binding pocket of the E. coli GyrB subunit. The key binding interactions were identified and their contribution to binding was rationalised by quantum theory of atoms in molecules (QTAIM) analysis. Our study shows that the benzyl or phenethyl substituents bound to the benzothiazole core interact with the lipophilic floor of the active site, which consists mainly of residues Gly101, Gly102, Lys103 and Ser108. Compounds with substituents at position 3 of the benzothiazole core were up to two orders of magnitude more effective than compounds with substituents at the carboxamide nitrogen. In addition, the 6-oxalylamino compounds were more potent inhibitors of E. coli DNA gyrase than the corresponding 6-acetamido analogues., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2024
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7. Synthesis of a new 2-prenylated quinoline as potential drug for metabolic syndrome with pan-PPAR activity and anti-inflammatory effects.
- Author
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Villarroel-Vicente C, García A, Zibar K, Schiel MA, Ferri J, Hennuyer N, Enriz RD, Staels B, Cortes D, and Cabedo N
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- Structure-Activity Relationship, Humans, Peroxisome Proliferator-Activated Receptors metabolism, Peroxisome Proliferator-Activated Receptors agonists, Molecular Structure, Lipopolysaccharides pharmacology, Lipopolysaccharides antagonists & inhibitors, Anti-Inflammatory Agents chemical synthesis, Anti-Inflammatory Agents pharmacology, Anti-Inflammatory Agents chemistry, Macrophages drug effects, Macrophages metabolism, Dose-Response Relationship, Drug, Benzopyrans pharmacology, Benzopyrans chemical synthesis, Benzopyrans chemistry, Animals, Mice, Metabolic Syndrome drug therapy, Metabolic Syndrome metabolism, Quinolines chemistry, Quinolines pharmacology, Quinolines chemical synthesis
- Abstract
We have previously reported the total synthesis and structure-activity relationships (SAR) of 2-prenylated benzopyrans with PPAR agonist activity. Herein, we have described the synthesis and PPAR activity of 2-prenylated benzopyrans and 2-prenylated quinolines. The benzopyran nucleus was generated via enamine-catalyzed Kabbe condensation, and the quinoline nucleus via Friedländer condensation. Results demonstrated that both benzopyran (5a) and quinoline (4b) derivatives bearing a γ,δ-unsaturated ester displayed a pan-PPAR agonism. They were full PPARα agonists, but showed different preferences for PPARγ and PPARβ/δ activation. It was noteworthy that quinoline 4b displayed full hPPARα activation (2-fold than WY-14,643), weak PPARβ/δ and partial PPARγ activation. In addition, quinoline 4b showed anti-inflammatory effects on macrophages by reducing LPS-induced expression of both MCP-1 and IL-6. Therefore, 4b emerges as a first-in-class promising hit compound for the development of potential therapeutics aimed at treating metabolic syndrome, metabolic dysfunction-associated fatty liver disease (MAFLD), and its associated cardiovascular comorbidities., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2024
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8. Inhibitory effect of galantamine and donepezil combination against cholinesterase: An in silico and in vitro study.
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Adarvez-Feresin CW, Ortiz JE, Piñeiro MD, Parravicini O, Enriz RD, Garro AD, and Feresin GE
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- Humans, Butyrylcholinesterase metabolism, Donepezil pharmacology, Cholinesterase Inhibitors pharmacology, Acetylcholinesterase metabolism, Structure-Activity Relationship, Molecular Docking Simulation, Galantamine pharmacology, Alzheimer Disease drug therapy
- Abstract
This study aimed to evaluate the in silico and in vitro inhibitory effect of the combined use of galantamine (GAL) and donepezil (DON) against acetylcholinesterase and butyrylcholinesterase (BuChE) enzymes. In silico and in vitro cholinesterase analysis were carried out for GAL and DON alone and combined. Molecular modeling studies were carried out (docking analysis, molecular dynamics simulation, and quantum theory of atoms in molecules). Cholinesterase's inhibitory activities by modified Ellman's method and the drug combination effect using the Chou-Talalay method were assayed. GAL/DON combination showed the co-occupancy of the ligands in both enzymes through in silico studies. Regarding in vitro BuChE inhibition analyses, three of five combinations showed an interaction between GAL and DON at the threshold of additive affect (0.9 < CI < 1.1), with a tendency toward a synergistic effect for higher concentrations. This is the first report showing the efficacy of the GAL/DON combinations inhibiting BuChE, showing the importance of analyzing the behavior of different ligands when co-occupancy into the active site is possible. These combinations might be a possible therapy to improved efficacy, reduced doses, minor side effects, and high levels of the neurotransmitter in the synaptic space for Alzheimer's disease., (© 2024 Deutsche Pharmazeutische Gesellschaft.)
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- 2024
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9. Second generation of pyrimidin-quinolone hybrids obtained from virtual screening acting as sphingosine kinase 1 inhibitors and potential anticancer agents.
- Author
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Vettorazzi M, Díaz I, Angelina E, Salido S, Gutierrez L, Alvarez SE, Cobo J, and Enriz RD
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- Protein Kinase Inhibitors, Models, Molecular, Cell Line, Tumor, Molecular Docking Simulation, Drug Screening Assays, Antitumor, Cell Proliferation, Structure-Activity Relationship, Molecular Structure, Quinolones pharmacology, Antineoplastic Agents chemistry, Phosphotransferases (Alcohol Group Acceptor)
- Abstract
We report here the virtual screening design, synthesis and activity of eight new inhibitors of SphK1. For this study we used a pre-trained Graph Convolutional Network (GCN) combined with docking calculations. This exploratory analysis proposed nine compounds from which eight displayed significant inhibitory effect against sphingosine kinase 1 (SphK1) demonstrating a high level of efficacy for this approach. Four of these compounds also displayed anticancer activity against different tumor cell lines, and three of them (5), (6) and (7) have shown a wide inhibitory action against many of the cancer cell line tested, with GI
50 below 5 µM, being (5) the most promising with TGI below 10 µM for the half of cell lines. Our results suggest that the three most promising compounds reported here are the pyrimidine-quinolone hybrids (1) and (6) linked by p-aminophenylsulfanyl and o-aminophenol fragments respectively, and (8) without such aryl linker. We also performed an exhaustive study about the molecular interactions that stabilize the different ligands at the binding site of SphK1. This molecular modeling analysis was carried out by using combined techniques: docking calculations, MD simulations and QTAIM analysis. In this study we also included PF543, as reference compound, in order to better understand the molecular behavior of these ligands at the binding site of SphK1.These results provide useful information for the design of new inhibitors of SphK1 possessing these structural scaffolds., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ricardo Daniel Enriz reports financial support was provided by National University of San Luis. Justo Cobo reports financial support was provided by University of Jaen. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)- Published
- 2024
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10. Rosmarinic Acid Present in Lepechinia floribunda and Lepechinia meyenii as a Potent Inhibitor of the Adenylyl Cyclase gNC1 from Giardia lamblia .
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Zurita A, Vega Hissi E, Cianci Romero A, Luján AM, Salido S, Yaneff A, Davio C, Cobo J, Carpinella MC, and Enriz RD
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Giardiasis is a parasitosis caused by Giardia lamblia with significant epidemiological and clinical importance due to its high prevalence and pathogenicity. The lack of optimal therapies for treating this parasite makes the development of new effective chemical entities an urgent need. In the search for new inhibitors of the adenylyl cyclase gNC1 obtained from G. lamblia , 14 extracts from Argentinian native plants were screened. Lepechinia floribunda and L. meyenii extracts exhibited the highest gNC1 inhibitory activity, with IC
50 values of 9 and 31 µg/mL, respectively. In silico studies showed rosmarinic acid, a hydroxycinnamic acid present in both mentioned species, to be a promising anti-gNC1 compound. This result was confirmed experimentally, with rosmarinic acid showing an IC50 value of 10.1 µM. Theoretical and experimental findings elucidate the molecular-level mechanism of rosmarinic acid, pinpointing the key interactions stabilizing the compound-enzyme complex and the binding site. These results strongly support that rosmarinic acid is a promising scaffold for developing novel compounds with inhibitory activity against gNC1, which could serve as potential therapeutic agents to treat giardiasis.- Published
- 2024
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11. Benzopyran hydrazones with dual PPARα/γ or PPARα/δ agonism and an anti-inflammatory effect on human THP-1 macrophages.
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García A, Vila L, Duplan I, Schiel MA, Enriz RD, Hennuyer N, Staels B, Cabedo N, and Cortes D
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- Humans, Hydrazones pharmacology, Hypoglycemic Agents, PPAR gamma agonists, Anti-Inflammatory Agents, PPAR alpha agonists, Benzopyrans chemistry
- Abstract
Peroxisome proliferator-activated receptors (PPARs) play a major role in regulating inflammatory processes, and dual or pan-PPAR agonists with PPARγ partial activation have been recognised to be useful to manage both metabolic syndrome and metabolic dysfunction-associated fatty liver disease (MAFLD). Previous works have demonstrated the capacity of 2-prenylated benzopyrans as PPAR ligands. Herein, we have replaced the isoprenoid bond by hydrazone, a highly attractive functional group in medicinal chemistry. In an attempt to discover novel and safety PPAR activators, we efficiently prepared benzopyran hydrazone/hydrazine derivatives containing benzothiazole (series 1) or 5-chloro-3-(trifluoromethyl)-2-pyridine moiety (series 2) with a 3- or 7-carbon side chain at the 2-position of the benzopyran nucleus. Benzopyran hydrazones 4 and 5 showed dual hPPARα/γ agonism, while hydrazone 14 exerted dual hPPARα/δ agonism. These three hydrazones greatly attenuated inflammatory markers such as IL-6 and MCP-1 on the THP-1 macrophages via NF-κB activation. Therefore, we have discovered novel hits (4, 5 and 14), containing a hydrazone framework with dual PPARα/γ or PPARα/δ partial agonism, depending on the length of the side chain. Benzopyran hydrazones emerge as potential lead compounds which could be useful for treating metabolic diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)
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- 2024
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12. The Mechanism of Antimicrobial Small-Cationic Peptides from Coarse-Grained Simulations.
- Author
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Frigini EN, Porasso RD, Beke-Somfai T, López Cascales JJ, Enriz RD, and Pantano S
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- Amino Acid Sequence, Molecular Dynamics Simulation, Lipid Bilayers chemistry, Antimicrobial Cationic Peptides pharmacology, Antimicrobial Cationic Peptides chemistry, Anti-Infective Agents pharmacology, Anti-Infective Agents chemistry
- Abstract
Antimicrobial cationic peptides (AMPs) are excellent candidates for use as therapeutic antimicrobial agents. Among them, short peptides possessing sequences of 9-11 amino acids have some advantages over long-sequence peptides. However, one of the main limitations of short peptides is that their mechanism of action at the molecular level is not well-known. In this article, we report a model based on multiscale molecular dynamics simulations of short peptides interacting with vesicles containing palmitoyl-oleoyl-phosphatidylglycerol (POPG)/palmitoyl-oleoyl-phosphatidylethanolamine (POPE). Simulations using this approach have allowed us to understand the different behaviors of peptides with antimicrobial activity with respect to those that do not produce this effect. We found remarkable agreement with a series of experimental results directly supporting our model. Moreover, these results allow us to understand the mechanism of action at the molecular level of these short peptides. Our simulations suggest that mechanical inhomogeneities appear in the membrane, promoting membrane rupture when a threshold concentration of peptides adsorbed on the membrane is achieved. These results explain the high structural demand for these peptides to maintain a delicate balance between the affinity for the bilayer surface, a low peptide-peptide repulsion (in order to reach the threshold concentration), and an acceptable tendency to penetrate into the bilayer. This mechanism is different from those proposed for peptides with long amino acid sequences. Such information is very useful from the medicinal chemistry point of view for the design of new small antimicrobial peptides.
- Published
- 2023
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13. Antinociceptive effect of cyclic and linear diterpenoids as new atypical agonists of κ-opioid receptors obtained from four species of the Baccharis genus, and vehiculated in nanometric niosomes.
- Author
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Funes M, Tosso RD, Machado ND, Fernández MA, Garro M, Díaz DD, Hikawczuk VJ, and Enriz RD
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- Liposomes, Molecular Structure, Analgesics pharmacology, Receptors, Opioid, Receptors, Opioid, kappa agonists, Baccharis
- Abstract
New natural analgesic compounds that act in KORs are important alternatives for potential therapeutical use in medicine. In this work, we report and compare here the antinociceptive activity displayed by cyclic and linear diterpenes, obtained from the genus Baccharis. The antinociceptive activities determined were relatively strong, in comparison whit morphine. The antinociceptive mechanism of action was made through naloxone administration (a non-selective antagonist of opioid receptors). The more active compounds were vehiculized successfully in niosomes at nanometric scale. The observed antinociceptive activity for Bartemidiolide oxide (BARTO), obtain from Baccharis artemisioides, was greater than Flabeloic acid dimer (DACD), the first compound isolated from Baccharis flabellata that was reported possessing antinociceptive effects. We also conducted docking calculations and molecular dynamics simulations, which suggested that the newly identified diterpenes might share the molecular action mechanism reported for Salvinorin A (SalA). Molecular simulations have allowed us to appreciate some subtle differences between molecular interactions of these ligands stabilizing their respective complexes; such information might be useful for designing and searching for new inhibitors of KORs., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)
- Published
- 2023
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14. Anti-inflammatory effects and improved metabolic derangements in ob/ob mice by a newly synthesized prenylated benzopyran with pan-PPAR activity.
- Author
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Marques P, Villarroel-Vicente C, Collado A, García A, Vila L, Duplan I, Hennuyer N, Garibotto F, Enriz RD, Dacquet C, Staels B, Piqueras L, Cortes D, Sanz MJ, and Cabedo N
- Subjects
- Mice, Animals, PPAR gamma metabolism, PPAR alpha metabolism, Tumor Necrosis Factor-alpha, Benzopyrans, NF-kappa B, Anti-Inflammatory Agents pharmacology, Anti-Inflammatory Agents therapeutic use, Inflammation drug therapy, PPAR-beta metabolism, PPAR delta, Metabolic Diseases
- Abstract
Background and Purpose: Selective peroxisome proliferator-activated receptors (PPARs) are widely used to treat metabolic complications; however, the limited effect of PPARα agonists on glucose metabolism and the adverse effects associated with selective PPARγ activators have stimulated the development of novel pan-PPAR agonists to treat metabolic disorders. Here, we synthesized a new prenylated benzopyran (BP-2) and evaluated its PPAR-activating properties, anti-inflammatory effects and impact on metabolic derangements., Experimental Approach: BP-2 was used in transactivation assays to evaluate its agonism to PPARα, PPARβ/δ and PPARγ. A parallel-plate flow chamber was employed to investigate its effect on TNFα-induced leukocyte-endothelium interactions. Flow cytometry and immunofluorescence were used to determine its effects on the expression of endothelial cell adhesion molecules (CAMs) and chemokines and p38-MAPK/NF-κB activation. PPARs/RXRα interactions were determined using a gene silencing approach. Analysis of its impact on metabolic abnormalities and inflammation was performed in ob/ob mice., Key Results: BP-2 displayed strong PPARα activity, with moderate and weak activity against PPARβ/δ and PPARγ, respectively. In vitro, BP-2 reduced TNFα-induced endothelial ICAM-1, VCAM-1 and fractalkine/CX
3 CL1 expression, suppressed mononuclear cell arrest via PPARβ/δ-RXRα interactions and decreased p38-MAPK/NF-κB activation. In vivo, BP-2 improved the circulating levels of glucose and triglycerides in ob/ob mice, suppressed T-lymphocyte/macrophage infiltration and proinflammatory markers in the liver and white adipose tissue, but increased the expression of the M2-like macrophage marker CD206., Conclusion and Implications: BP-2 emerges as a novel pan-PPAR lead candidate to normalize glycemia/triglyceridemia and minimize inflammation in metabolic disorders, likely preventing the development of further cardiovascular complications., Competing Interests: Declaration of Competing Interest No potential conflicts of interest relevant to this article were reported., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)- Published
- 2023
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15. Evaluating the conformational space of the active site of D 2 dopamine receptor. Scope and limitations of the standard docking methods.
- Author
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Tosso RD, Zarycz MNC, Schiel A, Goicoechea Moro L, Baldoni HA, Angelina E, and Enriz RD
- Subjects
- Binding Sites, Catalytic Domain, Ligands, Molecular Docking Simulation, Protein Binding, Dopamine, Quantum Theory
- Abstract
We report here for the first time the potential energy surfaces (PES) of phenyletilamine (PEA) and meta-tyramine (m-OH-PEA) at the D
2 dopamine receptor (D2DR) binding site. PESs not only allow us to observe all the critical points of the surface (minimums, maximums, and transition states), but also to note the ease or difficulty that each local minima have for their conformational inter-conversions and therefore know the conformational flexibility that these ligands have in their active sites. Taking advantage of possessing this valuable information, we analyze how accurate a standard docking study is in these cases. Our results indicate that although we have to be careful in how to carry out this type of study and to consider performing some extra-simulations, docking calculations can be satisfactory. In order to analyze in detail the different molecular interactions that are stabilizing the different ligand-receptor (L-R) complexes, we carried out quantum theory of atoms in molecules (QTAIM) computations and NMR shielding calculations. Although some of these techniques are a bit tedious and require more computational time, our results demonstrate the importance of performing computational simulations using different types of combined techniques (docking/MD/hybrid QM-MM/QTAIM and NMR shielding calculations) in order to obtain more accurate results. Our results allow us to understand in details the molecular interactions stabilizing and destabilizing the different L-R complexes reported here. Thus, the different activities observed for dopamine (DA), m-OH-PEA, and PEA can be clearly explained at molecular level., (© 2022 Wiley Periodicals LLC.)- Published
- 2022
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16. Arylated analogues of cypronazole: fungicidal effect and activity on human fibroblasts. Docking analysis and molecular dynamics simulations.
- Author
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Herrera Cano N, Andujar SA, Theoduloz C, Wunderlin DA, Santiago AN, Schmeda-Hirschmann G, Enriz RD, and Feresin GE
- 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 IC
50 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., (© 2022. The Author(s).)- Published
- 2022
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17. Pseudorotaxane formation affected by stereo-electronic effects. A theoretical and experimental study.
- Author
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Porasso RD, Sancho MI, Parajó M, García-Río L, and Enriz RD
- Abstract
We report a theoretical and experimental study on different complexes of pseudorotaxanes possessing pyridine axles. In order to evaluate the stereo-electronic effects of the methyl substituents in the pyridine ring, complexes with different substitution patterns were synthesized. In this way, it was possible to analyze the different behaviors of these complexes according to the positions of their methyl substituents. Combined techniques of molecular dynamics and quantum mechanical calculations with the help of molecular electrostatic potentials for a simpler visualization of the electronic effects were employed. We have sought experimental support of NMR spectroscopy analysis to corroborate the conclusions obtained from the molecular simulations. Our results not only clearly demonstrate that both electronic and steric effects play key roles in the feasibility of the formation of such complexes, but also the simulations reported here might predict the degree of difficulty of their formation. The combination of computational techniques employed here seems to be an excellent approach to be able to predict whether or not a complex can be formed and with what degree of difficulty. In addition, our experimental and theoretical results have allowed us to visualize the formation of external complexes in the rotaxanes reported here. In this case, the use of bolaforms with trimethylammonium groups at both ends was very useful to evaluate in detail the formation of the so-called external complexes in these systems.
- Published
- 2022
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18. Quinazoline-tethered hydrazone: A versatile scaffold toward dual anti-TB and EGFR inhibition activities in NSCLC.
- Author
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Emam AM, Dahal A, Singh SS, Tosso RD, Ibrahim SM, El-Sadek M, Jois SD, Enriz RD, and Kothayer H
- Subjects
- A549 Cells, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Antitubercular Agents chemical synthesis, Antitubercular Agents chemistry, Carcinoma, Non-Small-Cell Lung drug therapy, Cell Line, Tumor, ErbB Receptors antagonists & inhibitors, Erlotinib Hydrochloride pharmacology, Fibroblasts drug effects, Fibroblasts metabolism, Humans, Hydrazones chemical synthesis, Hydrazones chemistry, Lung Neoplasms, Models, Molecular, Mycobacterium tuberculosis drug effects, Quinazolines chemical synthesis, Quinazolines chemistry, Structure-Activity Relationship, Tuberculosis drug therapy, Antineoplastic Agents pharmacology, Antitubercular Agents pharmacology, Hydrazones pharmacology, Quinazolines pharmacology
- Abstract
Globally, lung cancer and tuberculosis are considered to be very serious and complex diseases. Evidence suggests that chronic infection with tuberculosis (TB) can often lead to lung tumors; therefore, developing drugs that target both diseases is of great clinical significance. In our study, we designed and synthesized a suite of 14 new quinazolinones (5a-n) and performed biological investigations of these compounds in Mycobacterium tuberculosis (MTB) and cancer cell lines. In addition, we conducted a molecular modeling study to determine the mechanism of action of these compounds at the molecular level. Compounds that showed anticancer activity in the preliminary screening were further evaluated in three cancer cell lines (A549, Calu-3, and BT-474 cells) and characterized in an epidermal growth factor receptor (EGFR) binding assay. Cytotoxicity in noncancerous lung fibroblast cells was also evaluated to obtain safety data. Our theoretical and experimental studies indicated that our compounds showed a mechanism of action similar to that of erlotinib by inhibiting the EGFR tyrosine kinase. In turn, the antituberculosis activity of these compounds would be produced by the inhibition of enoyl-ACP-reductase. From our findings, we were able to identify two potential lead compounds (5i and 5l) with dual activity and elevated safety toward noncancerous lung fibroblast cells. In addition, our data identified three compounds with excellent anti-TB activities (compounds 5i, 5l, and 5n)., (© 2021 Deutsche Pharmazeutische Gesellschaft.)
- Published
- 2021
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19. Anti-oxidant and anti-inflammatory effect of polar extracts obtained from waste product of wine making.
- Author
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Germanó MJ, Muñoz MD, Della-Vedova MC, Feresin GE, Rinaldi-Tosi M, Enriz RD, Ramirez DC, and Giannini FA
- Subjects
- Anti-Inflammatory Agents pharmacology, Flavonoids analysis, Plant Extracts pharmacology, Waste Products, Antioxidants analysis, Antioxidants pharmacology, Wine analysis
- Abstract
A lot of diseases are characterized by an increased inflammatory response with an exacerbated production of free radicals. The anti-inflammatory effect of different compounds with antioxidant capacity, as polyphenols present in grape is well known. Therefore, the objective is to evaluate the anti-oxidant and anti-inflammatory activity of waste product of wine production.Six different non-toxic-marc-polar extracts from Malbec and Syrah grape varieties were obtained, their total phenol and flavonoid content were evaluated, and their antioxidant and anti-inflammatory activity were determined.High content of total phenols and flavonoids were found mainly in extracts obtained from Syrah (80.51 ± 16.63 g equivalent to gallic acid/100 g and 25.47 ± 3.33 g equivalent to quercetin/100 g). In addition, they had a high antioxidant effect (above 88.5% of ABTS inhibition by Syrah extracts). Finally, all extracts decreased the nitric oxide (NO) production, but this was more accented when extract from Syrah obtained by infusion was used, which decreased NO levels to baseline (4.46 µM).Taking together, our results show the potential pharmaceutical use of waste product of wine making to prevent or to treat diseases which inflammatory response is exacerbated.
- Published
- 2021
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20. New short cationic antibacterial peptides. Synthesis, biological activity and mechanism of action.
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Lima B, Ricci M, Garro A, Juhász T, Szigyártó IC, Papp ZI, Feresin G, Garcia de la Torre J, Lopez Cascales J, Fülöp L, Beke-Somfai T, and Enriz RD
- Subjects
- Anti-Bacterial Agents chemistry, Antimicrobial Cationic Peptides chemistry, Circular Dichroism, Hydrophobic and Hydrophilic Interactions, Protein Structure, Secondary, Anti-Bacterial Agents chemical synthesis, Anti-Bacterial Agents pharmacology, Antimicrobial Cationic Peptides chemical synthesis, Antimicrobial Cationic Peptides pharmacology
- Abstract
We report a theoretical and experimental study on a new series of small-sized antibacterial peptides. Synthesis and bioassays for these peptides are reported here. In addition, we evaluated different physicochemical parameters that modulate antimicrobial activity (charge, secondary structure, amphipathicity, hydrophobicity and polarity). We also performed molecular dynamic simulations to assess the interaction between these peptides and their molecular target (the membrane). Biophysical characterization of the peptides was carried out with different techniques, such as circular dichroism (CD), linear dichroism (LD), infrared spectroscopy (IR), dynamic light scattering (DLS), fluorescence spectroscopy and TEM studies using model systems (liposomes) for mammalian and bacterial membranes. The results of this study allow us to draw important conclusions on three different aspects. Theoretical and experimental results indicate that small-sized peptides have a particular mechanism of action that is different to that of large peptides. These results provide additional support for a previously proposed four-step mechanism of action. The possible pharmacophoric requirement for these small-sized peptides is discussed. Furthermore, our results indicate that a net +4 charge is the adequate for 9 amino acid long peptides to produce antibacterial activity. The information reported here is very important for designing new antibacterial peptides with these structural characteristics., (Copyright © 2021 Elsevier B.V. All rights reserved.)
- Published
- 2021
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21. Novel Sulfonamide-Based Carbamates as Selective Inhibitors of BChE.
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Magar P, Parravicini O, Štěpánková Š, Svrčková K, Garro AD, Jendrzejewska I, Pauk K, Hošek J, Jampílek J, Enriz RD, and Imramovský A
- Subjects
- Acetylcholinesterase metabolism, Binding Sites, Butyrylcholinesterase metabolism, Carbamates chemical synthesis, Catalytic Domain, Humans, Molecular Docking Simulation, Molecular Dynamics Simulation, Structure-Activity Relationship, Sulfonamides chemical synthesis, Carbamates chemistry, Cholinesterase Inhibitors chemistry, Sulfonamides chemistry
- 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 {(2 S )-1-[(2-methoxybenzyl)sulfamoyl]-4-methylpentan-2-yl}carbamate ( 5k ), benzyl {(2 S )-1-[(4-chlorobenzyl)sulfamoyl]-4-methylpentan-2-yl}carbamate ( 5j ), and benzyl [(2 S )-1-(benzylsulfamoyl)-4-methylpentan-2-yl]carbamate ( 5c ) showed the highest BChE inhibition (IC
50 = 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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22. Structure activity relationships and the binding mode of quinolinone-pyrimidine hybrids as reversal agents of multidrug resistance mediated by P-gp.
- Author
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Laiolo J, Lanza PA, Parravicini O, Barbieri C, Insuasty D, Cobo J, Vera DMA, Enriz RD, and Carpinella MC
- Subjects
- Cell Death drug effects, Humans, K562 Cells, Molecular Dynamics Simulation, Protein Transport drug effects, Pyrimidines chemistry, Pyrimidines toxicity, Quinolones chemistry, Quinolones toxicity, Rhodamine 123 metabolism, Structure-Activity Relationship, Thermodynamics, ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism, Drug Resistance, Multiple drug effects, Pyrimidines pharmacology, Quinolones pharmacology
- Abstract
P-gp-associated multidrug resistance is a major impediment to the success of chemotherapy. With the aim of finding non-toxic and effective P-gp inhibitors, we investigated a panel of quinolin-2-one-pyrimidine hybrids. Among the active compounds, two of them significantly increased intracellular doxorubicin and rhodamine 123 accumulation by inhibiting the efflux mediated by P-gp and restored doxorubicin toxicity at nanomolar range. Structure-activity relationships showed that the number of methoxy groups, an optimal length of the molecule in its extended conformation, and at least one flexible methylene group bridging the quinolinone to the moiety bearing the pyrimidine favored the inhibitory potency of P-gp. The best compounds showed a similar binding pattern and interactions to those of doxorubicin and tariquidar, as revealed by MD and hybrid QM/MM simulations performed with the recent experimental structure of P-gp co-crystallized with paclitaxel. Analysis of the molecular interactions stabilizing the different molecular complexes determined by MD and QTAIM showed that binding to key residues from TMH 4-7 and 12 is required for inhibition., (© 2021. The Author(s).)
- Published
- 2021
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23. Covalence and π-electron delocalization influence on hydrogen bonds in proton transfer process of o-hydroxy aryl Schiff bases: A combined NMR and QTAIM analysis.
- Author
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Zarycz MNC, Schiel MA, Angelina E, and Enriz RD
- Abstract
Within the framework of the density functional theory approach, we studied the relationship between the chemical nature of intramolecular hydrogen bonds (HBs) and nuclear magnetic resonance (NMR) parameters, J-couplings and
1 H-chemical shifts [δ(1 H)], of the atoms involved in such bonds in o-hydroxyaryl Schiff bases during the proton transfer process. For the first time, the shape of the dependence of the degree of covalence in HBs on1 J(N-H),1 J(O-H),2h J(O-N), and δ(1 H) during the proton transfer process in o-hydroxyaryl Schiff bases was analyzed. Parameters obtained from Bader's theory of atoms in molecules were used to assess the dependence of covalent character in HBs with both the NMR properties. The influence of π-electronic delocalization on2h J(N-O) under the proton transfer process was investigated.2h J(O-N) in a Mannich base was also studied in order to compare the results with an unsaturated system. In addition, substituent effects on the phenolic ring were investigated. Our results indicate that the covalent character of HBs on both sides of the transition state undergoes a smooth exponential increase as the δ(1 H) moves downfield. The degree of covalence of the N⋯H (O⋯H) bond increases linearly as1 J(N-H) (1 J(O-H)) becomes more negative, even after reaching the transition state. Non-vanishing values of spin dipolar (SD) and paramagnetic spin orbital terms of2h J(O-N) show that π-electronic delocalization has a non-negligible effect on tautomeric equilibrium and gives evidence of the presence of the resonance assisted HB.Variation of the SD term of2h J(O-N) follows a similar pattern as the change in the para-delocalization aromaticity index of the chelate ring.- Published
- 2021
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24. A Potent N-(piperidin-4-yl)-1H-pyrrole-2-carboxamide Inhibitor of Adenylyl Cyclase of G. lamblia: Biological Evaluation and Molecular Modelling Studies.
- Author
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Vega Hissi EG, De Costa Guardamagna AB, Garro AD, Falcon CR, Anderluh M, Tomašič T, Kikelj D, Yaneff A, Davio CA, Enriz RD, and Zurita AR
- Subjects
- Adenylyl Cyclases chemistry, Dose-Response Relationship, Drug, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors chemistry, Models, Molecular, Molecular Structure, Structure-Activity Relationship, Adenylyl Cyclases metabolism, Enzyme Inhibitors pharmacology, Giardia lamblia enzymology
- Abstract
In this work, we report a derivative of N-(piperidin-4-yl)-1H-pyrrole-2-carboxamide as a new inhibitor for adenylyl cyclase of Giardia lamblia which was obtained from a study using structural data of the nucleotidyl cyclase 1 (gNC1) of this parasite. For such a study, we developed a model for this specific enzyme by using homology techniques, which is the first model reported for gNC1 of G. lamblia. Our studies show that the new inhibitor has a competitive mechanism of action against this enzyme. 2-Hydroxyestradiol was used as the reference compound for comparative studies. Results in this work are important from two points of view. on the one hand, an experimentally corroborated model for gNC1 of G. lamblia obtained by molecular modelling is presented; on the other hand, the new inhibitor obtained is an undoubtedly excellent starting structure for the development of new metabolic inhibitors for G. lamblia., (© 2021 Wiley-VCH GmbH.)
- Published
- 2021
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25. Antibacterial Effect of Chitosan-Gold Nanoparticles and Computational Modeling of the Interaction between Chitosan and a Lipid Bilayer Model.
- Author
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Fuster MG, Montalbán MG, Carissimi G, Lima B, Feresin GE, Cano M, Giner-Casares JJ, López-Cascales JJ, Enriz RD, and Víllora G
- 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-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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26. Hydroxynaphthalenecarboxamides and substituted piperazinylpropandiols, two new series of BRAF inhibitors. A theoretical and experimental study.
- Author
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Campos LE, Garibotto F, Angelina E, Kos J, Gonec T, Marvanova P, Vettorazzi M, Oravec M, Jendrzejewska I, Jampilek J, Alvarez SE, and Enriz RD
- Subjects
- Antineoplastic Agents pharmacology, Humans, Models, Molecular, Phosphorylation, Antineoplastic Agents therapeutic use, Melanoma drug therapy, Proto-Oncogene Proteins B-raf antagonists & inhibitors
- Abstract
The oncogenic mutated kinase BRAF
V600E is an attractive molecular target because it is expressed in several human cancers, including melanoma. To present, only three BRAF small inhibitors are approved by the FDA for the treatment of patients with metastatic melanoma: Vemurafenib, Dabrafenib and Encorafenib. Although many protocol treatments have been probed in clinical trials, BRAF inhibition has a limited effectiveness because patients invariably develop resistance and secondary toxic effects associated with the therapy. These limitations highlight the importance of designing new and better inhibitors with different structures that could establish different interactions in the active site of the enzyme and therefore decrease resistance progress. Considering the data from our previous report, here we studied two series of derivatives of structural scaffolds as potential BRAF inhibitors: hydroxynaphthalenecarboxamides and substituted piperazinylpropandiols. Our results indicate that structural analogues of substituted piperazinylpropandiols do not show significantly better activities to that previously reported. In contrast, the hydroxynaphthalenecarboxamides derivatives significantly inhibited cell viability and ERK phosphorylation, a measure of BRAF activity, in Lu1205 BRAFV600E melanoma cells. In order to better understand these experimental results, we carried out a molecular modeling study using different combined techniques: docking, MD simulations and quantum theory of atoms in molecules (QTAIM) calculations. Thus, by using this approach we determined that the molecular interactions that stabilize the different molecular complexes are closely related to Vemurafenib, a well-documented BRAF inhibitor. Furthermore, we found that bi-substituted compounds may interact more strongly respect to the mono-substituted analogues, by establishing additional interactions with the DFG-loop at the BRAF-active site. On the bases of these results we synthesized and tested a new series of hydroxynaphthalenecarboxamides bi-substituted. Remarkably, all these compounds displayed significant inhibitory effects on the bioassays performed. Thus, the structural information reported here is important for the design of new BRAFV600E inhibitors possessing this type of structural scaffold., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)- Published
- 2020
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27. Conformational and electronic study of dopamine interacting with the D 2 dopamine receptor.
- Author
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Tosso RD, Parravicini O, Zarycz MNC, Angelina E, Vettorazzi M, Peruchena N, Andujar S, and Enriz RD
- Subjects
- Electrons, Humans, Molecular Conformation, Molecular Docking Simulation, Molecular Dynamics Simulation, Density Functional Theory, Dopamine chemistry, Receptors, Dopamine D2 chemistry
- Abstract
We report an exhaustive conformational and electronic study on dopamine (DA) interacting with the D
2 dopamine receptor (D2 DR). For the first time, the complete surface of the conformational potential energy of the complex DA/D2 DR 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 D2 DR 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 D2 DR., (© 2020 Wiley Periodicals LLC.)- Published
- 2020
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28. Targeting defective sphingosine kinase 1 in Niemann-Pick type C disease with an activator mitigates cholesterol accumulation.
- Author
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Newton J, Palladino END, Weigel C, Maceyka M, Gräler MH, Senkal CE, Enriz RD, Marvanova P, Jampilek J, Lima S, Milstien S, and Spiegel S
- Subjects
- Animals, Carrier Proteins metabolism, Cell Line, Cholesterol metabolism, Cholesterol Esters metabolism, Endosomes metabolism, Fibroblasts, Humans, Intracellular Signaling Peptides and Proteins metabolism, Lysosomes metabolism, Membrane Glycoproteins metabolism, Mice, Niemann-Pick C1 Protein genetics, Niemann-Pick C1 Protein metabolism, Niemann-Pick Disease, Type C physiopathology, Primary Cell Culture, Protein Transport, Sphingolipids metabolism, Sphingosine genetics, Vesicular Transport Proteins genetics, Vesicular Transport Proteins metabolism, Niemann-Pick Disease, Type C metabolism, Phosphotransferases (Alcohol Group Acceptor) metabolism, Sphingosine metabolism
- 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., Competing Interests: Conflict of interest—The authors declare that they have no conflicts of interest with the contents of this article., (© 2020 Newton et al.)
- Published
- 2020
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29. Second-generation 4,5,6,7-tetrahydrobenzo[ d ]thiazoles as novel DNA gyrase inhibitors.
- Author
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Lamut A, Skok Ž, Barančoková M, Gutierrez LJ, Cruz CD, Tammela P, Draskovits G, Szili PÉ, Nyerges Á, Pál C, Molek P, Bratkovič T, Ilaš J, Zidar N, Zega A, Enriz RD, Kikelj D, and Tomašič T
- Subjects
- Anti-Bacterial Agents chemistry, Benzothiazoles chemistry, Dose-Response Relationship, Drug, Gram-Positive Bacteria enzymology, Gram-Positive Bacteria growth & development, Humans, Microbial Sensitivity Tests, Models, Molecular, Molecular Structure, Structure-Activity Relationship, Topoisomerase II Inhibitors chemistry, Anti-Bacterial Agents pharmacology, Benzothiazoles pharmacology, DNA Gyrase metabolism, Gram-Positive Bacteria drug effects, Topoisomerase II Inhibitors pharmacology
- 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 IC
50 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
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30. Design of new quinolin-2-one-pyrimidine hybrids as sphingosine kinases inhibitors.
- Author
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Vettorazzi M, Insuasty D, Lima S, Gutiérrez L, Nogueras M, Marchal A, Abonia R, Andújar S, Spiegel S, Cobo J, and Enriz RD
- Subjects
- Drug Design, Humans, Models, Molecular, Pyrimidines pharmacology, Phosphotransferases (Alcohol Group Acceptor) antagonists & inhibitors, Pyrimidines therapeutic use
- 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., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2020
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31. Searching new structural scaffolds for BRAF inhibitors. An integrative study using theoretical and experimental techniques.
- Author
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Campos LE, Garibotto FM, Angelina E, Kos J, Tomašič T, Zidar N, Kikelj D, Gonec T, Marvanova P, Mokry P, Jampilek J, Alvarez SE, and Enriz RD
- Subjects
- Antineoplastic Agents chemical synthesis, Antineoplastic Agents metabolism, Cell Line, Tumor, Drug Screening Assays, Antitumor, Humans, Molecular Docking Simulation, Molecular Structure, Protein Binding, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors metabolism, Proto-Oncogene Proteins B-raf metabolism, Vemurafenib pharmacology, Antineoplastic Agents pharmacology, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins B-raf antagonists & inhibitors
- 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., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
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32. Polycerasoidol, a Natural Prenylated Benzopyran with a Dual PPARα/PPARγ Agonist Activity and Anti-inflammatory Effect.
- Author
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Bermejo A, Collado A, Barrachina I, Marqués P, El Aouad N, Franck X, Garibotto F, Dacquet C, Caignard DH, Suvire FD, Enriz RD, Piqueras L, Figadère B, Sanz MJ, Cabedo N, and Cortes D
- Subjects
- Benzopyrans pharmacology, Humans, Molecular Structure, Structure-Activity Relationship, Anti-Inflammatory Agents chemistry, Anti-Inflammatory Agents pharmacology, Benzopyrans chemistry, PPAR alpha agonists, PPAR gamma agonists, Prenylation
- 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.
- Published
- 2019
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33. 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
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Muñoz MD, Gutierrez LJ, Delignat S, Russick J, Gomez Mejiba SE, Lacroix-Desmazes S, Enriz RD, and Ramirez DC
- Subjects
- Animals, Cyclic N-Oxides chemistry, HEK293 Cells, Humans, Inflammation immunology, Mice, Molecular Dynamics Simulation, Myeloid Differentiation Factor 88 chemistry, Myeloid Differentiation Factor 88 metabolism, NF-kappa B chemistry, NF-kappa B metabolism, Nitrogen Oxides chemistry, Protein Binding, Protein Domains, RAW 264.7 Cells, Toll-Like Receptor 2 antagonists & inhibitors, Toll-Like Receptor 2 chemistry, Cyclic N-Oxides metabolism, Inflammation metabolism, Nitrogen Oxides metabolism, Signal Transduction, Spin Labels, Toll-Like Receptor 2 metabolism
- 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., (Copyright © 2019 Elsevier B.V. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
34. Synthesis and biological evaluation of sphingosine kinase 2 inhibitors with anti-inflammatory activity.
- Author
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Vettorazzi M, Vila L, Lima S, Acosta L, Yépes F, Palma A, Cobo J, Tengler J, Malik I, Alvarez S, Marqués P, Cabedo N, Sanz MJ, Jampilek J, Spiegel S, and Enriz RD
- Subjects
- Anti-Inflammatory Agents chemistry, Anti-Inflammatory Agents pharmacology, Anti-Inflammatory Agents toxicity, Azepines chemistry, Azepines pharmacology, Cell Adhesion drug effects, Cell Survival drug effects, Drug Design, Endothelium, Vascular drug effects, Endothelium, Vascular immunology, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Enzyme Inhibitors toxicity, Epoxy Compounds chemistry, Epoxy Compounds pharmacology, Human Umbilical Vein Endothelial Cells, Humans, Molecular Docking Simulation, Neutrophils drug effects, Neutrophils immunology, Protein Binding, Structure-Activity Relationship, Anti-Inflammatory Agents chemical synthesis, Azepines chemical synthesis, Enzyme Inhibitors chemical synthesis, Epoxy Compounds chemical synthesis, Phosphotransferases (Alcohol Group Acceptor) antagonists & inhibitors
- Abstract
The synthesis of inhibitors of SphK2 with novel structural scaffolds is reported. These compounds were designed from a molecular modeling study, in which the molecular interactions stabilizing the different complexes were taken into account. Particularly interesting is that 7-bromo-2-(2-phenylethyl)-2,3,4,5-tetrahydro-1,4-epoxynaphtho[1,2-b]azepine, which is a selective inhibitor of SphK2, does not exert any cytotoxic effects and has a potent anti-inflammatory effect. It was found to inhibit mononuclear cell adhesion to the dysfunctional endothelium with minimal impact on neutrophil-endothelial cell interactions. The information obtained from our theoretical and experimental study can be useful in the search for inhibitors of SphK2 that play a prominent role in different diseases, especially in inflammatory and cardiovascular disorders., (© 2019 Deutsche Pharmazeutische Gesellschaft.)
- Published
- 2019
- Full Text
- View/download PDF
35. Mechanical properties of bilayers containing sperm sphingomyelins and ceramides with very long-chain polyunsaturated fatty acids.
- Author
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Ahumada-Gutierrez H, Peñalva DA, Enriz RD, Antollini SS, and Cascales JJL
- Subjects
- Animals, Male, Molecular Dynamics Simulation, Rats, Ceramides chemistry, Fatty Acids, Unsaturated chemistry, Lipid Bilayers chemistry, Spermatozoa chemistry, Sphingomyelins chemistry
- Abstract
Sphingomyelins (SM) and ceramides (Cer) with very long chain polyunsaturated fatty acids (V) are important components of spermatozoa membranes. In this study, the mechanical properties of bilayers of SM and Cer with nonhydroxy (n-V) and 2-hydroxy (h-V) fatty acid (30:5) were studied by molecular dynamics simulation at different temperatures and in the presence and the absence of salt. From our results, it was evidenced how n-V SM and h-V SM bilayers showed similar behavior. When n-V Cer was added to a h-V SM bilayer, the Gaussian curvature modulus and E
curve of binary bilayers decreased. This variation in the mechanical properties of the bilayer can be associated with an incipient step during the fecundation process., (Copyright © 2019 Elsevier B.V. All rights reserved.)- Published
- 2019
- Full Text
- View/download PDF
36. New substituted aminopyrimidine derivatives as BACE1 inhibitors: in silico design, synthesis and biological assays.
- Author
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Gutiérrez LJ, Parravicini O, Sánchez E, Rodríguez R, Cobo J, and Enriz RD
- Subjects
- Amyloid Precursor Protein Secretases antagonists & inhibitors, Aspartic Acid Endopeptidases antagonists & inhibitors, Binding Sites, Biological Assay, Catalytic Domain, Drug Design, Humans, Molecular Conformation, Molecular Docking Simulation, Molecular Dynamics Simulation, Protein Binding, Pyrimidines chemical synthesis, Pyrimidines pharmacology, Quantitative Structure-Activity Relationship, Amyloid Precursor Protein Secretases chemistry, Aspartic Acid Endopeptidases chemistry, Pyrimidines chemistry
- Abstract
We report in this work new substituted aminopyrimidine derivatives acting as inhibitors of the catalytic site of BACE1. These compounds were obtained from a molecular modeling study. The theoretical and experimental study reported here was carried out in several steps: docking analysis, Molecular Dynamics (MD) simulations, Quantum Theory Atom in Molecules (QTAIM) calculations, synthesis and bioassays and has allowed us to propose some compounds of this series as new inhibitors of the catalytic site of BACE1. The QTAIM study has allowed us to obtain an excellent correlation between the electronic densities and the experimental data of IC
50 . Also, using combined techniques (MD simulations and QTAIM calculations) enabled us to describe in detail the molecular interactions that stabilize the different L-R complexes. In addition, our results allowed us to determine what portion of these compounds should be changed in order to increase their affinity with the BACE1. Another interesting result is that a sort of synergism was observed when the effects of these new catalytic site inhibitors were combined with Ac-Tyr5-Pro6-Tyr7-Asp8-Ile9-Pro10-Leu11-NH2 , which we have recently reported as a modulator of BACE1 acting on its exosite.- Published
- 2019
- Full Text
- View/download PDF
37. Searching for improved mimetic peptides inhibitors preventing conformational transition of amyloid-β 42 monomer.
- Author
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Gera J, Szögi T, Bozsó Z, Fülöp L, Barrera EE, Rodriguez AM, Méndez L, Delpiccolo CML, Mata EG, Cioffi F, Broersen K, Paragi G, and Enriz RD
- Subjects
- Amyloid beta-Peptides chemistry, Amyloid beta-Peptides metabolism, Cell Line, Tumor, Humans, Molecular Docking Simulation, Oligopeptides chemical synthesis, Oligopeptides metabolism, Oligopeptides toxicity, Peptide Fragments chemistry, Peptide Fragments metabolism, Peptidomimetics chemical synthesis, Peptidomimetics metabolism, Peptidomimetics toxicity, Protein Binding, Amyloid beta-Peptides antagonists & inhibitors, Oligopeptides pharmacology, Peptide Fragments antagonists & inhibitors, Peptidomimetics pharmacology, Protein Conformation, alpha-Helical drug effects
- 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 Aβ42 aggregation as demonstrated by thioflavin T fluorescence, acting also as an inhibitor of the cytotoxicity exerted by Aβ42 aggregates. The early stage interaction between compound 7 and the Aβ42 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 Aβ42 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., (Copyright © 2018 Elsevier Inc. All rights reserved.)- Published
- 2018
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38. Antinociceptive effect of neo-clerodane diterpenes obtained from Baccharis flabellata.
- Author
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Funes M, Garro MF, Tosso RD, Maria AO, Saad JR, and Enriz RD
- Subjects
- Analgesics pharmacology, Animals, Argentina, Diterpenes, Clerodane pharmacology, Female, Male, Mice, Molecular Docking Simulation, Molecular Structure, Phytochemicals isolation & purification, Phytochemicals pharmacology, Plant Components, Aerial chemistry, Plant Extracts chemistry, Plants, Medicinal chemistry, Seasons, Analgesics isolation & purification, Baccharis chemistry, Diterpenes, Clerodane isolation & purification
- Abstract
We report here for the first time antinociceptive effects of extracts from Baccharis flabellata. Two extracts in this analysis, one obtained in summer and the other during winter time. Our results indicate that both extract show strong antinociceptive effects, being the extracts obtained during the summer significantly more active. Our results suggest that this activity is mainly due to the presence of the diene-acid clerodane ent-15,16-epoxy-19-hydroxy-1,3,13(16),14-clerodatetraen-18-oic acid (DAC) and its dimer called DACD. Employing naloxone as an antagonist of opioid receptors, we demonstrated that both compounds act on opioid receptors, being the antinociceptive effect of DACD stronger than DAC. Thus, the antinociceptive activity of DACD was almost two times stronger than DAC (44.8 over 24.6 s in the hot-plate test) after one hour of treatments. In order to better understand the mechanism of action at molecular level of these compounds, we conducted a molecular modeling study analyzing the molecular interactions of DAC and DACD complexes with the κ-ORs. Our results suggest interactions for both DAC and DACD with Gln115, Val118, Tyr119, Asn122 and Tyr313 stabilizing their complexes; however, these interactions are significantly stronger for DACD with respect to DAC. This finding could explain why DACD have a higher affinity for the κ-ORs. These results are in agreement with the obtained antinociceptive effect. In addition, our results indicate that these neoclerodanes would have a mechanism of action similar to that of salvinorin A; such information can be very useful for the design of new inhibitors of κ-ORs., (Copyright © 2018 Elsevier B.V. All rights reserved.)
- Published
- 2018
- Full Text
- View/download PDF
39. Theoretical models to predict the inhibitory effect of ligands of sphingosine kinase 1 using QTAIM calculations and hydrogen bond dynamic propensity analysis.
- Author
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Vettorazzi M, Menéndez C, Gutiérrez L, Andujar S, Appignanesi G, and Enriz RD
- Subjects
- Catalytic Domain, Hydrogen Bonding, Kinetics, Ligands, Protein Binding, Structure-Activity Relationship, Thermodynamics, Molecular Docking Simulation methods, Phosphotransferases (Alcohol Group Acceptor) antagonists & inhibitors, Phosphotransferases (Alcohol Group Acceptor) chemistry, Protein Kinase Inhibitors chemistry, Quantum Theory
- Abstract
We report here the results of two theoretical models to predict the inhibitory effect of inhibitors of sphingosine kinase 1 that stand on different computational basis. The active site of SphK1 is a complex system and the ligands under the study possess a significant conformational flexibility; therefore for our study we performed extended simulations and proper clusterization process. The two theoretical approaches used here, hydrogen bond dynamics propensity analysis and Quantum Theory of Atoms in Molecules (QTAIM) calculations, exhibit excellent correlations with the experimental data. In the case of the hydrogen bond dynamics propensity analysis, it is remarkable that a rather simple methodology with low computational requirements yields results in excellent accord with experimental data. In turn QTAIM calculations are much more computational demanding and are also more complex and tedious for data analysis than the hydrogen bond dynamic propensity analysis. However, this greater computational effort is justified because the QTAIM study, in addition to giving an excellent correlation with the experimental data, also gives us valuable information about which parts or functional groups of the different ligands are those that should be replaced in order to improve the interactions and thereby to increase the affinity for SphK1. Our results indicate that both approaches can be very useful in order to predict the inhibiting effect of new compounds before they are synthesized.
- Published
- 2018
- Full Text
- View/download PDF
40. Small Cationic Peptides: Influence of Charge on Their Antimicrobial Activity.
- Author
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López Cascales JJ, Zenak S, García de la Torre J, Lezama OG, Garro A, and Enriz RD
- Abstract
The first stage of the action mechanism of small cationic peptides with antimicrobial activity is ruled by electrostatic interactions between the peptide and the pathogen cell membrane. Thus, an increase in its activity could be expected with an increase in the positive charge on the peptide. By contrast, the opposite behavior has been observed when the charge increases to reach a critical value, beyond which the activity falls. This work studies the perturbation effects in a cell membrane model for two small cationic peptides with similar length and morphology but with different cationic charges. The synthesis and antibacterial activity of the two peptides used in this study are described. The thermodynamic study associated with the insertion of these peptides into the membrane and the perturbing effects on the bilayer structure provide valuable insights into the molecular action mechanism associated with the charge of these small cationic peptides., Competing Interests: The authors declare no competing financial interest.
- Published
- 2018
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41. The Antimicrobial Activity of Annona emarginata (Schltdl.) H. Rainer and Most Active Isolated Compounds against Clinically Important Bacteria.
- Author
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Dolab JG, Lima B, Spaczynska E, Kos J, Cano NH, Feresin G, Tapia A, Garibotto F, Petenatti E, Olivella M, Musiol R, Jampilek J, and Enriz RD
- Subjects
- Argentina, Flowers chemistry, Gram-Negative Bacteria drug effects, Gram-Positive Bacteria drug effects, Klebsiella pneumoniae drug effects, Medicine, Traditional, Methicillin-Resistant Staphylococcus aureus drug effects, Microbial Sensitivity Tests, Plant Bark chemistry, Plant Leaves chemistry, Annona chemistry, Anti-Infective Agents chemistry, Anti-Infective Agents pharmacology, Plant Extracts chemistry, Plant Extracts pharmacology
- Abstract
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.
- Published
- 2018
- Full Text
- View/download PDF
42. Cholinesterase-inhibitory effect and in silico analysis of alkaloids from bulbs of Hieronymiella species.
- Author
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Ortiz JE, Garro A, Pigni NB, Agüero MB, Roitman G, Slanis A, Enriz RD, Feresin GE, Bastida J, and Tapia A
- Subjects
- Acetylcholinesterase chemistry, Acetylcholinesterase metabolism, Argentina, Butyrylcholinesterase chemistry, Butyrylcholinesterase metabolism, Cholinesterase Inhibitors chemistry, Computer Simulation, Drug Evaluation, Preclinical methods, Gas Chromatography-Mass Spectrometry, Models, Molecular, Plant Extracts chemistry, Plant Extracts pharmacology, Plant Roots chemistry, Amaryllidaceae chemistry, Amaryllidaceae Alkaloids chemistry, Amaryllidaceae Alkaloids pharmacology, Cholinesterase Inhibitors pharmacology
- 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 (IC
50 = 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., (Copyright © 2017 Elsevier GmbH. All rights reserved.)- Published
- 2018
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43. Synthesis, Analysis, Cholinesterase-Inhibiting Activity and Molecular Modelling Studies of 3-(Dialkylamino)-2-hydroxypropyl 4-[(Alkoxy-carbonyl)amino]benzoates and Their Quaternary Ammonium Salts.
- Author
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Padrtova T, Marvanova P, Odehnalova K, Kubinova R, Parravicini O, Garro A, Enriz RD, Humpa O, Oravec M, and Mokry P
- Subjects
- Acetylcholinesterase, Benzoates chemical synthesis, Butyrylcholinesterase, Cholinesterase Inhibitors chemical synthesis, Enzyme Activation drug effects, Models, Chemical, Protein Binding, Quaternary Ammonium Compounds chemical synthesis, Benzoates chemistry, Benzoates pharmacology, Chemistry Techniques, Synthetic, Cholinesterase Inhibitors chemistry, Cholinesterase Inhibitors pharmacology, Models, Molecular, Quaternary Ammonium Compounds chemistry, Quaternary Ammonium Compounds pharmacology, Salts chemistry
- Abstract
Tertiary amines 3-(dialkylamino)-2-hydroxypropyl 4-[(alkoxycarbonyl)amino]benzoates and their quaternary ammonium salts were synthesized. The final step of synthesis of quaternary ammonium salts was carried out by microwave-assisted synthesis. Software-calculated data provided the background needed to compare fifteen new resulting compounds by their physicochemical properties. The acid dissociation constant (p K
a ) and lipophilicity index (log P ) of tertiary amines were determined; while quaternary ammonium salts were characterized by software-calculated lipophilicity index and surface tension. Biological evaluation aimed at testing acetylcholinesterase and butyrylcholinesterase-inhibiting activity of synthesized compounds. A possible mechanism of action of these compounds was determined by molecular modelling study using combined techniques of docking; molecular dynamics simulations and quantum mechanics calculations., Competing Interests: The authors declare no conflict of interest.- Published
- 2017
- Full Text
- View/download PDF
44. An integrative study to identify novel scaffolds for sphingosine kinase 1 inhibitors.
- Author
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Vettorazzi M, Angelina E, Lima S, Gonec T, Otevrel J, Marvanova P, Padrtova T, Mokry P, Bobal P, Acosta LM, Palma A, Cobo J, Bobalova J, Csollei J, Malik I, Alvarez S, Spiegel S, Jampilek J, and Enriz RD
- Subjects
- Dose-Response Relationship, Drug, Models, Molecular, Molecular Structure, Phosphotransferases (Alcohol Group Acceptor) metabolism, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors chemistry, Quantum Theory, Structure-Activity Relationship, Phosphotransferases (Alcohol Group Acceptor) antagonists & inhibitors, Protein Kinase Inhibitors pharmacology
- 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., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF
45. Tetrahydroisoquinolines functionalized with carbamates as selective ligands of D2 dopamine receptor.
- Author
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Parravicini O, Bogado ML, Rojas S, Angelina EL, Andujar SA, Gutierrez LJ, Cabedo N, Sanz MJ, López-Gresa MP, Cortes D, and Enriz RD
- Subjects
- Humans, Ligands, Receptors, Dopamine D1 antagonists & inhibitors, Carbamates pharmacology, Molecular Docking Simulation, Molecular Dynamics Simulation, Receptors, Dopamine D1 agonists, Receptors, Dopamine D2 agonists, Tetrahydroisoquinolines pharmacology
- Abstract
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.
- Published
- 2017
- Full Text
- View/download PDF
46. Molecular design and synthesis of novel peptides from amphibians skin acting as inhibitors of cholinesterase enzymes.
- Author
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Siano A, Garibotto FF, Andujar SA, Baldoni HA, Tonarelli GG, and Enriz RD
- Subjects
- Amino Acid Sequence, Animals, Anura, Cholinesterase Inhibitors chemical synthesis, Drug Design, Humans, Molecular Docking Simulation, Molecular Dynamics Simulation, Peptides chemical synthesis, Solid-Phase Synthesis Techniques methods, Structure-Activity Relationship, Acetylcholinesterase chemistry, Amphibian Proteins chemistry, Butyrylcholinesterase chemistry, Cholinesterase Inhibitors chemistry, Peptides chemistry
- Abstract
Cholinesterases are a family of enzymes that catalyze the hydrolysis of neurotransmitter acetylcholine. There are two types of cholinesterases, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), which differ in their distribution in the body. Currently, cholinesterase inhibitors (ChEI) represent the treatment of choice for Alzheimer's disease (AD). In this paper, we report the synthesis and inhibitory effect on both enzymes of four new peptides structurally related to P1-Hp-1971 (amphibian skin peptide found in our previous work. Sequence: TKPTLLGLPLGAGPAAGPGKR-NH
2 ). The bioassay data and cytotoxicity test show that some of the compounds possess a significant AChE and BChE inhibition and no toxic effect. The present work demonstrates that diminution of the size of the original peptide could potentially result in new compounds with significant cholinesterase inhibition activity, although it appears that there is an optimal size for the sequence. We also conducted an exhaustive molecular modeling study to better understand the mechanism of action of these compounds by combining docking techniques with molecular dynamics simulations on BChE. This is the first report about amphibian peptides and the second one of natural peptides with ChE inhibitory activity. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd., (Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.)- Published
- 2017
- Full Text
- View/download PDF
47. New small-size peptides modulators of the exosite of BACE1 obtained from a structure-based design.
- Author
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Gutierrez LJ, Angelina E, Gyebrovszki A, Fülöp L, Peruchena N, Baldoni HA, Penke B, and Enriz RD
- Subjects
- Humans, Molecular Conformation, Molecular Docking Simulation, Molecular Dynamics Simulation, Protein Interaction Domains and Motifs, Quantitative Structure-Activity Relationship, Amyloid Precursor Protein Secretases chemistry, Aspartic Acid Endopeptidases chemistry, Binding Sites, Drug Design, Models, Molecular, Peptides chemistry
- Abstract
We report here two new small-size peptides acting as modulators of the β-site APP cleaving enzyme 1 (BACE1) exosite. Ac-YPYFDPL-NH2 and Ac-YPYDIPL-NH2 displayed a moderate but significant inhibitory effect on BACE1. These peptides were obtained from a molecular modeling study. By combining MD simulations with ab initio and DFT calculations, a simple and generally applicable procedure to evaluate the binding energies of small-size peptides interacting with the exosite of the BACE1 is reported here. The structural aspects obtained for the different complexes were analyzed providing a clear picture about the binding interactions of these peptides. These interactions have been investigated within the framework of the density functional theory and the quantum theory of atoms in molecules using a reduced model. Although the approach used here was traditionally applied to the study of noncovalent interactions in small molecules complexes in gas phase, we show, through in this work, that this methodology is also a very powerful tool for the study of biomolecular complexes, providing a very detailed description of the binding event of peptides modulators at the exosite of BACE1.
- Published
- 2017
- Full Text
- View/download PDF
48. Dopaminergic isoquinolines with hexahydrocyclopenta[ij]-isoquinolines as D2-like selective ligands.
- Author
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Párraga J, Andujar SA, Rojas S, Gutierrez LJ, El Aouad N, Sanz MJ, Enriz RD, Cabedo N, and Cortes D
- Subjects
- Dopamine Agents metabolism, Dopamine Agents toxicity, Human Umbilical Vein Endothelial Cells drug effects, Humans, Isoquinolines metabolism, Isoquinolines toxicity, Ligands, Models, Molecular, Oxygen chemistry, Protein Conformation, Receptors, Dopamine D2 chemistry, Structure-Activity Relationship, Substrate Specificity, Cyclopentanes chemistry, Dopamine Agents chemistry, Dopamine Agents pharmacology, Isoquinolines chemistry, Isoquinolines pharmacology, Receptors, Dopamine D2 metabolism
- Abstract
Dopamine receptors (DR) ligands are potential drug candidates for treating neurological disorders including schizophrenia or Parkinson's disease. Three series of isoquinolines: (E)-1-styryl-1,2,3,4-tetrahydroisoquinolines (series 1), 7-phenyl-1,2,3,7,8,8a-hexahydrocyclopenta[ij]-IQs (HCPIQs) (series 2) and (E)-1-(prop-1-en-1-yl)-1,2,3,4- tetrahydroisoquinolines (series 3), were prepared to determine their affinity for both D1 and D2-like DR. The effect of different substituents on the nitrogen atom (methyl or allyl), the dioxygenated function (methoxyl or catechol), the substituent at the β-position of the THIQ skeleton, and the presence or absence of the cyclopentane motif, were studied. We observed that the most active compounds in the three series (2c, 2e, 3a, 3c, 3e, 5c and 5e) possessed a high affinity for D2-like DR and these remarkable features: a catechol group in the IQ-ring and the N-substitution (methyl or allyl). The series showed the following trend to D2-RD affinity: HCPIQs > 1-styryl > 1-propenyl. Therefore, the substituent at the β-position of the THIQ and the cyclopentane ring also modulated this affinity. Among these dopaminergic isoquinolines, HCPIQs stood out for unexpected selectivity to D2-DR since the Ki D1/D2 ratio reached values of 2465, 1010 and 382 for compounds 3a, 3c and 3e, respectively. None of the most active THIQs in D2 DR displayed relevant cytotoxicity in human neutrophils and HUVEC. Finally, and in agreement with the experimental data, molecular modeling studies on DRs of the most characteristic ligands of the three series revealed stronger molecular interactions with D2 DR than with D1 DR, which further supports to the encountered enhanced selectivity to D2 DR., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)
- Published
- 2016
- Full Text
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49. The Eighth Central European Conference "Chemistry towards Biology": Snapshot.
- Author
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Perczel A, Atanasov AG, Sklenář V, Nováček J, Papoušková V, Kadeřávek P, Žídek L, Kozłowski H, Wątły J, Hecel A, Kołkowska P, Koča J, Svobodová-Vařeková R, Pravda L, Sehnal D, Horský V, Geidl S, Enriz RD, Matějka P, Jeništová A, Dendisová M, Kokaislová A, Weissig V, Olsen M, Coffey A, Ajuebor J, Keary R, Sanz-Gaitero M, van Raaij MJ, McAuliffe O, Waltenberger B, Mocan A, Šmejkal K, Heiss EH, Diederich M, Musioł R, Košmrlj J, Polański J, and Jampílek J
- Subjects
- Drug Delivery Systems, Drug Design, Epigenesis, Genetic, Structure-Activity Relationship, Systems Biology, Chemistry, Pharmaceutical methods, Proteins chemistry
- Abstract
The Eighth Central European Conference "Chemistry towards Biology" was held in Brno, Czech Republic, on August 28-September 1, 2016 to bring together experts in biology, chemistry and design of bioactive compounds; promote the exchange of scientific results, methods and ideas; and encourage cooperation between researchers from all over the world. The topics of the conference covered "Chemistry towards Biology", meaning that the event welcomed chemists working on biology-related problems, biologists using chemical methods, and students and other researchers of the respective areas that fall within the common scope of chemistry and biology. The authors of this manuscript are plenary speakers and other participants of the symposium and members of their research teams. The following summary highlights the major points/topics of the meeting., Competing Interests: The authors declare no conflict of interest.
- Published
- 2016
- Full Text
- View/download PDF
50. Alkaloids from Hippeastrum argentinum and Their Cholinesterase-Inhibitory Activities: An in Vitro and in Silico Study.
- Author
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Ortiz JE, Pigni NB, Andujar SA, Roitman G, Suvire FD, Enriz RD, Tapia A, Bastida J, and Feresin GE
- Subjects
- Amaryllidaceae Alkaloids chemistry, Amaryllidaceae Alkaloids isolation & purification, Argentina, Gas Chromatography-Mass Spectrometry, Inhibitory Concentration 50, Models, Molecular, Molecular Structure, Nuclear Magnetic Resonance, Biomolecular, Plant Roots chemistry, Amaryllidaceae Alkaloids pharmacology, Butyrylcholinesterase drug effects
- Abstract
Two new alkaloids, 4-O-methylnangustine (1) and 7-hydroxyclivonine (2) (montanine and homolycorine types, respectively), and four known alkaloids were isolated from the bulbs of Hippeastrum argentinum, and their cholinesterase-inhibitory activities were evaluated. These compounds were identified using GC-MS, and their structures were defined by physical data analysis. Compound 2 showed weak butyrylcholinesterase (BuChE)-inhibitory activity, with a half-maximal inhibitory concentration (IC50) value of 67.3 ± 0.09 μM. To better understand the experimental results, a molecular modeling study was also performed. The combination of a docking study, molecular dynamics simulations, and quantum theory of atoms in molecules calculations provides new insight into the molecular interactions of compound 2 with BuChE, which were compared to those of galantamine.
- Published
- 2016
- Full Text
- View/download PDF
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