321 results on '"Eliezer J Barreiro"'
Search Results
2. LASSBio-596: a New Pre-clinical Candidate for Rheumatoid Arthritis?
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Elane Conceição dos Santos, Magna Suzana Alexandre-Moreira, Alyne Almeida de Lima, Eliane Aparecida Campesatto, Anderson Brandão Leite, Suellen Maria Albuquerque da Silva, Eliezer J. Barreiro, Geraldo José da Silva Neto, Lídia Moreira Lima, Ênio José Bassi, Aline Cavalcanti de Queiroz, and Max Denisson Maurício Viana
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medicine.medical_specialty ,medicine.drug_class ,Immunology ,Anti-Inflammatory Agents ,Phthalic Acids ,Pain ,Arthritis ,Peritonitis ,Context (language use) ,Pharmacology ,Anti-inflammatory ,Arthritis, Rheumatoid ,Internal medicine ,medicine ,Edema ,Humans ,Immunology and Allergy ,Hot plate test ,Analgesics ,Sulfonamides ,Plant Extracts ,business.industry ,medicine.disease ,Rheumatology ,Nociception ,Rheumatoid arthritis ,business - Abstract
Pain and inflammatory disorders are significant health problems because of prevalence and associated disabilities. In this context, LASSBio-596 is a hybrid compound able to modulate TNF-α and phosphodiesterases 4 and 5, exhibiting an anti-inflammatory effect in the pulmonary inflammatory model. Aiming at a better description of the activities of LASSBio-596, we initially conducted nociception tests (acetic acid-induced abdominal writhing, glutamate, and formalin-induced nociception and hot plate test) and later inflammatory tests (acute, peritonitis; and chronic, arthritis) that directed us to this last one. In the abdominal writhing test, there was a dose-dependent inhibition, whose response occurred at the maximum dose (50 mg/kg, p.o.), used in the subsequent tests. LASSBio-596 also inhibited nociception induced by chemical (glutamate by 31.9%; and formalin, in both phases, 1st phase: 25.7%; 2nd phase: 23.9%) and thermal agents (hotplate, by increased latency for pain at two different times). These effects were independent of the motor function, legitimated in rotarod. As there was a response in the inflammatory component of nociception, we performed the peritonitis test, in which migration was inhibited by LASSBio-596 by 39.9%. As the inflammatory process is present in autoimmune diseases, we also performed the arthritis test. LASSBio-596 reduced paw edema from the 15th day to the 21st day of treatment (no liver changes and with fewer paw injuries). In addition, LASSBio-596 decreased serum levels of TNF-α by 67.1%. These data demonstrated the antinociceptive effect of LASSBio-596 and reinforces its anti-inflammatory property (i.e., RA), amplifying the therapeutic potential of this molecule.
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- 2021
3. Abstract P2037: Activation Of A2A Adenosine Receptor Reduces Cardiac Dysfunction Resulting From Pulmonary Hypertension In Rats
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Jaqueline S Da Silva, Bruna Rocha, Gabriel F Gomide, Bianca Nascimento-Carlos, Tadeu Montagnoli, Bruno E Dematté, Rodolfo Maia, Eliezer J Barreiro, and Gisele Zapata-Sudo
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Physiology ,Cardiology and Cardiovascular Medicine - Abstract
Pulmonary hypertension (PH) is characterized by extensive pulmonary vascular remodeling, leading to right ventricle (RV) hypertrophy and dysfunction. This work evaluates the hypothesis that the activation of adenosine A2A receptor (AR-A2) by LASBio-1900 could interfere with the cardiac and vascular dysfunction on monocrotaline (MCT)-induced PH in rats. After 14 days of PH induction using a single injection of MCT (60 mg/kg i.p.), twelve male Wistar rats were randomly divided in groups and treated orally either with vehicle or LASSBio-1900 (180 μmol/kg/day). Hemodynamic parameters were obtained using the echocardiography and summarized in table 1. LASSBio-1900 reduced RV hypertrophy observed in PH because the Fulton index altered from 55.4 ± 2.3 to 35.3 ± 5.9% (p In conclusion, the agonist of AR-A2, named LASSBio-1900 improved RV function and pulmonary structural alteration in PH, indicating a new alternative for treatment of PH-induced RV dysfunction.
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- 2022
4. Abstract P1054: Oral Administration Of New Agonist Of Adenosine Receptor Reduces Inflammatory Process And Cardiac Remodeling Induced By Myocardial Infarction In Rats
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Bianca Nascimento-Carlos, Jaqueline S Da Silva, Bruna Rocha, Tadeu Montagnoli, Rodolfo Maia, Eliezer J Barreiro, and Gisele Zapata-Sudo
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Physiology ,Cardiology and Cardiovascular Medicine - Abstract
Treatment of acute myocardial infarction (AMI) is based on strategies to relief pain and increase survival. Thus, this work investigates the effects of a new agonist of adenosine receptor called LASSBio-1860 in an experimental model of AMI, in order to improve cardiac function. The protocols were approved by the Ethics Committee for the Use of Animals at Federal University of Rio de Janeiro (# 103/17). The experimental AMI was induced by the ligation of the anterior descending coronary artery in male Wistar rats (180-200 g), which were randomly divided into groups treated orally with vehicle (DMSO) or 70 μmol/kg of LASSBio-1860 for 7 days. At the end of the experimental protocol, hemodynamic parameters were obtained using echocardiography and the expression of markers involved in the inflammatory pathway (TNF-alpha, p38) and cardiac remodeling (p-ERK-1/2 and t-ERK) was evaluated. AMI increased the left ventricular (LV) wall thickness from 0.11 ± 0.04 to 0.29 ± 0.02 cm (p
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- 2022
5. Methyl Effect on the Metabolism, Chemical Stability, and Permeability Profile of Bioactive
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Jéssica de Siqueira, Guedes, Teiliane Rodrigues, Carneiro, Pedro de Sena Murteira, Pinheiro, Carlos Alberto Manssour, Fraga, Carlos Mauricio R, Sant Anna, Eliezer J, Barreiro, and Lídia Moreira, Lima
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Sulfonylhydrazones are privileged structures with multifaceted pharmacological activity. Exploring the hypoglycemic properties of these organic compounds, we previously revealed a new series of
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- 2022
6. Discovery of Putative Dual Inhibitor of Tubulin and EGFR by Phenotypic Approach on LASSBio-1586 Homologs
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Gisele Barbosa, Luis Gabriel Valdivieso Gelves, Caroline Marques Xavier Costa, Lucas Silva Franco, João Alberto Lins de Lima, Cristiane Aparecida-Silva, John Douglas Teixeira, Claudia dos Santos Mermelstein, Eliezer J. Barreiro, and Lidia Moreira Lima
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Drug Discovery ,Pharmaceutical Science ,Molecular Medicine ,tubulin ,microtubules ,homologs ,EGFR ,phenotypic assay - Abstract
Combretastatin A-4 (CA-4, 1) is an antimicrotubule agent used as a prototype for the design of several synthetic analogues with anti-tubulin activity, such as LASSBio-1586 (2). A series of branched and unbranched homologs of the lead-compound 2, and vinyl, ethinyl and benzyl analogues, were designed and synthesized. A comparison between the cytotoxic effect of these homologs and 2 on different human tumor cell lines was performed from a cell viability study using MTT with 48 h and 72 h incubations. In general, the compounds were less potent than CA-4, showing CC50 values ranging from 0.030 μM to 7.53 μM (MTT at 72 h) and 0.096 μM to 8.768 μM (MTT at 48 h). The antimitotic effect of the target compounds was demonstrated by cell cycle analysis through flow cytometry, and the cellular mechanism of cytotoxicity was determined by immunofluorescence. While the benzyl homolog 10 (LASSBio-2070) was shown to be a microtubule stabilizer, the lead-compound 2 (LASSBio-1586) and the methylated homolog 3 (LASSBio-1735) had microtubule destabilizing behavior. Molecular docking studies were performed on tubulin protein to investigate their binding mode on colchicine and taxane domain. Surprisingly, the benzyl homolog 10 was able to modulate EGFR phosphorylate activity in a phenotypic model. These data suggest LASSBio-2070 (10) as a putative dual inhibitor of tubulin and EGFR. Its binding mode with EGFR was determined by molecular docking and may be useful in lead-optimization initiatives.
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- 2022
7. In Mice Evaluation of Antinociceptive and Anti-inflammatory Activity of N-acylhydrazone Derivative LASSBio-1587
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Juliane C. Silva, Raimundo G. Oliveira-Júnior, Mariana G. Silva, Erica M. Lavor, Juliana M. D. Soares, Sarah R. G. Lima-Saraiva, Tâmara C. Diniz, Maria Alice M. B. Medeiros, Lídia M. Lima, Eliezer J. Barreiro, and Jackson Roberto G. S. Almeida
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General Chemistry - Published
- 2021
8. New Benzofuran N-Acylhydrazone Reduces Cardiovascular Dysfunction in Obese Rats by Blocking TNF-Alpha Synthesis
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Marina M. Silva, Gizele Cabral Costa, Eliezer J. Barreiro, Tadeu L Montagnoli, Pedro M. Pimentel-Coelho, Luis Eduardo Reina Gamba, Bryelle Eccard De Oliveira Alves, Margarete M. Trachez, José Nascimento, Roberto T. Sudo, Gisele Zapata-Sudo, Jaqueline S da Silva, Lídia Moreira Lima, Rosalia Mendez-Otero, and Allan K Alencar
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0301 basic medicine ,medicine.medical_specialty ,Diastole ,Cardiomyopathy ,Pharmaceutical Science ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Diabetic cardiomyopathy ,Internal medicine ,Drug Discovery ,Medicine ,Pharmacology ,Triglyceride ,business.industry ,Cholesterol ,Type 2 Diabetes Mellitus ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,chemistry ,Ventricle ,030220 oncology & carcinogenesis ,Tumor necrosis factor alpha ,business - Abstract
Introduction Diabetic obese patients are susceptible to the development of cardiovascular disease, including hypertension and cardiac dysfunction culminating in diabetic cardiomyopathy (DC), which represents a life-threatening health problem with increased rates of morbidity and mortality. The aim of the study is to characterize the effects of a new benzofuran N-acylhydrazone compound, LASSBio-2090, on metabolic and cardiovascular alterations in Zucker diabetic fatty (ZDF) rats presenting DC. Methods Male non-diabetic lean Zucker rats (ZL) and ZDF rats treated with vehicle (dimethylsulfoxide) or LASSBio-2090 were used in this study. Metabolic parameters, cardiovascular function, left ventricle histology and inflammatory protein expression were analyzed in the experimental groups. Results LASSBio-2090 administration in ZDF rats reduced glucose levels to 85.0 ± 1.7 mg/dL (p < 0.05). LASSBio-2090 also lowered the cholesterol and triglyceride levels from 177.8 ± 31.2 to 104.8 ± 5.3 mg/dL and from 123.0 ± 11.4 to 90.9 ± 4.8 mg/dL, respectively, in obese diabetic rats (p < 0.05). LASSBio-2090 normalized plasma insulin, insulin sensitivity and endothelial function in aortas from diabetic animals (p < 0.05). It also enhanced systolic and diastolic left-ventricular function and reverted myocardial remodeling by blocking the threefold elevation of TNF-α levels in hearts from ZDF rats. Conclusion LASSBio-2090 alleviates metabolic disturbance and cardiomyopathy in an obese and diabetic rat model, thus representing a novel strategy for the treatment of cardiovascular complications in obesity-associated type 2 diabetes mellitus.
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- 2020
9. Bioisosteric Replacement of Arylamide-Linked Spine Residues with N-Acylhydrazones and Selenophenes as a Design Strategy to Novel Dibenzosuberone Derivatives as Type I 1/2 p38α MAP Kinase Inhibitors
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Philipp Nahidino, Stefan Laufer, Tatu Pantsar, Benedict-Tilman Berger, Eliezer J. Barreiro, Mark Kudolo, Stefan Knapp, Michael Forster, and Júlia Galvez Bulhões Pedreira
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chemistry.chemical_classification ,0303 health sciences ,biology ,P38α mapk ,Stereochemistry ,Dibenzosuberone ,Metabolic stability ,01 natural sciences ,3. Good health ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,03 medical and health sciences ,Enzyme ,chemistry ,Mitogen-activated protein kinase ,Drug Discovery ,biology.protein ,Molecular Medicine ,Structure–activity relationship ,030304 developmental biology ,SPINE (molecular biology) ,Whole blood - Abstract
The recent disclosure of type I 1/2 inhibitors for p38α MAPK demonstrated how the stabilization of the R-spine can be used as a strategy to greatly increase the target residence time (TRT) of inhibitors. Herein, for the first time, we describe N-acylhydrazone and selenophene residues as spine motifs, yielding metabolically stable inhibitors with high potency on enzymatic, NanoBRET, and whole blood assays, improved metabolic stability, and prolonged TRT.
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- 2020
10. Carbamoyl-N-aryl-imine-urea: a new framework to obtain a putative leishmanicidal drug-candidate
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Lídia Moreira Lima, Magna Suzana Alexandre-Moreira, Felipe T. Martins, Antonio C. Doriguetto, Marina Amaral Alves, Aline Cavalcanti de Queiroz, Anderson Brandão Leite, and Eliezer J. Barreiro
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0303 health sciences ,Miltefosine ,Chemistry ,General Chemical Engineering ,Meglumine antimoniate ,Leishmaniasis ,General Chemistry ,Pharmacology ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,Cutaneous leishmaniasis ,030220 oncology & carcinogenesis ,Toxicity ,medicine ,Amastigote ,Cytotoxicity ,030304 developmental biology ,Pentamidine ,medicine.drug - Abstract
Leishmaniasis is a neglected parasitic disease, and current treatment includes limitations of toxicity, variable efficacy, high costs and inconvenient doses and treatment schedules. Therefore, new leishmanicidal drugs are still an unquestionable medical need. In this paper we described the design conception of a new framework, the carbamoyl-N-aryl-imine-urea, to obtain putative leishmanicidal drug-candidates. Compounds 9a–e and 10a–e were designed and synthesized and their leishmanicidal activity was studied in comparison to pentamidine, miltefosine and meglumine antimoniate. The conformational profile of the new carbamoyl-N-aryl-imine-urea framework was investigated by X-ray diffraction studies, using compound 9a as a model. The plasma stability of this putative peptide mimetic subunit was studied for compound 10e (LASSBio-1736). Among the congeneric series, LASSBio-1736 was identified as a new antileishmanial drug-candidate, displaying plasma stability, cytotoxicity against amastigote forms of L. amazonensis and L. braziliensis, and leishmanicidal activity in a cutaneous leishmaniasis murine model, without preliminary evidence of hepatic or renal toxicity.
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- 2020
11. Comparative chemical and biological hydrolytic stability of homologous esters and isosteres
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Hygor M. R. de Souza, Jéssica S. Guedes, Rosana H. C. N. Freitas, Luis G. V. Gelves, Harold H. Fokoue, Carlos Mauricio R. Sant’Anna, Eliezer J. Barreiro, and Lidia M. Lima
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Pharmacology ,Male ,Models, Molecular ,Dose-Response Relationship, Drug ,Molecular Structure ,Hydrolysis ,Esters ,General Medicine ,Carboxylesterase ,Rats ,Structure-Activity Relationship ,Drug Discovery ,Microsomes, Liver ,Animals ,Prodrugs ,Enzyme Inhibitors ,Rats, Wistar - Abstract
Esters are one of the major functional groups present in the structures of prodrugs and bioactive compounds. Their presence is often associated with hydrolytic lability. In this paper, we describe a comparative chemical and biological stability of homologous esters and isosteres in base media as well as in rat plasma and rat liver microsomes. Our results provided evidence for the hydrolytic structure lability relationship and demonstrated that the hydrolytic stability in plasma and liver microsome might depend on carboxylesterase activity. Molecular modelling studies were performed in order to understand the experimental data. Taken together, the data could be useful to design bioactive compounds or prodrugs based on the correct choice of the ester subunit, addressing compounds with higher or lower metabolic lability.
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- 2022
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12. Reduction of cardiac and renal dysfunction by new inhibitor of DPP4 in diabetic rats
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Margarete M. Trachez, Lídia Moreira Lima, Roberto T. Sudo, Rosalia Mendez-Otero, Josenildo S Araujo, Luiza V.P. Mendes, Tadeu L Montagnoli, Gisele Zapata-Sudo, Allan K Alencar, Eliezer J. Barreiro, Pedro M. Pimentel-Coelho, Valéria M.N. Cunha, Luis Eduardo Reina Gamba, Bryelle Eccard De Oliveira Alves, Jaqueline S da Silva, and Gláucia Maria Moraes de Oliveira
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Male ,endocrine system diseases ,Dipeptidyl Peptidase 4 ,Type 2 diabetes ,Pharmacology ,Streptozocin ,Diabetes Mellitus, Experimental ,Ventricular Dysfunction, Left ,03 medical and health sciences ,0302 clinical medicine ,Pharmacotherapy ,Glucagon-Like Peptide 1 ,Metabolic disturbance ,medicine ,Animals ,Rats, Wistar ,Endothelial dysfunction ,Dipeptidyl-Peptidase IV Inhibitors ,Experimental model ,business.industry ,Sitagliptin Phosphate ,nutritional and metabolic diseases ,Type 2 Diabetes Mellitus ,Heart ,General Medicine ,medicine.disease ,Streptozotocin ,Rats ,Diabetes Mellitus, Type 2 ,030220 oncology & carcinogenesis ,Sitagliptin ,Kidney Diseases ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Increased mortality due to type 2 diabetes mellitus (T2DM) has been associated with renal and/or cardiovascular dysfunction. Dipeptidyl dipeptidase-4 inhibitors (iDPP-4s) may exert cardioprotective effects through their pleiotropic actions via glucagon-like peptide 1-dependent mechanisms. In this study, the pharmacological profile of a new iDPP-4 (LASSBio-2124) was investigated in rats with cardiac and renal dysfunction induced by T2DM.T2DM was induced in rats by 2 weeks of a high-fat diet followed by intravenous injection of streptozotocin. Metabolic disturbance and cardiac, vascular, and renal dysfunction were analyzed in the experimental groups.Sitagliptin and LASSBio-2124 administration after T2DM induction reduced elevated glucose levels to 319.8 ± 13.2 and 279.7 ± 17.8 mg/dL, respectively (p 0.05). LASSBio-2124 also lowered the cholesterol and triglyceride levels from 76.8 ± 8.0 to 42.7 ± 3.2 mg/dL and from 229.7 ± 25.4 to 100.7 ± 17.1 mg/dL, in diabetic rats. Sitagliptin and LASSBio-2124 reversed the reduction of the plasma insulin level. LASSBio-2124 recovered the increased urinary flow in diabetic animals and reduced 24-h proteinuria from 23.7 ± 1.5 to 13.3 ± 2.8 mg (p 0.05). It also reduced systolic and diastolic left-ventricular dysfunction in hearts from diabetic rats.The effects of LASSBio-2124 were superior to those of sitagliptin in the cardiovascular systems of T2DM rats. This new prototype showed promise for the avoidance of comorbidities in a T2DM experimental model, and thus may constitute an innovative therapeutic agent for the treatment of these conditions in the clinical field in future.
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- 2019
13. Effect of S-Se Bioisosteric Exchange on Affinity and Intrinsic Efficacy of Novel
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Júlia Galvez Bulhões, Pedreira, Rafaela Ribeiro, Silva, François G, Noël, and Eliezer J, Barreiro
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Male ,Models, Molecular ,conformational effect ,N-methylation effect ,Adenosine A2 Receptor Agonists ,Receptor, Adenosine A2A ,Hydrazones ,Thiophenes ,Article ,A2A receptor ,Selenium ,chalcogen interaction ,Animals ,Humans ,Rats, Wistar ,N-acylhydrazone derivatives ,sulfur-selenium isosterism ,Sulfur - Abstract
In this work, we evaluated the conformational effect promoted by the isosteric exchange of sulfur by selenium in the heteroaromatic ring of new N-acylhydrazone (NAH) derivatives (3–8, 13, 14), analogues of the cardioactive compounds LASSBio-294 (1) and LASSBio-785 (2). NMR spectra analysis demonstrated a chemical shift variation of the iminic Csp2 of NAH S/Se-isosters, suggesting a stronger intramolecular chalcogen interaction for Se-derivatives. To investigate the pharmacological profile of these compounds at the adenosine A2A receptor (A2AR), we performed a previously validated functional binding assay. As expected for bioisosteres, the isosteric-S/Se replacement affected neither the affinity nor the intrinsic efficacy of our NAH derivatives (1–8). However, the N-methylated compounds (2, 6–8) presented a weak partial agonist profile at A2AR, contrary to the non-methylated counterparts (1, 3–5), which appeared as weak inverse agonists. Additionally, retroisosterism between aromatic rings of NAH on S/Se-isosters mimicked the effect of the N-methylation on intrinsic efficacy at A2AR, while meta-substitution in the phenyl ring of the acyl moiety did not. This study showed that the conformational effect of NAH-N-methylation and aromatic rings retroisosterism changed the intrinsic efficacy on A2AR, indicating the S/Se-chalcogen effect to drive the conformational behavior of this series of NAH.
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- 2021
14. Design and Synthesis In Silico Drug-like Prediction and Pharmacological Evaluation of Cyclopolymethylenic Homologous of LASSBio-1514
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Magna Suzana Alexandre-Moreira, Carlos Eduardo da Silva Monteiro, Aline Cavalcanti de Queiroz, Eliezer J. Barreiro, Lídia Moreira Lima, Walfrido Bispo Júnior, Gisele Zapata-Sudo, Cristiane Aparecida-Silva, and Tiago Fernandes da Silva
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Male ,in silico drug-like ,Indomethacin ,Anti-Inflammatory Agents ,Molecular Conformation ,Pharmaceutical Science ,Organic chemistry ,Pharmacology ,Analytical Chemistry ,chemistry.chemical_compound ,Mice ,QD241-441 ,Oral administration ,Drug Discovery ,Medicine ,pain ,media_common ,anti-inflammatory ,Analgesics ,Chronic pain ,analgesic ,Pharmaceutical Preparations ,Chemistry (miscellaneous) ,Hyperalgesia ,Molecular Medicine ,medicine.symptom ,acylhydrazone ,Drug ,medicine.drug_class ,In silico ,media_common.quotation_subject ,Analgesic ,Inflammation ,Anti-inflammatory ,Article ,Molecular modification ,Animals ,Humans ,homologation ,Computer Simulation ,Physical and Theoretical Chemistry ,Rats, Wistar ,Aspirin ,business.industry ,Hydrazones ,medicine.disease ,Molecular Weight ,chemistry ,Drug Design ,Caco-2 Cells ,business - Abstract
Acylhydrazones are still an important framework to the design of new bioactive compounds. As treatment of chronic pain represents a clinical challenge, we decided to modify the structure of LASSBio-1514 (1), previously described as anti-inflammatory and analgesic prototype. Applying the homologation as a strategy for molecular modification, we designed a series of cyclopentyl- (2a–e), cyclobutyl- (3a–e), and cyclopropylacylhydrazones (4a–e) that were synthetized and evaluated in murine models of inflammation and pain. A comparison of their in silico physicochemical and drug-like profile was conducted, as well as their anti-inflammatory and analgesic effect. Compounds 4a (LASSBio-1755) and 4e (LASSBio-1757) displayed excellent in silico drug-like profiles and were identified as new analgesic lead-candidates in acute and chronic model of pain, through oral administration.
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- 2021
15. Chemical Intuition in Drug Design and Discovery
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Júlia Galvez Bulhões Pedreira, Eliezer J. Barreiro, and Lucas S. Franco
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Drug ,0303 health sciences ,Chemical descriptors ,Molecular Structure ,Management science ,Computer science ,Drug discovery ,Chemistry, Pharmaceutical ,media_common.quotation_subject ,General Medicine ,Chemist ,01 natural sciences ,Piperazines ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,03 medical and health sciences ,Expert opinion ,Drug Discovery ,030304 developmental biology ,Intuition ,media_common - Abstract
The medicinal chemist plays the most important role in drug design, discovery and development. The primary goal is to discover leads and optimize them to develop clinically useful drug candidates. This process requires the medicinal chemist to deal with large sets of data containing chemical descriptors, pharmacological data, pharmacokinetics parameters, and in silico predictions. The modern medicinal chemist has a large number of tools and technologies to aid him in creating strategies and supporting decision-making. Alongside with these tools, human cognition, experience and creativity are fundamental to drug research and are important for the chemical intuition of medicinal chemists. Therefore, fine-tuning of data processing and in-house experience are essential to reach clinical trials. In this article, we will provide an expert opinion on how chemical intuition contributes to the discovery of drugs, discuss where it is involved in the modern drug discovery process, and demonstrate how multidisciplinary teams can create the optimal environment for drug design, discovery, and development.
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- 2019
16. Identification of LASSBio-1945 as an inhibitor of SARS-CoV-2 main protease (M
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Lucas S, Franco, Rodolfo C, Maia, and Eliezer J, Barreiro
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Chemistry - Abstract
In December 2019, an infectious disease was detected in Wuhan, China, caused by a new pathogenic coronavirus, named SARS-CoV-2. It spread very rapidly, and on March 11th of 2020, the outbreak was declared a pandemic by the World Health Organization. Currently, effective treatment options remain limited. SARS-CoV-2 enzyme main protease (M(PRO)) plays a pivotal role in the viral life cycle, making it a putative drug target. In order to identify suitable hits to develop inhibitors with adequate antiviral properties, we explored the LASSBio Chemical Library employing multiple strategies of virtual screening. A fragment-based pharmacophore model enabled the identification of key interactions involved in the molecular recognition at the catalytic site of M(PRO), namely, with amino acid residues His41, His163 and Glu166. Docking-based virtual screening was performed, leading to the identification of LASSBio-1945 (9), a new hit of M(PRO), presenting an IC(50) = 15.97 μM. This compound, an 1,3-benzodioxolyl sulfonamide, represents an interesting starting point for subsequent hit-to-lead optimization steps and, to the best of our knowledge, a new distinct chemotype for M(PRO) inhibition.
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- 2020
17. Bioisosteric Replacement of Arylamide-Linked Spine Residues with
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Júlia G B, Pedreira, Philipp, Nahidino, Mark, Kudolo, Tatu, Pantsar, Benedict-Tilman, Berger, Michael, Forster, Stefan, Knapp, Stefan, Laufer, and Eliezer J, Barreiro
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Mitogen-Activated Protein Kinase 14 ,Structure-Activity Relationship ,Time Factors ,Drug Stability ,Drug Design ,Organoselenium Compounds ,Hydrazones ,Microsomes, Liver ,Humans ,Dibenzocycloheptenes ,Amides ,Protein Kinase Inhibitors - Abstract
The recent disclosure of type I 1/2 inhibitors for p38α MAPK demonstrated how the stabilization of the R-spine can be used as a strategy to greatly increase the target residence time (TRT) of inhibitors. Herein, for the first time, we describe
- Published
- 2020
18. Novel VEGFR-2 inhibitors with an N-acylhydrazone scaffold
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Maria Claudia Barbosa, Thaysa Paschoalin, Marisa Ionta, Eliezer J. Barreiro, Fernanda P. Pauli, and Juliana Martins
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Angiogenesis ,Pharmaceutical Science ,Neovascularization, Physiologic ,Angiogenesis Inhibitors ,Chick Embryo ,01 natural sciences ,Chorioallantoic Membrane ,Neovascularization ,Structure-Activity Relationship ,Drug Discovery ,medicine ,Animals ,Molecular Targeted Therapy ,Protein Kinase Inhibitors ,Molecular Structure ,010405 organic chemistry ,Chemistry ,Hydrazones ,Kinase insert domain receptor ,Vascular Endothelial Growth Factor Receptor-2 ,In vitro ,0104 chemical sciences ,Angiogenesis inhibitor ,Molecular Docking Simulation ,010404 medicinal & biomolecular chemistry ,Chorioallantoic membrane ,Docking (molecular) ,Drug Design ,Cancer research ,medicine.symptom ,Tyrosine kinase - Abstract
Vascular endothelial growth factor receptor 2 (VEGFR-2) is a tyrosine kinase that mediates a large number of cell responses associated with angiogenesis. The control of the angiogenic pathway in tumorigenesis by the inhibition of VEGFR-2 is considered a promising therapeutic strategy for the prevention and control of solid tumor growth. In this study, the design, synthesis, and biological evaluation of a novel series of VEGFR-2 inhibitors with an N-acylhydrazone (NAH) scaffold (9a-h) are reported. The molecular design is validated by docking studies and by in vitro inhibitory activity assays. Compounds 9b, 9c, 9d, and 9f effectively inhibited neovascularization induced by VEGF in the chorioallantoic membrane assay. Thus, these NAH derivatives are promising antiangiogenic prototypes.
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- 2020
19. Carbamoyl
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Marina A, Alves, Aline C, de Queiroz, Anderson Brandão, Leite, Felipe T, Martins, Antonio C, Doriguetto, Eliezer J, Barreiro, Magna S, Alexandre-Moreira, and Lídia M, Lima
- Abstract
Leishmaniasis is a neglected parasitic disease, and current treatment includes limitations of toxicity, variable efficacy, high costs and inconvenient doses and treatment schedules. Therefore, new leishmanicidal drugs are still an unquestionable medical need. In this paper we described the design conception of a new framework, the carbamoyl
- Published
- 2020
20. Case Study on Receptor Tyrosine Kinases EGFR, VEGFR, and PDGFR
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Maria Letícia de Castro Barbosa, Lídia Moreira Lima, Eliezer J. Barreiro, and Daniel N. do Amaral
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biology ,Drug discovery ,medicine.drug_class ,Cancer ,medicine.disease ,Monoclonal antibody ,Receptor tyrosine kinase ,Immune system ,biology.protein ,Cancer research ,medicine ,Tyrosine kinase ,Platelet-derived growth factor receptor ,Intracellular - Abstract
Receptor tyrosine kinases (RTKs) are cell-surface proteins that trigger key cellular responses, such as survival, proliferation, differentiation, migration, and cell-cycle control. As increased activity, abundance, and/or cellular distribution of wild-type and mutant forms of RTKs is often associated with tumor establishment, growth, and progression, several drugs directed to clinically relevant RTKs have entered the pharmaceutical market since the beginning of the twenty-first century, representing innovative approaches for cancer treatment. The modulation strategies include small-molecule tyrosine kinase inhibitors (TKIs), targeting the ATP-binding site of the intracellular TK domain, and monoclonal antibodies directed to the extracellular domain, interfering with RTK activation and/or marking RTK-expressing cells for destruction by the immune system. Even though these drugs clearly represented an impressive breakthrough in the therapy of RTK-addicted tumors, resistance development and detection of refractory tumors have given rise to novel therapeutic challenges, pushing the drug discovery process forward. This chapter focuses particularly on the discussion of several case studies on the development of small-molecule tyrosine kinase inhibitors (TKIs) directed to EGFR, VEGFR, and PDGFR, clinically relevant RTKs, and the subset of advances in this field.
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- 2020
21. N-Acylhydrazones as drugs
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Carlos A. M. Fraga, Eliezer J. Barreiro, Daniel Alencar Rodrigues, Sreekanth Thota, Pedro de Sena Murteira Pinheiro, and Lídia Moreira Lima
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0301 basic medicine ,Drug ,Molecular Structure ,Chemistry ,Drug discovery ,media_common.quotation_subject ,Organic Chemistry ,Clinical Biochemistry ,Hydrazones ,Pharmaceutical Science ,Antineoplastic Agents ,Pharmacology ,Biochemistry ,Clinical trial ,03 medical and health sciences ,030104 developmental biology ,Neoplasms ,Drug Discovery ,Humans ,Molecular Medicine ,Molecular Biology ,media_common - Abstract
Over the last two decades, N-acylhydrazone (NAH) has been proven to be a very versatile and promising motif in drug design and medicinal chemistry. Herein, we discuss the current and future challenges in the emergence of bioactive NAH-based scaffolds and to developing strategies to overcome the failures in drug discovery. The NAH-related approved drugs nitrofurazone, nitrofurantoin, carbazochrome, testosterone 17-enanthate 3-benzilic acid hydrazine, nifuroxazide, dantrolene, and azumolene are already used as therapeutics in various countries. PAC-1 is an NAH-based therapeutic agent that entered clinical trials in 2015. Another NAH-derived scaffold, LASSBio-294, is in preclinical trials. This review highlights the detailed comprehensive assessment and therapeutic landscape of bioactive NAH motif scaffolds in preclinical and clinical studies published to date and their promise and associated challenges in current and future drug discovery of NAH-based drugs that will progress to clinical use.
- Published
- 2018
22. The novel piperazine-containing compound LQFM018: Necroptosis cell death mechanisms, dopamine D4 receptor binding and toxicological assessment
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Alane Pereira Cortez, Marcella Ferreira Rodrigues, Flávio Silva de Carvalho, Carlos A. M. Fraga, Luciano M. Lião, Fabiana Bettanin Costa, Ricardo Menegatti, Boniek G. Vaz, Andrezza Furquim da Cruz, Wanessa Machado Andrade, François Noël, Luiz Antonio Soares Romeiro, Renato Ivan de Ávila, Germán Sanz, Eliezer J. Barreiro, Marize Campos Valadares, and Karinna Bannach Reis
- Subjects
0301 basic medicine ,Pharmacology ,Programmed cell death ,Cell cycle checkpoint ,Chemistry ,Necroptosis ,General Medicine ,Cell membrane ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,medicine.anatomical_structure ,Cancer cell ,medicine ,Propidium iodide ,Cytotoxicity ,Receptor - Abstract
Piperazine is a promising scaffold for drug development due to its broad spectrum of biological activities. Based on this, the new piperazine-containing compound LQFM018 (2) [ethyl 4-((1-(4-chlorophenyl)-1H-pyrazol-4-yl)methyl)piperazine-1-carboxylate] was synthetized and some biological activities investigated. In this work, we described its ability to bind aminergic receptors, antiproliferative effects as well as the LQFM018 (2)-triggered cell death mechanisms, in K562 leukemic cells, by flow cytometric analyses. Furthermore, acute oral systemic toxicity and potential myelotoxicity assessments of LQFM018 (2) were carried out. LQFM018 (2) was originally obtained by molecular simplification from LASSBio579 (1), an analogue compound of clozapine, with 33% of global yield. Binding profile assay to aminergic receptors showed that LQFM018 (2) has affinity for the dopamine D4 receptor (Ki = 0.26 μM). Moreover, it showed cytotoxicity in K562 cells, in a concentration and time-dependent manner; IC50 values obtained were 399, 242 and 119 μM for trypan blue assay and 427, 259 and 50 μM for MTT method at 24, 48 or 72 h, respectively. This compound (427 μM) also promoted increase in LDH release and cell cycle arrest in G2/M phase. Furthermore, it triggered necrotic morphologies in K562 cells associated with intense cell membrane rupture as confirmed by Annexin V/propidium iodide double-staining. LQFM018 (2) also triggered mitochondrial disturb through loss of ΔΨm associated with increase of ROS production. No significant accumulation of cytosolic cytochrome c was verified in treated cells. Furthermore, it was verified an increase of expression of TNF-R1 and mRNA levels of CYLD with no involviment in caspase-3 and -8 activation and NF-κB in K562 cells. LQFM018 (2) showed in vitro myelotoxicity potential, but it was orally well tolerated and classified as UN GHS category 5 (LD50 > 2000–5000 mg/Kg). Thus, LQFM018 (2) seems to have a non-selective action considering hematopoietic cells. In conclusion, it is suggested LQFM018 (2) promotes cell death in K562 cells via necroptotic signaling, probably with involvement of dopamine D4 receptor. These findings open new perspectives in cancer therapy by use of necroptosis inducing agents as a strategy of reverse cancer cell chemoresistance.
- Published
- 2018
23. Oxidative imbalance in mice intoxicated by microcystin-LR can be minimized
- Author
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Natalia Casquilho, Rodrigo S. Fortunato, Renata Tiemi Okuro, Clarissa Bichara Magalhães, Alysson R. Carvalho, Maria Diana Moreira-Gomes, Lídia Moreira Lima, Samuel Santos Valença, Eliezer J. Barreiro, Emanuel K. Feitosa-Lima, Raquel M. Soares, Walter A. Zin, Sandra M.F.O. Azevedo, and Victor H Ortenzi
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Male ,0301 basic medicine ,medicine.medical_specialty ,Microcystins ,medicine.medical_treatment ,Intraperitoneal injection ,Phthalic Acids ,Toxicology ,medicine.disease_cause ,Antioxidants ,Superoxide dismutase ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Blood serum ,Oral administration ,Internal medicine ,medicine ,Animals ,Lung ,Liver injury ,Sulfonamides ,NADPH oxidase ,biology ,Chemistry ,medicine.disease ,Malondialdehyde ,Oxidative Stress ,030104 developmental biology ,Endocrinology ,Liver ,030220 oncology & carcinogenesis ,biology.protein ,Marine Toxins ,Chemical and Drug Induced Liver Injury ,Oxidation-Reduction ,Oxidative stress - Abstract
Microcystins-LR (MC-LR) is a cyanotoxin produced by cyanobacteria. We evaluated the antioxidant potential of LASSBio-596 (LB-596, inhibitor of phosphodiesterases 4 and 5), per os, and biochemical markers involved in lung and liver injury induced by exposure to sublethal dose of MC-LR. Fifty male Swiss mice received an intraperitoneal injection of 60 μL of saline (CTRL group, n = 20) or a sublethal dose of MC-LR (40 μg/kg, TOX group, n = 20). After 6 h the animals received either saline (TOX and CTRL groups) or LB-596 (50 mg/kg, TOX + LASS group, n = 10) by gavage. At 6 h after exposure, respiratory mechanics was evaluated in 10 CTRL and 10 TOX mice: there was a significant increase of all lung mechanics parameters (static elastance, viscoelastic component of elastance and lung resistive and viscoelastic/inhomogeneous pressures) in TOX compared to CTRL. 8 h after saline or MC-LR administration, i.e., 2 h after treatment with LB-596, blood serum levels of alanine aminotransferase and aspartate aminotransferase, activity of superoxide dismutase, catalase, and content of malondialdehyde and carbonyl in lung and liver, NADPH oxidase 2 and 4 mRNA expressions, dual oxidase enzyme activity and H2O2 generation were analyzed in lung homogenates. All parameters were significantly higher in TOX than in the other groups. There was no significant difference between CTRL and TOX + LASS. MC-LR deteriorated lung and liver functions and induced redox imbalance in them, which was prevented by oral administration of LB-596.
- Published
- 2018
24. Ru(II) Compounds: Next-Generation Anticancer Metallotherapeutics?
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Sreekanth Thota, Daniel Alencar Rodrigues, Debbie C. Crans, and Eliezer J. Barreiro
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Drug ,010405 organic chemistry ,Drug discovery ,media_common.quotation_subject ,chemistry.chemical_element ,A protein ,Antineoplastic Agents ,Biological Transport ,010402 general chemistry ,01 natural sciences ,Combinatorial chemistry ,Ruthenium ,0104 chemical sciences ,chemistry ,Drug Discovery ,Organometallic Compounds ,Animals ,Humans ,Molecular Medicine ,Ruthenium Compounds ,Medical science ,media_common - Abstract
Metal based therapeutics are a precious class of drugs in oncology research that include examples of theranostic drugs, which are active in both diagnostic, specifically imaging, and therapeutics applications. Ruthenium compounds have shown selective bioactivity and the ability to overcome the resistance that platinum-based therapeutics face, making them effective oncotherapeutic competitors in rational drug invention approaches. The development of antineoplastic ruthenium therapeutics is of particular interest because ruthenium containing complexes NAMI-A, KP1019, and KP1339 entered clinical trials and DW1/2 is in preclinical levels. The very robust, conformationally rigid organometallic Ru(II) compound DW1/2 is a protein kinase inhibitor and presents new Ru(II) compound designs as anticancer agents. Over the recent years, numerous strategies have been used to encapsulate Ru(II) derived compounds in a nanomaterial system, improving their targeting and delivery into neoplastic cells. A new photodynamic therapy based Ru(II) therapeutic, TLD-1433, has also entered clinical trials. Ru(II)-based compounds can also be photosensitizers for photodynamic therapy, which has proven to be an effective new, alternative, and noninvasive oncotherapy modality.
- Published
- 2018
25. Synthesis, X-ray diffraction study and pharmacological evaluation of 3-amino-4-methylthiophene-2-acylcarbohydrazones
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Morgana Vital de Araújo, Lídia Moreira Lima, Fanny N. Costa, Fabio Furlan Ferreira, Magna Suzana Alexandre-Moreira, Stefan Laufer, Thays de Lima Matos Freire Dias, Sonja Herrmann, Tabea Schübel, Maria Claudia Barbosa, and Eliezer J. Barreiro
- Subjects
Double bond ,Imine ,Anti-Inflammatory Agents ,010402 general chemistry ,p38 Mitogen-Activated Protein Kinases ,01 natural sciences ,Mass Spectrometry ,privileged structure ,X-ray ,Mice ,chemistry.chemical_compound ,X-Ray Diffraction ,In vivo ,Animals ,Relative potency ,lcsh:Science ,chemistry.chemical_classification ,Analgesics ,Multidisciplinary ,010405 organic chemistry ,Spectroscopy methods ,Hydrazones ,N-acylhydrazone ,Combinatorial chemistry ,antinociceptive ,0104 chemical sciences ,chemistry ,Drug Design ,X-ray crystallography ,p38MAPK ,Common key ,lcsh:Q ,Divergent synthesis - Abstract
N-acylhydrazone is an interesting privileged structure that has been used in the molecular design of a myriad of bioactive compounds. In order to identify new antinociceptive drug candidates, we described herein the design, synthesis, X-ray diffraction study and the pharmacological evaluation of a series of 3-amino-4-methylthiophene-2-acylcarbohydrazone derivatives (8a-t). Compounds were prepared in good overall yields through divergent synthesis from a common key intermediate and were characterized by classical spectroscopy methods. X-ray diffraction study was employed for unequivocal determination of the imine double bond stereochemistry. 8a-t were evaluated in vivo through oral administration using the classical writhing test in mice. N-acylhydrazone derivatives 8j and 8l displayed relative potency similar to dipyrone, highlighting them as promising analgesic lead-candidates for further investigation.
- Published
- 2018
26. Lung and liver responses to 1- and 7-day treatments with LASSBio-596 in mice subchronically intoxicated by microcystin-LR
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Lídia Moreira Lima, Vinicius Oliveira, Maria Diana Moreira-Gomes, Sandra M.F.O. Azevedo, Walter A. Zin, Raquel M. Soares, Natalia Casquilho, Christina Maeda Takiya, Giovanna Carvalho, and Eliezer J. Barreiro
- Subjects
Male ,0301 basic medicine ,Time Factors ,Microcystins ,Anti-Inflammatory Agents ,Phthalic Acids ,Administration, Oral ,Physiology ,Apoptosis ,Microcystin-LR ,Inflammation ,Toxicology ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,medicine ,Animals ,Lung ,Liver injury ,Sulfonamides ,business.industry ,Lung mechanics ,Histology ,medicine.disease ,Inflammatory biomarkers ,030104 developmental biology ,medicine.anatomical_structure ,Liver ,chemistry ,Immunology ,Respiratory Mechanics ,Marine Toxins ,medicine.symptom ,business - Abstract
Microcystin-LR (MC-LR) can cause serious injuries upon short- and long-term exposures that can be prevented by LASSBio-596 (LB-596), an anti-inflammatory compound. We aimed to test LB-596 following subchronic exposure to MC-LR. Swiss mice received 10 intraperitoneal injections of distilled water (DW) or MC-LR (20 μg/kg bw) every 2 days. On the 10th injection animals receiving DW were gavaged with DW or 50 mg/kg bw of LB-596 for 1 or 7 days (C1D, C7D, CL1D and CL7D groups), whereas those exposed to MC-LR received either DW or 50 mg/kg of LB-596 for 1 or 7 days (T1D, T7D, TL1D and TL7D groups). Twelve hours after the last gavage we assessed respiratory mechanics, and extracted lung and liver for histology, apoptosis, inflammatory biomarkers and MC-LR content. C1D, C7D, CL1D and CL7D were all similar. Mechanical parameters were significantly higher in T1D and T7D compared to the other groups. LB-596 reversed these changes on day 1 of administration. LB-596 reduced inflammatory mediators in lung and liver on day 1 of treatment. On day 7 apoptosis in liver and lung fell even more. Briefly, 7-day administration completely reversed lung and liver changes.
- Published
- 2018
27. Structural Characteristics of Protein Kinases and Their Inhibitors in Clinical Use
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Eliezer J. Barreiro, Maria Letícia de Castro Barbosa, and Fernanda P. Pauli
- Subjects
General Chemistry - Abstract
Proteinas cinases (PKs) sao enzimas responsaveis pela transferencia do grupo gama-fosfato do trifosfato de adenosina (ATP) para proteinas-alvo, mediando uma ampla gama de transducoes de sinais e regulando diferentes atividades celulares. A desregulacao e/ou superexpressao dessas proteinas cinases resulta em respostas celulares inadequadas, culminando no estabelecimento e desenvolvimento de diversas doencas, e.g. diabetes, doencas inflamatorias e câncer. Uma vez que as PKs representam cerca de 22% das proteinas codificadas pelo genoma humano passiveis de modulacao farmacologica, sao amplamente reconhecidas como alvos terapeuticos promissores para o tratamento de diversas doencas. Esta revisao detalha as principais caracteristicas estruturais das proteinas cinases, bem como suas funcoes fisiologicas e os seus inibidores em uso clinico.
- Published
- 2018
28. Effect of S–Se Bioisosteric Exchange on Affinity and Intrinsic Efficacy of Novel N-acylhydrazone Derivatives at the Adenosine A2A Receptor
- Author
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Júlia Galvez Bulhões Pedreira, Rafaela Ribeiro Silva, François G. Noël, and Eliezer J. Barreiro
- Subjects
conformational effect ,Organic Chemistry ,Pharmaceutical Science ,Analytical Chemistry ,A2A receptor ,QD241-441 ,N-acylhydrazone derivatives ,Chemistry (miscellaneous) ,Drug Discovery ,chalcogen interaction ,N-methylation effect ,Molecular Medicine ,sulfur-selenium isosterism ,Physical and Theoretical Chemistry - Abstract
In this work, we evaluated the conformational effect promoted by the isosteric exchange of sulfur by selenium in the heteroaromatic ring of new N-acylhydrazone (NAH) derivatives (3–8, 13, 14), analogues of the cardioactive compounds LASSBio-294 (1) and LASSBio-785 (2). NMR spectra analysis demonstrated a chemical shift variation of the iminic Csp2 of NAH S/Se-isosters, suggesting a stronger intramolecular chalcogen interaction for Se-derivatives. To investigate the pharmacological profile of these compounds at the adenosine A2A receptor (A2AR), we performed a previously validated functional binding assay. As expected for bioisosteres, the isosteric-S/Se replacement affected neither the affinity nor the intrinsic efficacy of our NAH derivatives (1–8). However, the N-methylated compounds (2, 6–8) presented a weak partial agonist profile at A2AR, contrary to the non-methylated counterparts (1, 3–5), which appeared as weak inverse agonists. Additionally, retroisosterism between aromatic rings of NAH on S/Se-isosters mimicked the effect of the N-methylation on intrinsic efficacy at A2AR, while meta-substitution in the phenyl ring of the acyl moiety did not. This study showed that the conformational effect of NAH-N-methylation and aromatic rings retroisosterism changed the intrinsic efficacy on A2AR, indicating the S/Se-chalcogen effect to drive the conformational behavior of this series of NAH.
- Published
- 2021
29. Structural characterization and cytotoxicity studies of different forms of a combretastatin A4 analogue
- Author
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Amanda Laura Ibiapino, Tiago Rodrigues, Laysa Pires de Figueiredo, Daniel N. do Amaral, Eliezer J. Barreiro, Fabio Furlan Ferreira, Letícia S. Ferraz, and Lídia Moreira Lima
- Subjects
Combretum caffrum ,biology ,Stereochemistry ,Angiogenesis ,Melanoma ,Organic Chemistry ,010402 general chemistry ,010403 inorganic & nuclear chemistry ,biology.organism_classification ,medicine.disease ,01 natural sciences ,0104 chemical sciences ,Analytical Chemistry ,Inorganic Chemistry ,chemistry.chemical_compound ,chemistry ,Anhydrous ,medicine ,Viability assay ,Cytotoxicity ,Spectroscopy ,Powder diffraction ,Derivative (chemistry) - Abstract
It is well known that combretastatin A4 (CA-4), which is a natural stilbene isolated from Combretum caffrum, is used to inhibit angiogenesis. However, depending on the dose administered to the patient, it can cause some side-effects. Herein, we present the synthesis and structural characterization of a novel N-acylhydrazone derivative – LASSBio-1735 – a CA-4 analogue. LASSBio-1735 has displayed in vitro antiproliferative activity against HL-60 (human leukemia), SF-295 (human glioblastoma), MDA-MB435 (melanoma) and HCT-8 (ileocecal adenocarcinoma) tumor cells. We found different hydration levels in two batches of the as-synthesized compound. As a consequence, we could successfully determine the crystal structures – by using X-ray powder diffraction data and a simulated annealing procedure – of the anhydrous and hydrated forms. The effects on cell viability of anhydrous and hydrated forms of LASSBio-1735 were comparatively evaluated in different tumor cell lines, and the hydrated form exhibited higher cytotoxicity in human leukemia K562 cells. These findings lead us to perform a quantitative phase analysis on one of the samples and may shed some light on the search for possible new solvates and/or hydrates.
- Published
- 2017
30. The antithrombotic and haemostatic effects of LASSBio-752: a synthetic, orally active compound in an arterial and venous thrombosis model in rats
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Lídia Moreira Lima, Russolina B. Zingali, Eliezer J. Barreiro, and Flávia S. Frattani
- Subjects
Carotid Artery Diseases ,Male ,Administration, Oral ,Pharmaceutical Science ,030204 cardiovascular system & hematology ,Hemostatics ,03 medical and health sciences ,0302 clinical medicine ,Fibrinolytic Agents ,Oral administration ,Thromboembolism ,Occlusion ,Antithrombotic ,Animals ,Medicine ,Platelet ,030212 general & internal medicine ,Rats, Wistar ,Thrombus ,Venous Thrombosis ,Pharmacology ,business.industry ,Thrombosis ,medicine.disease ,Rats ,Venous thrombosis ,Treatment Outcome ,Anesthesia ,Female ,business ,Fibrinolytic agent - Abstract
Objectives In this work, we further investigated the effect of the compound LASSBio-752 in thrombosis models in rats. Methods Arterial and venous thrombosis model, ex-vivo recalcification time and aPTT and PT. Key findings In the venous thrombosis model, oral administration of LASSBio-752 [48.2 mg (100 μmol)/kg] one hour before the thrombus induction decreased thrombus weight by 37 ± 0.2%. Interestingly, the antithrombotic action of this compound [48.2 mg (100 μmol)/kg] occurred at 87.5 ± 2.1% of inhibition after 24 h of administration and showed a lasting activity. When tested on the arterial thrombosis model, after a 1-h interval, there was already an increase in time to total occlusion of 34 ± 2.4 min, but the greatest effect was observed at intervals between 6 and 15 h of administration, when no occlusion of the artery was observed. The antithrombotic effect was reduced after 24 h when the occlusion time was 23.8 ± 2.3 min, close to that of the control, 17.6 ± 2.0 min. We also observed that bleeding was not excessive in any of the intervals tested. Conclusions Our results indicate that compound LASSBio-752 is a potential candidate for utilization in the treatment of thromboembolic diseases.
- Published
- 2017
31. Adenosine A2A receptor agonist prevents cardiac remodeling and dysfunction in spontaneously hypertensive male rats after myocardial infarction
- Author
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Leanne Groban, Emanuele B Ferraz, Hao Wang, Eliezer J. Barreiro, Daniele Gabriel-Costa, Jaqueline S da Silva, Roberto T. Sudo, Carlos A. M. Fraga, Gisele Zapata-Sudo, and José Nascimento
- Subjects
0301 basic medicine ,Agonist ,medicine.medical_specialty ,medicine.drug_class ,Pharmaceutical Science ,Hemodynamics ,Adenosine A2A receptor ,Exercise intolerance ,030204 cardiovascular system & hematology ,03 medical and health sciences ,0302 clinical medicine ,Fibrosis ,Internal medicine ,Drug Discovery ,medicine ,Myocardial infarction ,Pharmacology ,business.industry ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,Ventricle ,Heart failure ,cardiovascular system ,Cardiology ,medicine.symptom ,business - Abstract
Background This work evaluated the hypothesis that 3,4-methylenedioxybenzoyl-2-thienylhydrazone (LASSBio-294), an agonist of adenosine A2A receptor, could be beneficial for preventing cardiac dysfunction due to hypertension associated with myocardial infarction (MI). Methods Male spontaneously hypertensive rats (SHR) were randomly divided into four groups (six animals per group): sham-operation (SHR-Sham), and myocardial infarction rats (SHR-MI) were treated orally either with vehicle or LASSBio-294 (10 and 20 mg.kg-1.d-1) for 4 weeks. Echocardiography and in vivo hemodynamic parameters measured left ventricle (LV) structure and function. Exercise tolerance was evaluated using a treadmill test. Cardiac remodeling was accessed by LV collagen deposition and tumor necrosis factor α expression. Results Early mitral inflow velocity was significantly reduced in the SHR-MI group, and there was significant recovery in a dose-dependent manner after treatment with LASSBio-294. Exercise intolerance observed in the SHR-MI group was prevented by 10 mg.kg-1.d-1 of LASS-Bio-294, and exercise tolerance exceeded that of the SHR-Sham group at 20 mg.kg-1.d-1. LV end-diastolic pressure increased after MI, and this was prevented by 10 and 20 mg.kg-1.d-1 of LASSBio-294. Sarcoplasmic reticulum Ca2+ ATPase levels were restored in a dose-dependent manner after treatment with LASSBio-294. Fibrosis and inflammatory processes were also counteracted by LASSBio-294, with reductions in LV collagen deposition and tumor necrosis factor α expression. Conclusion In summary, oral administration of LASSBio-294 after MI in a dose-dependent manner prevented the development of cardiac dysfunction, demonstrating this compound's potential as an alternative treatment for heart failure in the setting of ischemic heart disease with superimposed chronic hypertension.
- Published
- 2017
32. Structural and physicochemical characterization of sulfonylhydrazone derivatives designed as hypoglycemic agents
- Author
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Eliezer J. Barreiro, Lídia Moreira Lima, Fabio Furlan Ferreira, Amanda Laura Ibiapino, Laysa Pires de Figueiredo, and Francesco Punzo
- Subjects
Chemistry ,Stereochemistry ,02 engineering and technology ,General Chemistry ,Crystal structure ,010402 general chemistry ,021001 nanoscience & nanotechnology ,Crystal morphology ,01 natural sciences ,Catalysis ,Mechanical Allodynia ,0104 chemical sciences ,law.invention ,Characterization (materials science) ,Murine model ,law ,Materials Chemistry ,Thermal stability ,Crystallization ,0210 nano-technology ,Powder diffraction ,Nuclear chemistry - Abstract
In this work, we present the physicochemical characterization and structural determination of two sulfonylhydrazone derivatives: LASSBio-1773 and LASSBio-1774. The former compound has displayed hypoglycemic activity and has reduced the thermal hyperalgesia and mechanical allodynia in a murine model of diabetic neuropathic pain induced by streptozotocin. In order to stablish the differences in the three-dimensional characteristics of these original bioactive compounds, we determined their crystal structures – by using X-ray powder diffraction data and a simulated annealing procedure – and studied their thermal stability. Furthermore, we performed crystal morphology prediction and compared it with SEM photomicrographs: the evidenced good agreement allowed us to suggest alternative crystallization routes – to overcome the low-solubility of LASSBio-1773 and LASSBio-1774 – as evidenced by IDR tests.
- Published
- 2017
33. IMPROVEMENT OF INFLAMMATORY-INDUCED PAIN AND JOINT DAMAGE BY NOVEL N-ACYLHYDRAZONE DERIVATIVE (LASSBIO-1027) IN MURINE MODELS
- Author
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Carlos A. M. Fraga, Roberto T. Sudo, Bismarck Rezende, Eliezer J. Barreiro, Guilherme C Montes, Tadeu L Montagnoli, Rodolfo C. Maia, and Gisele Zapata-Sudo
- Subjects
chemistry.chemical_compound ,chemistry ,Stereochemistry ,Applied Mathematics ,General Mathematics ,Joint damage ,Derivative (chemistry) - Published
- 2018
34. LASSBio-596 protects gastric mucosa against the development of ethanol-induced gastric lesions in mice
- Author
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Deysen Kerlla Fernandes Bezerra Girão, Carlos Eduardo da Silva Monteiro, Johnatan Alisson Oliveira Sousa, André Luiz dos Reis Barbosa, Pedro Marcos Gomes Soares, Cecilia Mendes Morais de Carvalho, Kaira Emanuella Sales da Silva-Leite, Eliezer J. Barreiro, Lídia Moreira Lima, and Marcellus H.L.P. Souza
- Subjects
0301 basic medicine ,Male ,Benzylamines ,Necrosis ,Amidines ,Phthalic Acids ,Inflammation ,Pharmacology ,Nitric oxide ,03 medical and health sciences ,chemistry.chemical_compound ,Hemoglobins ,Mice ,0302 clinical medicine ,Malondialdehyde ,medicine ,Gastric mucosa ,Animals ,Drug Interactions ,Peroxidase ,Sulfonamides ,biology ,Dose-Response Relationship, Drug ,Ethanol ,Stomach ,Glutathione ,Hydrogen-Ion Concentration ,030104 developmental biology ,medicine.anatomical_structure ,NG-Nitroarginine Methyl Ester ,chemistry ,Cytoprotection ,Gastric Mucosa ,Myeloperoxidase ,biology.protein ,Cytokines ,medicine.symptom ,030217 neurology & neurosurgery ,Omeprazole - Abstract
LASSBio-596 (2-[4-(1,4-thiazinan-4-ylsulfonyl) phenylcarbamoyl] benzoic acid) is a molecular hybrid of anti-tumor necrosis factor α (TNF-α) and phosphodiesterase 5 inhibitors, and its anti-inflammatory effects have been demonstrated in experimental models of inflammation. The aim of this study was to evaluate the gastroprotective effect of LASSBio-596 in an ethanol-induced acute gastritis model. Before induction of gastric damage, mice were pretreated with LASSBio-596 (20 mg per os (p.o.), Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME; 3 mg/kg, intraperitoneally [i.p.]) or with 1400W (10 mg/kg, i.p.) given alone or in their combinations. Thirty minutes later, gastric damage was induced by intragastric instillation of 50% ethanol (0.5 ml/25 g, by gavage). After 1 h, gastric damage (hemorrhagic or ulcerative lesions) was measured by planimetry. Samples of the stomach were also taken for histopathological assessment and for assays of tissue myeloperoxidase (MPO), glutathione (GSH), malondialdehyde (MDA), and inflammatory cytokines. Ethanol administration induced the development of gastric lesions in mice. LASSBio-596 reduced gastric damage, epithelial cell loss and hemorrhage, and restored the antioxidant defense system by decreasing the levels of MDA and the consumption of GSH in gastric mucosa. LASSBio-596 also decreased gastric TNF-α and interleukin-1β (IL-1β) protein levels, MPO enzymatic activity, and hemoglobin levels. Treatment with the nitric oxide synthase inhibitors L-NAME and 1400W reversed the effects of LASSBio-596 on ethanol-induced gastric lesions. LASSBio-596 did not alter mucus content and pH of gastric secretions. In summary, LASSBio-596 exerts protective effects against ethanol-induced gastric injury. The gastroprotective effects of LASSBio seem to be NO-dependent.
- Published
- 2019
35. Gastroprotective effects of N-acylarylhydrazone derivatives on ethanol-induced gastric lesions in mice are dependent on the NO/cGMP/K
- Author
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Carlos A. M. Fraga, Carlos Eduardo da Silva Monteiro, Pedro Marcos Gomes Soares, Johnatan Alisson Oliveira Sousa, Emmanuel P. Souza, Álvaro Xavier Franco, Victor Emanuel Araujo Matos, Marcellus H.L.P. Souza, André Luiz dos Reis Barbosa, and Eliezer J. Barreiro
- Subjects
0301 basic medicine ,Male ,Thiophenes ,Pharmacology ,Nitric Oxide ,Biochemistry ,Nitric oxide ,Glibenclamide ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,KATP Channels ,Enos ,medicine ,Animals ,Cyclic GMP ,Peroxidase ,biology ,Ethanol ,Stomach ,Hydrazones ,Potassium channel blocker ,Glutathione ,Malondialdehyde ,biology.organism_classification ,Molecular Docking Simulation ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,Gastric Mucosa ,030220 oncology & carcinogenesis ,Myeloperoxidase ,biology.protein ,medicine.drug ,Signal Transduction - Abstract
The gastroprotective effects of N-acylarylhydrazone derivatives on ethanol-induced gastric lesions in mice were investigated with respect to the NO/cGMP/KATP pathway. To investigate our hypothesis, the mice were intraperitoneally pretreated with glibenclamide, L-NAME, or ODQ 30 min before treatment with DMSO, LASSBio-294 (1, 2, and 4 mg/kg, p.o.), LASSBio-897 (0.5, 1, and 2 mg/kg, p.o.), or omeprazole. After 1 h, the mice received absolute ethanol (4 ml/kg) by gavage to induce gastric mucosal lesions, and the microscopic and macroscopic parameters were evaluated. GSH (non-protein sulfhydryl groups) and MDA (malondialdehyde) concentrations, hemoglobin levels, nitric oxide production, myeloperoxidase (MPO) activity, and TNF-α and IL-1β levels were also analyzed in the stomach after absolute ethanol administration. Pretreatment with LASSBio-294 or LASSBio-897 significantly reduced the microscopic and macroscopic lesion area. The compounds restored the GSH, MDA, and hemoglobin levels and reduced MPO activity. Moreover, the compounds significantly reduced nitrate and nitrite concentrations in the stomach samples after ethanol administration. Molecular docking studies revealed that LASSBio-294 and LASSBio-897 interact with active sites of the eNOS (endothelial nitric oxide synthase) enzymes through hydrogen bonds. LASSBio-294 and LASSBio-897 also reduced TNF-α and IL-1β levels. It was observed that a NO synthase inhibitor, an ATP-sensitive potassium channel blocker, and a guanylate cyclase inhibitor significantly reversed the gastroprotective effects of these compounds. Thus, the gastroprotective effect of LASSBio-294 and LASSBio-897 against gastric lesions is mediated through the NO/cGMP cascade, followed by blocking of the KATP channels.
- Published
- 2019
36. What is hidden in the biodiversity? The role of natural products and medicinal chemistry in the drug discovery process
- Author
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Eliezer J. Barreiro
- Subjects
0303 health sciences ,Biological Products ,Multidisciplinary ,010405 organic chemistry ,Process (engineering) ,Management science ,Drug discovery ,Chemistry, Pharmaceutical ,Biodiversity ,Historical Article ,History, 20th Century ,01 natural sciences ,Natural (archaeology) ,0104 chemical sciences ,03 medical and health sciences ,new drugs candidates ,medicinal chemistry ,Drug Discovery ,Humans ,lcsh:Q ,natural biophores as drug scaffolds ,lcsh:Science ,030304 developmental biology ,natural products as lead-compounds to drugs - Abstract
Abstract: This manuscript describes the role of natural products in the process of drug discovery. In fact, several different natural compounds have been used as inspiration to develop new drugs. Some relevant examples are presented in chronological order.
- Published
- 2019
37. A novel scaffold for EGFR inhibition: Introducing N-(3-(3-phenylureido)quinoxalin-6-yl) acrylamide derivatives
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Jonas Lategahn, Stefan Laufer, Daniel Rauh, Harold Hilarion Fokoue, Eduardo Miguez Bastos da Silva, Lídia Moreira Lima, Eliezer J. Barreiro, Daniel N. do Amaral, and Carlos Mauricio R. Sant'Anna
- Subjects
0301 basic medicine ,Mutant ,lcsh:Medicine ,Antineoplastic Agents ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Cell Line, Tumor ,Neoplasms ,medicine ,Humans ,Epidermal growth factor receptor ,lcsh:Science ,Protein Kinase Inhibitors ,Acrylamides ,Multidisciplinary ,biology ,Melanoma ,lcsh:R ,medicine.disease ,Small molecule ,In vitro ,ErbB Receptors ,Molecular Docking Simulation ,030104 developmental biology ,chemistry ,Cell culture ,Docking (molecular) ,Drug Design ,Cancer research ,biology.protein ,lcsh:Q ,Growth inhibition ,030217 neurology & neurosurgery - Abstract
Clinical data acquired over the last decade on non-small cell lung cancer (NSCLC) treatment with small molecular weight Epidermal Growth Factor Receptor (EGFR) inhibitors have shown significant influence of EGFR point mutations and in-frame deletions on clinical efficacy. Identification of small molecules capable of inhibiting the clinically relevant EGFR mutant forms is desirable, and novel chemical scaffolds might provide knowledge regarding selectivity among EGFR forms and shed light on new strategies to overcome current clinical limitations. Design, synthesis, docking studies and in vitro evaluation of N-(3-(3-phenylureido)quinoxalin-6-yl) acrylamide derivatives (7a-m) against EGFR mutant forms are described. Compounds 7h and 7l were biochemically active in the nanomolar range against EGFRwt and EGFRL858R. Molecular docking and reaction enthalpy calculations have shown the influence of the combination of reversible and covalent binding modes with EGFR on the inhibitory activity. The inhibitory profile of 7h against a panel of patient-derived tumor cell lines was established, demonstrating selective growth inhibition of EGFR related cells at 10 μM among a panel of 30 cell lines derived from colon, melanoma, breast, bladder, kidney, prostate, pancreas and ovary tumors.
- Published
- 2019
38. Evaluation of Functional Selectivity of Haloperidol, Clozapine, and LASSBio-579, an Experimental Compound With Antipsychotic-Like Actions in Rodents, at G Protein and Arrestin Signaling Downstream of the Dopamine D
- Author
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Rafaela R, Silva, Lucas T, Parreiras-E-Silva, Thais E T, Pompeu, Diego A, Duarte, Carlos A M, Fraga, Eliezer J, Barreiro, Ricardo, Menegatti, Claudio M, Costa-Neto, and François, Noël
- Subjects
Pharmacology ,schizophrenia ,antipsychotics ,D2 ,β-arrestin ,biased agonism ,clozapine ,LASSBio-579 ,functional selectivity ,Original Research - Abstract
LASSBio-579, an N-phenylpiperazine antipsychotic lead compound, has been previously reported as a D2 receptor (D2R) ligand with antipsychotic-like activities in rodent models of schizophrenia. In order to better understand the molecular mechanism of action of LASSBio-579 and of its main metabolite, LQFM 037, we decided to address the hypothesis of functional selectivity at the D2R. HEK-293T cells transiently coexpressing the human long isoform of D2 receptor (D2LR) and bioluminescence resonance energy transfer (BRET)-based biosensors were used. The antagonist activity was evaluated using different concentrations of the compounds in the presence of a submaximal concentration of dopamine (DA), after 5 and 20 min. For both signaling pathways, haloperidol, clozapine, and our compounds act as DA antagonists in a concentration-dependent manner, with haloperidol being by far the most potent, consistent with its nanomolar D2R affinity measured in binding assays. In our experimental conditions, only haloperidol presented a robust functional selectivity, being four- to fivefold more efficient for inhibiting translocation of β-arrestin-2 (β-arr2) than for antagonizing Gi activation. Present data are the first report on the effects of LASSBio-579 and LQFM 037 on the β-arr2 signaling pathway and further illustrate that the functional activity could vary depending on the assay conditions and approaches used.
- Published
- 2018
39. β-lactam antibiotics: An overview from a medicinal chemistry perspective
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Lídia Moreira Lima, Bianca N. M. Silva, Gisele Barbosa, and Eliezer J. Barreiro
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Carbapenem ,medicine.drug_class ,Chemistry, Pharmaceutical ,medicine.medical_treatment ,Antibiotics ,Pharmacology ,beta-Lactams ,01 natural sciences ,beta-Lactamases ,03 medical and health sciences ,Antibiotic resistance ,Drug Discovery ,polycyclic compounds ,medicine ,Animals ,Humans ,Monobactam ,Monobactams ,030304 developmental biology ,0303 health sciences ,Bacteria ,Molecular Structure ,010405 organic chemistry ,Chemistry ,Hydrolysis ,Organic Chemistry ,Bacterial Infections ,General Medicine ,biochemical phenomena, metabolism, and nutrition ,Antimicrobial ,Anti-Bacterial Agents ,0104 chemical sciences ,Penicillin ,Models, Chemical ,Beta-lactamase ,beta-Lactamase Inhibitors ,medicine.drug - Abstract
β-Lactam antibiotics are one of the most relevant drug classes of antibacterial agents worldwide. The discovery and the market of first β-lactam antibiotic (Penicillin G) is a symbolic landmark of modern chemotherapy. Since then, several other β-lactam antibiotics have been introduced in the therapy, revolutionizing the treatment of bacterial infections. Their antibacterial efficacy has been kept in check by the emergence of bacterial resistance. Among the resistance mechanisms, the expression of β-lactamase enzymes is one of the most studied and prevalent. The combined use of beta-lactamase inhibitors with broad spectrum activity β-lactam antibiotics has been an effective strategy to circumvent the resistance issue. This review discusses, with a focus on structural aspects, the different classes of beta-lactam antibiotics (penicillins, cephalosporins, carbapenems, monobactams and penems) in light of their stability, sensitivity to β-lactamases, mechanism of action and spectrum of antimicrobial activity. β-Lactamase inhibitors (structurally correlated and non-correlated to the β-lactam system) and their proposed inhibition mechanisms are also discussed.
- Published
- 2020
40. Design, synthesis, structural characterization and in vitro cytotoxic activity of mononuclear Ru(II)complexes
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Srujana Vallala, Sreekanth Thota, Eliezer J. Barreiro, Daniel Alencar Rodrigues, and Rajeshwar Yerra
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Denticity ,010405 organic chemistry ,HL60 ,Stereochemistry ,Organic Chemistry ,chemistry.chemical_element ,010402 general chemistry ,01 natural sciences ,In vitro ,0104 chemical sciences ,Ruthenium ,chemistry.chemical_compound ,chemistry ,Octahedron ,Cell culture ,Cytotoxic T cell ,General Pharmacology, Toxicology and Pharmaceutics ,Cytotoxicity - Abstract
The synthesis and characterization of ruthenium complexes (Ru-1–Ru-6) of the type [Ru(R)2(K)]2+ (where R = 1,10-phenanthroline/2,2′-bipyridyl and K = acetyl coumarin-inh, pyrazole-tch, acetyl coumarin-tsz, are described. These ligands form bidentate octahedral ruthenium complexes. The in vitro cytotoxic activities of the complexes measurement against the human cancer T-lymphocyte cell lines. In vitro evaluation of these title complexes revealed cytotoxicity from 0.34 to 1.4 µg/mL against CEM, 0.28 to 1.8 µg/mL against L1210, 0.44 to 2.5 µg/mL against Molt4/C8, 0.98 to 1.6 µg/mL against HL60, and 0.66 to 1.4 µg/mL against BEL7402. Ruthenium complexes Ru-5 & Ru-6 showed that quite significant anticancer activities over standard drugs.
- Published
- 2016
41. The total synthesis of calcium atorvastatin
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Eliezer J. Barreiro, Adriano Siqueira Vieira, and Luiz C. Dias
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Atorvastatin ,chemistry.chemical_element ,Calcium ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Medicinal chemistry ,Aldehyde ,Chemistry Techniques, Analytical ,Aldol reaction ,medicine ,Organic chemistry ,Physical and Theoretical Chemistry ,Boron ,chemistry.chemical_classification ,Aldehydes ,Molecular Structure ,010405 organic chemistry ,Organic Chemistry ,Total synthesis ,Asymmetric induction ,0104 chemical sciences ,chemistry ,Yield (chemistry) ,medicine.drug - Abstract
A practical and convergent asymmetric route to calcium atorvastatin (1) is reported. The synthesis of calcium atorvastatin (1) was performed using the remote 1,5-anti asymmetric induction in the boron-mediated aldol reaction of β-alkoxy methylketone (4) with pyrrolic aldehyde (3) as a key step. Calcium atorvastatin was obtained from aldehyde (3) after 6 steps, with a 41% overall yield.
- Published
- 2016
42. Semicarbazone derivatives as promising therapeutic alternatives in leishmaniasis
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Lídia Moreira Lima, Magna Suzana Alexandre-Moreira, Marina Amaral Alves, Aline Cavalcanti de Queiroz, and Eliezer J. Barreiro
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Cell Membrane Permeability ,Phosphorylcholine ,Immunology ,Leishmania mexicana ,Antiprotozoal Agents ,Leishmaniasis, Cutaneous ,Pharmacology ,Biology ,Cell Line ,chemistry.chemical_compound ,Inhibitory Concentration 50 ,Mice ,In vivo ,medicine ,Animals ,Amastigote ,Semicarbazone ,Pentamidine ,Phospholipids ,Membrane Potential, Mitochondrial ,Semicarbazones ,Miltefosine ,Analysis of Variance ,Mice, Inbred BALB C ,Macrophages ,Cell Cycle ,Cell Membrane ,Leishmaniasis ,General Medicine ,medicine.disease ,Flow Cytometry ,In vitro ,Infectious Diseases ,chemistry ,Apoptosis ,Caspases ,Parasitology ,Female ,medicine.drug - Abstract
In the present study, we investigated the in vitro and in vivo leishmanicidal activity of synthetic compounds, containing a semicarbazone scaffold as a peptide mimetic framework. The leishmanicidal effect against amastigotes of Leishmania amazonensis was also evaluated at concentration of 100 μM–0.01 nM. The derivatives 2e, 2f, 2g and 1g, beyond the standards miltefosine and pentamidine, significantly diminished the number of L. amazonensis amastigotes in macrophages. These derivatives were also active against amastigotes of L. braziliensis. As 2g presented potent leishmanicidal activity against the amastigotes of L. amazonensis in macrophages, we also investigated the in vivo leishmanicidal activity of this compound against L. amazonensis. Approximately 105 L. amazonensis promastigotes were subcutaneously inoculated into the dermis of the right ear of BALB/c mice, which were subsequently treated with 2g (p.o. or i.p.), miltefosine (p.o.) or glucantime (i.p.) at 30 μmol/kg/day x 28 days. Thus, a similar reduction in the lesion size was observed after the administration of 2g through oral (63.7 ± 10.1%) and intraperitoneal (61.8 ± 3.7%) routes. A larger effect was observed after treatment with miltefosine (97.7 ± 0.4%), and glucantime did not exhibit activity at the dose administered. With respect to the ear parasite load, 2g diminished the number of parasites by p.o. (30.5 ± 5.1%) and i.p. (33.3 ± 4.3%) administration. In addition, 2g induced in vitro apoptosis, autophagy and cell cycle alterations on L. amazonensis promastigotes. In summary, the derivative 2g might represent a lead candidate for antileishmanial drugs, as this compound displayed pronounced leishmanicidal activity.
- Published
- 2018
43. Potent immunosuppressive activity of a phosphodiesterase-4 inhibitor N-acylhydrazone in models of lipopolysaccharide-induced shock and delayed-type hypersensitivity reaction
- Author
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Elisalva Teixeira Guimarães, Eliezer J. Barreiro, Didier Salmon, Dahara Keyse Carvalho Silva, Tatiana B. dos Santos, Cássio Santana Meira, Diogo Rodrigo Magalhães Moreira, Milena Botelho Pereira Soares, and Tiago Fernandes da Silva
- Subjects
0301 basic medicine ,Lipopolysaccharides ,Male ,Lipopolysaccharide ,Immunology ,Inflammation ,Pharmacology ,Nitric Oxide ,Dexamethasone ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Glucocorticoid receptor ,Hormone Antagonists ,medicine ,Immunology and Allergy ,Animals ,Hypersensitivity, Delayed ,Mice, Inbred BALB C ,biology ,Molecular Structure ,Chemistry ,Macrophages ,Antagonist ,Hydrazones ,NF-kappa B ,Shock ,Hypersensitivity reaction ,Mifepristone ,030104 developmental biology ,RAW 264.7 Cells ,Concanavalin A ,030220 oncology & carcinogenesis ,Toxicity ,Benzamides ,biology.protein ,Cytokines ,Phosphodiesterase 4 Inhibitors ,medicine.symptom ,Immunosuppressive Agents ,medicine.drug - Abstract
Immunosuppressive drugs are widely used for the treatment of immune-mediated diseases and inflammation, but the toxicity and side effects of the available immunosuppressors make the search of new agents of great relevance. Here, we evaluated the immunomodulatory activity of an N-acylhydrazone derivative, (E)-N′-(3,4-dimethoxybenzylidene)-4-methoxybenzohydrazide (LASSBio-1386), a phosphodiesterase-4 (PDE-4) inhibitor. LASSBio-1386 inhibited lymphocyte activation in a concentration-dependent fashion, decreasing lymphoproliferation and IFN-γ and IL-2 production stimulated by anti-CD3/CD28 mAbs or concanavalin A (Con A) and inducing cell-cycle arrest in the G0/G1 phase. These effects were not blocked by RU486, a glucocorticoid receptor (GR) antagonist, indicating an effect independent of glucocorticoid receptor activation. Combination index-isobologram analysis indicates a synergistic effect between LASSBio-1386 and dexamethasone in lymphoproliferation inhibition. LASSBio-1386 presented immunomodulatory action in macrophage cultures, as observed by a significant and concentration-dependent decrease in NO and TNF-α production, an effect achieved by reducing IĸB expression and NF-κB activation. In the mouse model of endotoxic shock, LASSBio-1386 at 50 and 100 mg/kg protected 50 and 85% of mice against LPS-induced lethality, respectively. In agreement to its in vitro action, treatment with 100 mg/kg of LASSBio-1386 reduced TNF-α and IL-1β serum levels, while increased IL-6 and IL-10. Finally, LASSBio-1386 reduced the paw edema in a BSA-induced delayed-type hypersensitivity model. These findings demonstrate the immunomodulatory and immunosuppressant effects of LASSBio-1386 and indicate this molecule is a promising pharmacologic agent for immune-mediated diseases.
- Published
- 2018
44. Synthesis, aqueous solubility, metabolic stability and pharmacological profile of simplified urea derivatives
- Author
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Lídia Moreira Lima, Cristina Setim Freitas, Roberta Olmo Pinheiro, Marina Amaral Alves, Eliezer J. Barreiro, Raquel de Oliveira Lopes, and Fernando Q. Cunha
- Subjects
010405 organic chemistry ,Chemistry ,Drug Discovery ,Aqueous solubility ,PLANTAS MEDICINAIS ,Pharmaceutical Science ,Molecular Medicine ,Organic chemistry ,Urea derivatives ,Metabolic stability ,010402 general chemistry ,01 natural sciences ,0104 chemical sciences - Published
- 2018
45. Partial agonism and fast dissociation of LASSBio-579 at dopamine D2 receptor
- Author
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Thais E.T. Pompeu, Barbara Bosier, François Noël, Emmanuel Hermans, Carlos A. M. Fraga, Fernando M. do Monte, Ricardo Menegatti, and Eliezer J. Barreiro
- Subjects
Intrinsic activity ,Aripiprazole ,Pharmacology ,Transfection ,Partial agonist ,Piperazines ,Atypical antipsychotics ,Radioligand Assay ,Dopamine receptor D2 ,Dissociation kinetics ,Radioligand ,Haloperidol ,medicine ,Humans ,Receptor ,Clozapine ,Biological Psychiatry ,Receptors, Dopamine D2 ,Chemistry ,Residence time ,Cell Membrane ,Corpus Striatum ,Receptor–ligand kinetics ,Kinetics ,HEK293 Cells ,Guanosine 5'-O-(3-Thiotriphosphate) ,Dopamine Agonists ,Schizophrenia ,Antipsychotic Agents ,medicine.drug - Abstract
In an attempt to better understand the molecular mechanism of action of the antipsychotic lead LASSBio-579 and of its main metabolite LQFM 037, the aim of this work was to evaluate their intrinsic activity and binding kinetics at the dopamine D2 receptor. In transfected HEK cells expressing the D2L receptor under an inducible promoter, LASSBio-579 and LQFM 037, but not clozapine, behaved as weak partial agonists in [35S]-GTPγS binding assays performed in optimized conditions previously shown to evidence the partial agonist profile of aripiprazole. Besides, data obtained in radioligand competition assays on rat striatal membranes suggested a rapid association to and dissociation from the D2-like receptors. Using the kinetic rate index based on the strategy of the dual-point competition association assay, we showed that our compounds share a similar kinetic profile with clozapine, distinct from the typical antipsychotic haloperidol. These two characteristics could contribute to the atypical-like profile observed after administration of LASSBio-579 to rodents, in models of positive and negative symptoms of schizophrenia.
- Published
- 2015
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46. Design, synthesis and in vitro trypanocidal and leishmanicidal activities of novel semicarbazone derivatives
- Author
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Hugo Cerecetto, Mercedes González, Magna Suzana Alexandre-Moreira, Iara M. Landre, Aline Cavalcanti de Queiroz, Marina Amaral Alves, Lídia Moreira Lima, Javier Varela, Antonio C. Doriguetto, and Eliezer J. Barreiro
- Subjects
Models, Molecular ,Chagas disease ,Trypanosoma cruzi ,In silico ,Antiprotozoal Agents ,Molecular Conformation ,Structure-Activity Relationship ,chemistry.chemical_compound ,Parasitic Sensitivity Tests ,Drug Discovery ,medicine ,Nifurtimox ,Semicarbazone ,Leishmania major ,Semicarbazones ,Pharmacology ,Dose-Response Relationship, Drug ,Organic Chemistry ,Leishmaniasis ,General Medicine ,medicine.disease ,Druglikeness ,In vitro ,Biochemistry ,chemistry ,Drug Design ,Pentamidine ,medicine.drug - Abstract
Trypanosomatids are protozoan parasites that cause various diseases in human, such as leishmaniasis, Chagas disease and sleeping sickness. The highly syntenic genomes of the trypanosomatid species lead the assumption that they can encode similar proteins, indicating the possibility to design new antitrypanosomatid drugs with dual trypanosomicidal and leishmanicidal activities. In this work a series of compounds (6a–h and 7a–h), containing a semicarbazone scaffold as a peptide mimetic framework, was designed and synthesized. From this series compound 7g (LASSBio-1483) highlighted, showing dual in vitro trypanosomicidal and leishmanicidal activities, with potency similar to the standard drugs nifurtimox and pentamidine. This data, taken together with its good in silico druglikeness profile and its great chemical and plasma stability, make LASSBio-1483 (7g) a new antitrypanosomatid lead-candidate.
- Published
- 2015
47. Design, synthesis, characterization, cytotoxic and structure activity relationships of novel Ru(II) complexes
- Author
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Eliezer J. Barreiro, Rajeshwar Yerra, Srujana Vallala, and Sreekanth Thota
- Subjects
chemistry.chemical_compound ,Chemistry ,Cell culture ,Stereochemistry ,Ligand ,HL60 ,Cytotoxic T cell ,chemistry.chemical_element ,General Chemistry ,Platinum ,Semicarbazone ,IC50 ,Ruthenium - Abstract
Platinum containing compounds have shown antineoplastic potential, but their clinical applications have been limited by high toxicity. Ruthenium containing complexes have long been known to be well suited for biological applications, and have long been utilized as replacements to popular platinum based-drugs. Here, we report a novel series of ruthenium(II) arene compounds bearing thiosemicarbazone and isonicotinylhydrazone ligands with potent anticancer activity their structure activity relationships and apoptosis was studied. The cytotoxic activity of the new ruthenium(II) arene compounds has been evaluated in several cell lines (Molt 4/C8, L1210, CEM, HL60 and BEL7402). Among them, ten complexes were found to be excellent in vitro growth inhibitory activity against various cell lines with IC50 in the sub-micromolar range.
- Published
- 2015
48. Investigating the therapeutic effects of LASSBio-596 in an in vivo model of cylindrospermopsin-induced lung injury
- Author
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Lídia Moreira Lima, Giovanna Carvalho, Vinicius Oliveira, Eliezer J. Barreiro, Alysson R. Carvalho, Mariana Barcellos Avila, Walter A. Zin, and Sandra M.F.O. Azevedo
- Subjects
medicine.medical_treatment ,Bacterial Toxins ,Anti-Inflammatory Agents ,Phthalic Acids ,Lung injury ,Pharmacology ,Toxicology ,chemistry.chemical_compound ,Alkaloids ,In vivo ,Animals ,Medicine ,Uracil ,Saline ,Mice, Inbred BALB C ,Sulfonamides ,Cyanobacteria Toxins ,business.industry ,Therapeutic effect ,Histology ,Lung Injury ,Cyanotoxin ,Survival Analysis ,chemistry ,Immunology ,Toxicity ,Cylindrospermopsin ,business - Abstract
The cyanotoxin cylindrospermopsin (CYN) has lately been reported with a notorious toxicity to mammals. LASSBio-596 is a compound with anti-inflammatory actions. We aimed at evaluating the therapeutic effects of LASSBio-596 in a model of CYN-induced lung injury. Protocol #1: BALB/c mice received intratracheally (i.t.) 50-μL of saline or semi-purified extract of CYN (70 μg/kg). 18 h later, animals that received saline were gavaged with saline (SALSAL) or 50 mg/kg of LASSBio-596 (SALLAS), and mice that received CYN were gavaged with either saline (TOXSAL) or 50 mg/kg of LASSBio-596 (TOXLAS). Pulmonary mechanics was measured 6 h after gavage. Lungs were prepared for histology and inflammatory mediators determination. Protocol #2: Mice received 50-μL of CYN (70 μg/kg, i.t.) and 18 h later were gavaged with saline (NOT TREATED), or 50 mg/kg of LASSBio-596 (TREATED). Survival rates and pulmonary mechanics of the survivors were assessed. CYN exposure increased mechanical components, alveolar collapse, PMN cells and fiber deposition in the lungs, as well as the production of IL-1β, IL-6 and KC in Protocol #1. LASSBio-596 attenuated those changes. TREATED mice in Protocol #2 presented significantly higher survival rates and tended to improve lung mechanics. Briefly, LASSBio-596 showed positive effects in mice exposed to CYN.
- Published
- 2015
49. Investigation of Low Bioavailability Using Physiologically Based Pharmacokinetic Modeling: A Case Example (Lassbio-596)
- Author
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Carlos Alberto Tagliati, Manuela de Lima Toccafondo Vieira, Eliezer J. Barreiro, and Lídia Moreira Lima
- Subjects
Physiologically based pharmacokinetic modelling ,Chromatography ,Tissue concentrations ,Pharmacokinetics ,Chemistry ,Bacterial degradation ,Pharmacokinetic modeling ,General Medicine ,Tissue distribution ,Solubility ,Bioavailability - Abstract
Aim: Investigate the possible mechanism (s) of the poor bioavailability of a lipophilic compound in rats using the physiologically based pharmacokinetic (PBPK) modeling approach. Methodology: A rat PBPK model was constructed using data from intravenous administration, and verified by comparing predicted tissue concentrations (kidneys, liver and lungs) with experimental Method Article Vieira et al.; BJAST, 5(6): 613-620, 2015; Article no.BJAST.2015.059 614 data from tissue distribution studies. Using parameter sensitivity analysis, the model was used to investigate the absorption characteristics of the compound and the probable causes of the low absorbed fraction. Results: Sensitivity analysis of absorption parameters was performed to understand the absorption characteristic of the compound in regard to permeability, solubility and intra-gut degradation. Taking in consideration the latter factor, the oral pharmacokinetics of the tested compound was satisfactorily predicted in rats. Conclusion: The PBPK simulation results suggest that chemical or/and bacterial degradation of the compound in the gastrointestinal tract may be a probable cause of the low bioavailability observed.
- Published
- 2015
50. Structural characterization of LASSBio-1289: a new vasoactive N-methyl-N-acylhydrazone derivative
- Author
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Carlos A. M. Fraga, Fabio Furlan Ferreira, Fanny N. Costa, Juliana Alves Pereira Sato, Francesco Punzo, Miguel Divino da Rocha, and Eliezer J. Barreiro
- Subjects
chemistry.chemical_classification ,Double bond ,Chemistry ,Stereochemistry ,Imine ,Ab initio ,General Chemistry ,Crystal structure ,Condensed Matter Physics ,chemistry.chemical_compound ,Crystallography ,General Materials Science ,Solvent effects ,Powder diffraction ,Derivative (chemistry) ,Monoclinic crystal system - Abstract
LASSBio-1289 compound has been found to promote intense vasodilation and antihypertensive activity. It is an innovative compound, without structural similarities to the three main classes of calcium antagonists (1,4-dihydropyridines, benzothiazepines and phenylalkylamines) commonly used. A complete knowledge of the structure, including stereochemistry, is essential to lead optimization in drug discovery. For this reason, in this work we determined the crystal structure of this novel vasoactive N-methyl-N-acylhydrazone derivative by means of X-ray powder diffraction data and an ab initio simulating annealing approach, allowing us to observe the relative configuration E of the imine double bond and its conformation as well as its most relevant intermolecular interactions. These findings were also checked by a FTIR analysis and confirmed in solution by NMR. The compound crystallized under a monoclinic crystal system with space group P21/c and unit cell parameters a = 14.5118(3) A, b = 12.1374(2) A, c = 7.5498(1) A, β = 91.113(1)°, V = 1329.53(4) A3, Z = 4, Z′ = 1 and ρcalc = 1.44042(4) g cm−3. Moreover, a crystal morphology prediction, experimentally compared with SEM inferred images, allowed a direct comparison of the microcrystalline habit and quality, allowing a study of the potential solvent effect on the crystal growth.
- Published
- 2015
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