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J Med Chem ; 64(4): 1904-1929, 2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33626870


The modulation of melatonin signaling in peripheral tissues holds promise for treating metabolic diseases like obesity, diabetes, and nonalcoholic steatohepatitis. Here, several benzimidazole derivatives have been identified as novel agonists of the melatonin receptors MT1 and MT2. The lead compounds 10b, 15a, and 19a demonstrated subnanomolar potency at MT1/MT2 receptors, high oral bioavailability in rodents, peripherally preferred exposure, and excellent selectivity in a broad panel of targets. Two-month oral administration of 10b in high-fat diet rats led to a reduction in body weight gain similar to dapagliflozin with superior results on hepatic steatosis and triglyceride levels. An early toxicological assessment indicated that 10b (also codified as ACH-000143) was devoid of hERG binding, genotoxicity, and behavioral alterations at doses up to 100 mg/kg p.o., supporting further investigation of this compound as a drug candidate.

Med Chem ; 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31763975


BACKGROUND: Antimicrobial resistance is a persistent problem about infections treatment and carries needing for develop new antimicrobial agents. Inhibiting of bacterial ß-ketoacyl acyl carrier protein synthase III (FabH), which catalyzes the condensation reaction between a CoA-attached acetyl group and an ACP-attached malonyl group in bacteria is an interesting strategy to find new antibacterial agents. OBJECTIVE: The aim of this work was to design and synthesize arylsulfonylhydrazones potentially FabH inhibitors and evaluate their antimicrobial activity. METHODS: MIC50 of sulfonylhydrazones against E. coli and S. aureus was determined. Antioxidant activity was evaluated by DPPH (1-1'-diphenyl-2-picrylhydrazyl) assay and cytotoxicity against LL24 lung fibroblast cells was verified by MTT method. Principal component analysis (PCA) was performed in order to suggest a structure-activity relationship. Molecular docking allowed to propose sulfonylhydrazones interactions with FabH. RESULTS: The most active compound showed activity against S. aureus and E. coli, with MIC50 = 0.21 and 0.44 µM, respectively. PCA studies correlated better activity to lipophilicity and molecular docking indicated that sulfonylhydrazone moiety is important to hydrogen-bond with FabH while methylcatechol ring performs π-π stacking interaction. The DPPH assay revealed that some sulfonylhydrazones derived from the methylcatechol series had antioxidant activity. None of the evaluated compounds was cytotoxic to human lung fibroblast cells, suggesting that the compounds might be considered safe at the tested concentration. CONCLUSION: Arylsufonylhydrazones is a promising scaffold to be explored for design of new antimicrobial agents.

Tuberculosis (Edinb) ; 99: 11-16, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27449999


Tuberculosis (TB) is an important infectious disease caused by Mycobacterium tuberculosis (Mtb) and responsible for thousands of deaths every year. Although there are antimycobacterial drugs available in therapeutics, just few new chemical entities have reached clinical trials, and in fact, since introduction of rifampin only two important drugs had reached the market. Pyrazinoic acid (POA), the active agent of pyrazinamide, has been explored through prodrug approach to achieve novel molecules with anti-Mtb activity, however, there is no activity evaluation of these molecules against non-replicating Mtb until the present. Additionally, pharmacokinetic must be preliminary evaluated to avoid future problems during clinical trials. In this paper, we have presented six POA esters as prodrugs in order to evaluate their anti-Mtb activity in replicating and non-replicating Mtb, and these showed activity highly influenced by medium composition (especially by albumin). Lipophilicity seems to play the main role in the activity, possibly due to controlling membrane passage. Novel duplicated prodrugs of POA were also described, presenting interesting activity. Cytotoxicity of these prodrugs set was also evaluated, and these showed no important cytotoxic profile.

Antituberculosos/farmacologia , Ésteres/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Pró-Fármacos/farmacologia , Pirazinamida/análogos & derivados , Animais , Antituberculosos/síntese química , Antituberculosos/toxicidade , Proliferação de Células/efeitos dos fármacos , Chlorocebus aethiops , Relação Dose-Resposta a Droga , Ésteres/síntese química , Ésteres/toxicidade , Concentração Inibidora 50 , Testes de Sensibilidade Microbiana , Viabilidade Microbiana/efeitos dos fármacos , Estrutura Molecular , Mycobacterium tuberculosis/crescimento & desenvolvimento , Pró-Fármacos/síntese química , Pró-Fármacos/toxicidade , Pirazinamida/síntese química , Pirazinamida/farmacologia , Pirazinamida/toxicidade , Relação Estrutura-Atividade , Células Vero
Curr Clin Pharmacol ; 10(2): 139-159, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-24433443


Tuberculosis (TB), a 19th century disease, is still present in the beginning of the Third Millennium. It has been considered pandemic, since around two billion people are infected with M. tuberculosis. Multi-drug resistant TB has been the biggest challenge for chemotherapy. In order to face this severe health problem, many institutions, private and public ones, have been investing in the search for new and better drug candidates. The pipeline of potential anti-TB drugs presents new molecules and formulations that have been submitted to pre-clinical and clinical assays. Medicinal Chemistry has an important role towards the objective of finding new leads through classic and modern processes. This paper reviews some aspects of this search, emphasizing the features of the main compounds under investigation and those that are in preliminary and final clinical trials and includes the contribution of our laboratory (LAPEN) in the area of designing new anti-TB drug candidates.