RESUMO
The disturbing emergence of multidrug-resistant strains of Mycobacterium tuberculosis (Mtb) has been driving the scientific community to urgently search for new and efficient antitubercular drugs. Despite the various drugs currently under evaluation, isoniazid is still the key and most effective component in all multi-therapeutic regimens recommended by the WHO. This paper describes the QSAR-oriented design, synthesis and in vitro antitubercular activity of several potent isoniazid derivatives (isonicotinoyl hydrazones and isonicotinoyl hydrazides) against H37Rv and two resistant Mtb strains. QSAR studies entailed RFs and ASNNs classification models, as well as MLR models. Strict validation procedures were used to guarantee the models' robustness and predictive ability. Lipophilicity was shown not to be relevant to explain the activity of these derivatives, whereas shorter N-N distances and lengthy substituents lead to more active compounds. Compounds 1, 2, 4, 5 and 6, showed measured activities against H37Rv higher than INH (i.e., MIC ≤ 0.28 µM), while compound 9 exhibited a six fold decrease in MIC against the katG (S315T) mutated strain, by comparison with INH (i.e., 6.9 vs. 43.8 µM). All compounds were ineffective against H37RvINH (ΔkatG), a strain with a full deletion of the katG gene, thus corroborating the importance of KatG in the activation of INH-based compounds. The most potent compounds were also shown not to be cytotoxic up to a concentration 500 times higher than MIC.
Assuntos
Antituberculosos/farmacologia , Desenho de Fármacos , Isoniazida/análogos & derivados , Isoniazida/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Animais , Antituberculosos/síntese química , Antituberculosos/química , Chlorocebus aethiops , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Isoniazida/química , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Células VeroRESUMO
Human neutrophil elastase (HNE) is an attractive target for treating chronic and acute inflammatory lung diseases. An optimization campaign of the kojic acid scaffold to develop new potent HNE inhibitors is reported. O3-Pivaloyl derivatives were shown to be the most potent inhibitors with IC5o values down to 80 nM. These compounds presented excellent selectivity and cytotoxicity profiles with suitable ligand efficiency.
Assuntos
Elastase de Leucócito/metabolismo , Proteínas Secretadas Inibidoras de Proteinases/síntese química , Pironas/química , Animais , Linhagem Celular , Estabilidade de Medicamentos , Humanos , Concentração Inibidora 50 , Cinética , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Proteínas Secretadas Inibidoras de Proteinases/farmacologia , Piridonas/síntese química , Piridonas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
The synthesis, inhibitory activity and mode of action of oxazolidine-2,4-diones against porcine pancreatic elastase, here used as a model for human neutrophil elastase, are reported. The nature of N-substitution at the oxazolidine-2,4-dione scaffold has large effect on the inhibitory potency against elastase. N-Acyl and N-sulfonyloxazolidine-2,4-diones emerged as potent pseudo-irreversible inhibitors, displaying high second-order rate constants for PPE inactivation. The title compounds were also shown to be potent inhibitors of human neutrophil elastase (HNE) and proteinase-3, and weak inhibitors of human cathepsin G. The results herein presented show that the oxazolidine-2,4-diones represent a new promising class of serine protease inhibitors.