RESUMO
Paracoccidioidomycosis is an endemic mycosis in Latin America for which there is a high mortality rate and limited treatment options. There are no specific drugs to treat the systemic disease. Thus, there is a need for further studies focused on the development of specific drugs. In this work we synthesized new hybrids pyrimido[4,5-d]pyridazinone-N-acylhydrazone (5a-p) by simple methodologies with good yields. The antifungal activity of compounds was evaluated against P. brasiliensis (Pb18) and Candida spp. Compounds 5a, 5f, 5i, 5 k, 5m and 5n showed significant inhibition against Pb18 with MIC of 0.125 to 64 µg mL-1. Compound 5a is the most promising, showing potent fungicidal profile with MFC of 0.5 µg mL-1, synergic effect with amphotericin B, besides showing no toxicity against HeLa and Vero cells.
Assuntos
Antifúngicos/farmacologia , Candida/efeitos dos fármacos , Hidrazonas/farmacologia , Paracoccidioides/efeitos dos fármacos , Piridazinas/farmacologia , Animais , Antifúngicos/síntese química , Antifúngicos/química , Chlorocebus aethiops , Relação Dose-Resposta a Droga , Células HeLa , Humanos , Hidrazonas/síntese química , Hidrazonas/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Piridazinas/síntese química , Piridazinas/química , Relação Estrutura-Atividade , Células VeroRESUMO
A series of isoxazolopyridazinones and analogues has been prepared and evaluated as Leishmania mexicana phosphodiesterase (PDE) inhibitors. Some of the synthesized compounds showed a moderate PDE inhibitory activity at 100 microM and preliminary structure-activity relationships were discussed.
Assuntos
Leishmania mexicana/efeitos dos fármacos , Leishmania mexicana/enzimologia , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/metabolismo , Piridazinas/farmacologia , Animais , Hidrólise , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/química , Piridazinas/síntese química , Piridazinas/química , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
Nitroaromatic compounds such as nifuroxazide are used in many human enteropathogenic bacteria infections without causing an increase in the plasmidial antibiotic resistance of the aerobic Gram-negative intestinal Enterobacteriaceae. For these reasons, these compounds have been synthesized using the rational approach of Topliss' decision tree. Generally, this approach allows us to obtain the most active derivative from the series in a few steps. These compounds were tested against Mycobacterium tuberculosis in vitro and the most active of the series identified. A new lead for potential tuberculostatic activity has been predicted and will be used in further QSAR studies.