ABSTRACT
A new series of pyrazolo[3,4-d]pyridazin-7-one derivatives were synthesised and evaluated for their in vitro antileishmanial activity against Leishmania amazonensis promastigote and axenic amastigote forms. The results showed that the pyrazolo[3,4-d]-pyridazin-7-one-N-acylhydrazone-(bi)thiophene hybrids 5b, 6b and 6d exhibit better antileishmanial activity with IC50 84.96, 3.63 and 10.79 µM, against the promastigote form and IC50 32.71, 2.32 and >100 µM against the axenic amastigote form, respectively. The active compounds had their cytotoxicity tested against macrophages and fibroblast cells with a higher selectivity index than 10 for compounds 6b and 6d. Molecular docking studies were performed for all active compounds using the enzyme trypanothione reductase (TR) to investigate a possible action mechanism. The results suggested that active compounds had interactions with the residues of amino acids Gly 13, Thr 51, Thr 160, Gly 161, Tyr 198, Arg 287, Asp 327, Thr 335, which may inhibit the enzyme TR.
Subject(s)
Drug Design , Leishmania mexicana/drug effects , Thiophenes/chemical synthesis , Thiophenes/pharmacology , Animals , Chemistry Techniques, Synthetic , Inhibitory Concentration 50 , Leishmania mexicana/enzymology , Mice , Molecular Docking Simulation , NADH, NADPH Oxidoreductases/chemistry , NADH, NADPH Oxidoreductases/metabolism , Parasitic Sensitivity Tests , Protein Conformation , Structure-Activity Relationship , Thiophenes/chemistry , Thiophenes/metabolismABSTRACT
Several 6-aryl-4-substituted benzylidene/furfurylidene pyridazin(2H)-3-one derivatives (4a-f) were synthesized and evaluated as analgesic and anti-inflammatory agents in mice and rats, respectively. All compounds were tested by using Eddy's hot plate and the carrageenan-induced hind paw oedema method for the evaluation of analgesic and anti-inflammatory activities, respectively. Results showed that compounds 4f, 4b, 4d, and 4e exhibited higher analgesic and anti-inflammatory activities than other remaining compounds. All title compounds (4a-f) were characterized by IR, NMR and Mass spectroscopy.
Diversos derivados benzilideno/furfurilideno piridazin(2H)-3-ona 6-aril-4-substituídos (4a-f) foram sintetizados e avaliados como analgésicos e anti-inflamatórios em camundongos e ratos, respectivamente. Todos os compostos foram testados utilizando-se o método de placa quente de Eddy e o de edema de pata induzido por carragenana para a avaliação das atividades analgésica e anti-inflamatória, respectivamente. Os resultados mostraram que os compostos 4f, 4b, 4d e 4e exibiram atividade analgésica e anti-inflamatória mais alta do que os compostos restantes. Todos os compostos (4a-f) foram caracterizados por IV, RMN e espectrometria de massas.