Antileishmanial and Antitoxoplasmal Activities of 1,4-dihydropyridines

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Abstract: We have synthesized 24 1,4-dihydropyridine compounds (1,4-DHPs) with different substituents at the aromatic ring by microwave-assisted one-pot Hantzsch multicomponent reac-tion and evaluated their in vitro activities against Toxoplasma gondii and Leishmania major. We have found that compound 9 ((±)-ethyl 2,7,7-trimethyl-4-(2-nitrophenyl)-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate) is active against L. major amastigotes (IC50 = 10.6 µM), but it is poorly selective for L. major over Vero cells (SI = 1.13) and macrophages (SI = 0.42). Among the evaluated 1,4-DHPs, compound 4 ((±)-ethyl 4-(4-(benzyloxy)phenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate) is the most active against T. gondii, providing the lowest IC50 (3.1 µM) and the highest selectivity for this parasite (SI = 5.57) over Vero cells. Docking studies revealed that compound 4 has high affinity for the T. gondii target (PDB ID: 4JBV). Furthermore, ADME-T predictions indicated that compound 4 meets the drug-likeness criteria without violating any Lipinski, Vger, or Egan’s rules.

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