1,2,4-Oxadiazole Derivatives: Physicochemical Properties, Antileishmanial Potential, Docking and Molecular Dynamic Simulations of Leishmania infantum Target Proteins

Visceral leishmaniasis (VL), caused by protozoa of the genus , remains a significant public health concern due to its potentially lethal nature if untreated. Current chemotherapy options are limited by severe toxicity and drug resistance. Derivatives of 1,2,4-oxadiazole have emerged as promising drug candidates due to their broad biological activity. This study investigated the effects of novel 1,2,4-oxadiazole derivatives ( - ) on , the etiological agent of VL. In silico predictions using SwissADME suggest that these compounds have high oral absorption and good bioavailability. Among them, showed the most promise, with higher selectivity against promastigotes and lower cytotoxicity towards L929 fibroblasts and J774.G8 macrophages. exhibited selectivity indices of 18.7 and 61.7 against promastigotes and amastigotes, respectively, compared to peritoneal macrophages. Ultrastructural analyses revealed severe morphological damage in both parasite forms, leading to cell death. Additionally, decreased the mitochondrial membrane potential in promastigotes, as shown by flow cytometry. Molecular docking and dynamic simulations indicated a strong affinity of for the CYP51 enzyme. Overall, is a promising and effective compound against .