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Visceral leishmaniasis (VL), caused by protozoa of the genus Leishmania, 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 (Ox1–Ox7) on Leishmania infantum, the etiological agent of VL. In silico predictions using SwissADME suggest that these compounds have high oral absorption and good bioavailability. Among them, Ox1 showed the most promise, with higher selectivity against promastigotes and lower cytotoxicity towards L929 fibroblasts and J774.G8 macrophages. Ox1 exhibited selectivity indices of 18.7 and 61.7 against L. infantum promastigotes and amastigotes, respectively, compared to peritoneal macrophages. Ultrastructural analyses revealed severe morphological damage in both parasite forms, leading to cell death. Additionally, Ox1 decreased the mitochondrial membrane potential in promastigotes, as shown by flow cytometry. Molecular docking and dynamic simulations indicated a strong affinity of Ox1 for the L. infantum CYP51 enzyme. Overall, Ox1 is a promising and effective compound against L. infantum.

Visceral leishmaniasis (VL), caused by protozoa of the genus Leishmania, 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 (Ox1–Ox7) on Leishmania infantum, the etiological agent of VL. In silico predictions using SwissADME suggest that these compounds have high oral absorption and good bioavailability. Among them, Ox1 showed the most promise, with higher selectivity against promastigotes and lower cytotoxicity towards L929 fibroblasts and J774.G8 macrophages. Ox1 exhibited selectivity indices of 18.7 and 61.7 against L. infantum promastigotes and amastigotes, respectively, compared to peritoneal macrophages. Ultrastructural analyses revealed severe morphological damage in both parasite forms, leading to cell death. Additionally, Ox1 decreased the mitochondrial membrane potential in promastigotes, as shown by flow cytometry. Molecular docking and dynamic simulations indicated a strong affinity of Ox1 for the L. infantum CYP51 enzyme. Overall, Ox1 is a promising and effective compound against L. infantum. [ABSTRACT FROM AUTHOR]

In this Review, we reviewed the efforts to expand the applications of conceptual density functional theory reactivity descriptors and hard and soft acid and base principles for macromolecules and other strategies that focused on low-level quantum chemistry methods. Currently, recent applications are taking advantage of modifications of these descriptors using semiempirical electronic structures to explain enzymatic catalysis reactions, protein-binding processes, and structural analysis in proteins. We have explored these new solutions along with their implementations in the software PRIMoRDiA, discussing their impact on the field and its perspectives. We show the main issues in the analysis of the electronic structure of macromolecules, which are the application of the same calculation protocols used for small molecules without considering particularities in those large systems' electronic configuration. The major result of our discussions is that the use of semiempirical methods is crucial to obtain such a type of analysis, which can provide a powerful dimension of information and be part of future low-cost predictive tools. We expect semiempirical methods continue playing an important role in the quantum chemistry evaluation of large molecules. As computational resources advance, semiempirical methods might lead us to explore the electronic structure of even larger biological macromolecular entities and sets of structures representing larger timescales. [ABSTRACT FROM AUTHOR]