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 <i>Leishmania</i>, 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 (<b>Ox1</b>-<b>Ox7</b>) on <i>Leishmania infantum</i>, the etiological agent of VL. In silico predictions using SwissADME suggest that these compounds have high oral absorption and good bioavailability. Among them, <b>Ox1</b> showed the most promise, with higher selectivity against promastigotes and lower cytotoxicity towards L929 fibroblasts and J774.G8 macrophages. <b>Ox1</b> exhibited selectivity indices of 18.7 and 61.7 against <i>L. infantum</i> promastigotes and amastigotes, respectively, compared to peritoneal macrophages. Ultrastructural analyses revealed severe morphological damage in both parasite forms, leading to cell death. Additionally, <b>Ox1</b> decreased the mitochondrial membrane potential in promastigotes, as shown by flow cytometry. Molecular docking and dynamic simulations indicated a strong affinity of <b>Ox1</b> for the <i>L. infantum</i> CYP51 enzyme. Overall, <b>Ox1</b> is a promising and effective compound against <i>L. infantum</i>.
Authors
- Deyzi Caroline da Silva Barbosa (ORCID: https://orcid.org/0000-0002-9026-6528)
- Gerd B. Rocha (ORCID: https://orcid.org/0000-0001-9805-9497)
- Ronaldo N. de Oliveira (ORCID: https://orcid.org/0000-0002-6111-2351)
- Maria Carolina Accioly Brelaz de Castro (ORCID: https://orcid.org/0000-0003-2205-0618)
- Regina Célia Bressan Queiroz de Figueiredo (ORCID: https://orcid.org/0000-0001-5806-0944)
- Elton Marlon de Araújo Lima
- Vanderlan Nogueira Holanda (ORCID: https://orcid.org/0000-0001-5309-0036)
- C Silva (ORCID: https://orcid.org/0000-0002-0215-755X)
- Marton Kaique de Andrade Cavalcante (ORCID: https://orcid.org/0000-0001-9995-7352)
- Elton José Ferreira Chaves (ORCID: https://orcid.org/0000-0001-8573-2216)
Institutions
- Universidade Federal da Paraíba (BR)
- Universidade Federal de Pernambuco (BR)
- Universidade Federal do Espírito Santo (BR)
- Fundação Oswaldo Cruz (BR)
- Universidade Federal Rural de Pernambuco (BR)
Publication Details
- Journal
- Molecules
- Published
- 2024-09-30
- DOI
- https://doi.org/10.3390/molecules29194654
- Citations
- 6
- Primary Topic
- Research on Leishmaniasis Studies
- Type
- article
- Field-Weighted Citation Impact
- 3.26
Funders
- Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
- Conselho Nacional de Desenvolvimento Científico e Tecnológico
- Financiadora de Estudos e Projetos
- Fundação de Apoio à Pesquisa do Estado da Paraíba
- Fundação de Amparo à Ciência e Tecnologia do Estado de Pernambuco
- Universidade Federal de Pernambuco
- Centro Nacional de Processamento de Alto Desempenho em São Paulo
- Instituto Nacional de Ciência e Tecnologia: Nanotecnologia para Marcadores Integrados
- Institut National d'assurance Maladie-Invalidité
- Universidade Federal da Paraíba