Insights into a new class of antileishmanial compounds: an in vitro and in silico study of 1,2,4-oxadiazol-5(4H)-one derivatives

  • Bioorg Chem. 2026 Jul 15:176:109839. doi: 10.1016/j.bioorg.2026.109839.
Larissa G Maciel  1 ,  Janaína V Dos Anjos  2 ,  Julyanne M S de Sousa  3 ,  Vanessa M R de Souza  3 ,  Maria G G S Sousa  3 ,  Jéssika O Viana  4 ,  Saraliny B França  5 ,  Euzébio G Barbosa  6 ,  Karen C Weber  4 ,  Klinger A F Rodrigues  7 ,  Francisco J B Mendonça-Junior  8 ,  Thiago M de Aquino  9 ,  Teresinha G da Silva  10 ,  Pascal Marchand  11
Affiliations
  • 1. Nantes Université, Cibles et médicaments des infections et de l'immunité, IICiMed, UR 1155, F-44000 Nantes, France. Electronic address: [email protected].
  • 2. Laboratory of Medicinal Organic Synthesis, Department of Fundamental Chemistry, Federal University of Pernambuco, Recife, PE 50740-560, Brazil.
  • 3. Infectious Diseases Laboratory, Federal University of Parnaíba Delta, Parnaíba, PI 64202-020, Brazil.
  • 4. Department of Chemistry, Federal University of Paraíba, João Pessoa, PB 58051-900, Brazil.
  • 5. Nantes Université, Cibles et médicaments des infections et de l'immunité, IICiMed, UR 1155, F-44000 Nantes, France.
  • 6. Department of Pharmacy, Federal University of Rio Grande do Norte, Natal, RN 59012-570, Brazil.
  • 7. Center for Basic and Applied Immunology - NIBA, Federal University of Maranhão, São Luís, MA 65080-805, Brazil.
  • 8. Laboratory of Synthesis and Drug Delivery, Department of Biological Sciences, State University of Paraíba, João Pessoa, PB 58071-160, Brazil.
  • 9. Laboratory of Synthesis and Research in Medicinal Chemistry, Federal University of Alagoas, Maceió, AL 57072-900, Brazil.
  • 10. Department of Antibiotics, Federal University of Pernambuco, Recife, PE 50670-910, Brazil.
  • 11. Nantes Université, Cibles et médicaments des infections et de l'immunité, IICiMed, UR 1155, F-44000 Nantes, France. Electronic address: [email protected].
PMID: 41962188 DOI: 10.1016/j.bioorg.2026.109839
Abstract

This research introduces a series of 1,2,4-oxadiazol-5-one derivatives as promising antileishmanial agents. As a preliminary SAR exploration, seven new A3-coupling (amine, alkyne and aldehyde) compounds were obtained and tested against promastigote and amastigote forms of the Parasite for L. amazonensis, L. braziliensis, L. infantum and L. donovani. Most of them displayed low micromolar potency (0.48-3.83 μM for antiamastigote) with low cytotoxicity (96.61-204.19 μM). Pharmacomodulations in 4-aromatic ring position attached to C-3 atom of the 1,2,4-oxadiazolone core, as well as the amine portion, were preliminarily explored. The most active compound 5a, showed potency comparable to amphotericin B, but more than 130-fold less toxic. Furthermore, we investigated the role of the enzyme Adenosine Kinase (AK) as a potential molecular target of this series. AK is a crucial enzyme in purine metabolism and a potential drug target in Leishmania spp. Therefore, we investigated AK from L. braziliensis, L. donovani, and L. infantum through homology modeling, molecular docking, and molecular dynamics simulations, using T. brucei AK as a reference. Computational simulations revealed favorable interactions between 5a and key active site residues (e.g., Ser63, Asn66/295/299) of all three Leishmania AKs and stable complex formation over 500 ns, correlating with in vitro results. These findings suggest that Leishmania AK is a promising target for the development of specific inhibitors, and compound 5a represents a hit compound for further optimization.

Keywords
1,2,4-oxadiazolone; 5-Oxo-1,2,4-oxadiazole; A(3) coupling reaction; Anti-amastigote activity; Molecular docking; Molecular dynamics.
Products