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

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.