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A series of novel 4-acetyl-1,3,4-oxadiazole derivatives was designed and synthesized for their biological evaluation in vitro against Trypanosoma cruzi (T. cruzi) and Leishmania mexicana (L. mexicana). Additionally, all compounds were evaluated by molecular docking on the cruzain of T. cruzi (TcCz) and the cysteine protease B (CPB) of L. mexicana (LmCPB) to know their potential mechanism of binding. Compound OX-12 had better trypanocidal activity against NINOA (IC 50 =10.5 μM) and A1 (IC 50 =21.7 μM) T. cruzi strains that reference drug benznidazole (IC 50 =30.3 μM and 39.8 μM, respectively). Compound OX-2 had the best biological activity against L. mexicana in M379 (IC 50 =11.9 μM) and FCQEPS (IC 50 =34.0 μM) strains that the reference drug glucantime (IC 50 >120 μM). All the compounds showed important interactions with residues on the active site of TcCz (Gly66, Trp26, Leu67, and Ala138) and LmCPB (Gly67, Asn62, Leu68, and Ala140). Finally, the molecular dynamics simulations of the compound OX-12 shown moderate stability from 40-115 ns with an RMSD value of 6.5 Å. Meanwhile, compound OX-2 showed a minor stability in complex with CPB from 25-200 ns of simulation (RMSD<9 Å). These results encourage to develop more potent and efficient trypanocidal and leishmanicidal agents using the 1,3,4-oxadiazole scaffold., (© 2024 Wiley-VCH GmbH.)