In vitro, in vivo, and computational insights into oxadiazole-pyrimidine-linked thiocoumarins as potent therapeutics for chagas disease

Chagas disease, caused by Trypanosoma cruzi , remains a significant global health burden with limited treatment options. The present research report evaluated previously synthesized oxadiazole derivatives as potential Trypanocidal agents. A structure-based molecular docking analysis, incorporating molecular docking and dynamics simulations, was employed to predict binding interactions with the key protein (PDB ID: 4C28). Promising compounds were tested in vitro against bloodstream trypomastigotes of two T. cruzi strains (NINOA and INC-5), followed by in vivo studies to confirm efficacy. Several compounds demonstrated superior activity compared to standard drugs, benznidazole and nifurtimox. The most potent compounds, B9 and B10 , exhibited high parasite lysis with low cytotoxicity towards the murine macrophage cell line J774A. In vivo evaluations further confirmed their efficacy against infections. ADME profiling suggested favourable pharmacokinetics. These findings highlight the therapeutic promise of oxadiazole-pyrimidine scaffolds ( B1 - B10 ) for Chagas disease treatment and warrant further preclinical development. Oxadiazole-Pyrimidine-linked Thiocoumarins were identified as potential treatments for Chagas disease. Molecular docking and dynamics simulations revealed promising candidates with superior in vitro and in vivo activity against T. cruzi compared to standard drugs. Lead compounds exhibited high efficacy, low cytotoxicity, and favourable pharmacokinetics. • Oxadiazole-pyrimidine-Thiocoumarins identified as anti- Trypanosoma cruzi agents. • Docking and dynamics showed strong binding of compounds B9 and B10 to 4C28. • In vitro assays confirmed the potent Trypanocidal activity of B9 and B10 . • In vivo studies showed efficacy against chronic-phase T. cruzi infection. • ADME profiling indicated high bioavailability, BBB permeability, and low toxicity.