Identifying thiourea-based hybrids of quinazoline and oxospirochromane as inhibitors of Plasmodium cysteine proteases arresting the parasitic growth at the early trophozoite stage.

Malaria, an infectious disease, impacts approximately half of the global population. To tackle the growing problem of drug resistance to treatments such as artemisinin-based combination therapies (ACT), we synthesized thiourea-based compounds (QS1-QS16) by blending quinazoline and oxospirochromane. These compounds underwent testing to assess their in-vitro efficacy against both drug-sensitive and drug-resistant strains of the Plasmodium parasite. Among all the synthesized compounds, QS5 showed good inhibitory efficacy against Pf3D7 and PfW2 with IC50 3.18 and 3.98 µM respectively, and QS13 with IC50 3.56 and 4.43 µM respectively. The promising compounds were screened against the Plasmodium parasite's falcipain-2 and falcipain-3 enzymes. The ligands QS5 and QS13 displayed inhibition against PfFP-2 (IC50 3.9 and 4.9 µM) and PfFP-3 (IC50 4.6 and 5.9 µM) respectively. Furthermore, the selected molecules showed no significant cytotoxicity in non-cancerous Vero cell lines, and hemolysis assays on healthy RBCs confirmed the molecules' specific antiplasmodial activity. Docking investigations explored ligand interaction with PfFP2 and PfFP3 binding sites. We investigated thiourea-based compounds, notably QS5 and QS13, as potential solutions to combat drug-resistant malaria strains. Our findings suggest that these compounds exhibit promising activity against the parasite at its early stages, offering hope for developing new antimalarial therapies.