Fluorine-containing benzothiazole as a novel trypanocidal agent: design, in silico study, synthesis and activity evaluation

Trypanosoma cruzi (T. cruzi) is the etiologic agent of Chagas disease. In the bloodstream of humans, this parasite is in the trypomastigote stage and can infect host cells. Its metabolism is dependent on the glycolysis pathway, and one enzyme important for the optimal functioning of this metabolic pathway is triosephosphate isomerase (TIM). The significant difference (48 %) between the interfacial residues of TIMs from humans and trypanosomes and the importance of these residues for the stability of T. cruzi TIM (TcTIM) make this enzyme a possible therapeutic target. In the present study, 204 benzazole derivatives were designed as TcTIM inhibitors, including some well-known ligands. Compounds were analyzed with docking simulations and a QSAR study, and their molecular physicochemical properties were calculated. The five compounds selected from in silico screening were later synthesized and assayed in vitro for their trypanocidal activity on a resistant strain of T. cruzi. All compounds showed affinity for the aromatic cluster of the TcTIM interface, with important electrostatic, hydrophobic and π–π interactions. The benzothiazole derivatives had better physicochemical attributes than the currently prescribed drug, benznidazol. Although BT1and BT2 showed toxicity problems, BT3 did not. The QSAR study indicates that the inhibition of TcTIM improves when the compounds (especially benzothiazoles) are substituted with hyper-conjugated systems and there is a sulfur atom in their structure. It was found with in vitro assays that compound BT3 is a better trypanocidal agent than the currently used drug on the market for the treatment of Chagas disease, benznidazol.