Using the Scaffold of FDA-Approved Drugs with Trypanocidal Activity to Identify New Anti-Trypanosoma cruzi Agents: An In Silico and In Vitro Approach.

Chagas disease affects millions of people worldwide, including those in Latin America. The only drugs available for its treatment are benznidazole and nifurtimox. However, these drugs present high toxicity and limited efficacy. Therefore, the search for new treatments continues. In this regard, computer-assisted drug design has been implemented in scientific research for drug repurposing, allowing for reduced costs and time. Therefore, the objective of this work was to search for analogs of FDA-approved drugs with activity against Trypanosoma cruzi through ligand-based virtual screening and their biological evaluation against blood trypomastigotes. The compound TD-095 (LC50 = 48.60 and 13.75 µM), a ketanserin analogue, TS-936 (LC50 = 71.55 and 37.54 µM), a terfenadine analogue, and TD-831 (LC50 = 75.94 and 26.17 µM), a sulfasalazine analogue, were considered as potential trans-sialidase inhibitors; TIM-967 (LC50 = 69.70 and 39.69 µM) and LK-284 (LC50 = 116.7 and 82.29 µM), two sulfonylurea analogues, were considered as potential triosephosphate isomerase inhibitors, showing better trypanocidal activity against NINOA and INC-5 strains, respectively, than the reference drugs. Molecular dynamics simulations predicted the stability of the compounds in complex with their respective proteins. Finally, the ADMET predictive analysis showed favorable properties for the compounds. These results support continued research into new agents against Trypanosoma cruzi, using structures of drugs already approved by the FDA.