A Novel Triose Phosphate Isomerase Inhibitor With Dual Trypanosomicidal Activity was Identified Using Artificial Intelligence-Based Virtual Screening.

Chagas disease and leishmaniasis are neglected protozoan diseases recognized by the World Health Organization as major public health problems. These diseases affect millions of people worldwide, yet effective treatments remain unavailable. Triosephosphate isomerase (TIM), a glycolytic enzyme that exhibits high catalytic efficiency for the isomerization of glyceraldehyde-3-phosphate and dihydroxyacetone-phosphate exclusively in its dimeric form, was subjected to virtual screening. Using a deep neural network for structure-based drug design that predicts binding affinity between small molecules and proteins of known structure, 12.5 million commercially available compounds were screened. From this, 82 compounds were selected for in vitro evaluation. Six compounds inhibited TIM from Trypanosoma cruzi, three of which exhibited anti-T. cruzi activity. Eight compounds demonstrated activity against the parasites T. cruzi and Leishmania infantum. Two compounds showed similar potency against both parasites: 3-(1-acetyl-5-(4-bromophenyl)-4,5-dihydro-1H-pyrazol-3-yl)-4-hydroxy-6-methyl-2H-pyran-2-one (IC50 = 16 ± 3 μM) and 3-[(4-bromophenyl)sulfanyl]-1-(3-nitrophenyl)propan-1-one (IC50 = 12 ± 1 μM). These compounds exhibit favorable selectivity and toxicological profiles, as well as in vivo activity, indicating their potential for future drug development.