Chagas disease and African sleeping sickness are neglected tropical diseases (NTD) caused by
Trypanosoma parasites, with current treatments facing challenges like toxicity and resistance. This
study integrates machine learning and Quantitative Structure-Activity Relationship (QSAR) models
to repurpose Food and Drug Administration (FDA)-approved drugs as potential treatments for
these diseases. A dataset of 21,608 compounds with inhibitory activity against Trypanosoma cruzi
and Trypanosoma brucei was analyzed using PubChem fingerprints. Random Forest and Extreme
Gradient Boosting models were trained and applied to screen the ZINC-22 database for new
therapeutic options. Posaconazole was predicted as the top candidate for multitarget activity against
both Trypanosoma species, followed by pentamidine, a drug already approved for sleeping sickness.
Additionally, 40 other drug candidates were identified by the models (pIC50 > 6 and coefficient of
variation < 0.05), mainly antineoplastics (32%) and antifungals (19%). This approach demonstrates
the potential of computational techniques in accelerating the discovery of drug candidates for
neglected infectious diseases.