Ligand-based discovery of novel trypanosomicidal drug-like compounds: In silico identification and experimental support

Two-dimensional bond-based linear indices and linear discriminant analysis are used in this report to perform a quantitative structure–activity relationship study to identify new trypanosomicidal compounds. A database with 143 anti-trypanosomal and 297 compounds having other clinical uses, are utilized to develop the theoretical models. The best discriminant models computed using bond-based linear indices provides accuracies greater than 90 for both training and test sets. Our models identify as anti-trypanosomals five out of nine compounds of a set of already-synthesized substances. The in vitro anti-trypanosomal activity of this set against epimastigote forms of Trypanosoma cruzi is assayed. Both models show a perfect agreement between theoretical predictions and experimental results. The compounds identified as active ones show more than 98% of anti-epimastigote elimination (AE) at a concentration of 100 μg/mL. Besides, three compounds show more than 70% of AE at a concentration of 10 μg/mL. Finally, compounds with the best “activity against epimastigote forms/unspecific cytotoxicity” ratio are evaluated using an amastigote susceptibility assay. It should be noticed that, compound Va7-71 exhibit a 100% of intracellular amastigote elimination and shows similar activity when compared to a standard trypanosomicidal as nifurtimox. Finally, we can emphasize that, the present algorithm constitutes a step forward in the search for efficient ways of discovering new anti-trypanosomal compounds.

Graphical abstractTwo QSAR models to identify new trypanosomicidal compounds were developed. three compounds showed more than 70% of anti-epimastigote elimination at 10 μg/mL. Additionally, compound Va7-71 has a 100% of intracellular amastigote elimination.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► The two discriminant models had accuracies bigger than 90 for training and test sets. ► Our models identify as anti-trypanosomals five/nine new-synthesized compounds. ► Anti-trypanosomal activity against epimastigote forms of T. cruzi is assayed in vitro. ► Three compounds showed more than 70% of AE at a concentration of 10 μg/mL. ► Compound Va7-71 has a 100% of intracellular amastigote elimination.