title: Ligand-based discovery of novel trypanosomicidal drug-like compounds: in silico identification and experimental support.
abstract: 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.
authors: Applied Chemistry Research Center, Faculty of Chemistry-Pharmacy and Department of Drug Design, Chemical Bioactive Center, Central University of Las Villas, Santa Clara 54830, Villa Clara, Cuba. jacgarit@yahoo.es
authors: Juan Alberto
authors: JA
authors: Castillo-Garit
authors: Maria Celeste
authors: MC
authors: Vega
authors: Miriam
authors: M
authors: Rolón
authors: Yovani
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authors: Marrero-Ponce
authors: Alicia
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authors: Gómez-Barrio
authors: José A
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authors: Escario
authors: Alfredo Alvarez
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authors: Bello
authors: Alina
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authors: Montero
authors: Francisco
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authors: Torrens
authors: Facundo
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authors: Pérez-Giménez
authors: Vicente J
authors: VJ
authors: Arán
authors: Concepción
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authors: Abad