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

• Published in: European journal of medicinal chemistry Vol. 46; no. 8; pp. 3324 - 3330
• Main Authors: Castillo-Garit, Juan Alberto, Vega, Maria Celeste, Rolón, Miriam, Marrero-Ponce, Yovani, Gómez-Barrio, Alicia, Escario, José A., Bello, Alfredo Alvarez, Montero, Alina, Torrens, Francisco, Pérez-Giménez, Facundo, Arán, Vicente J., Abad, Concepción
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier Masson SAS 01.08.2011; Elsevier
• Subjects: Algorithms; Amastigote susceptibility assay; Animals; Anti-epimastigote elimination; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiparasitic agents; Biological and medical sciences; Bond-based linear indices; Cell Survival - drug effects; Chagas Disease - drug therapy; Chagas Disease - parasitology; Databases, Factual; Discriminant Analysis; Drug Discovery - methods; Fibroblasts - parasitology; High-Throughput Screening Assays; Humans; Life Cycle Stages - drug effects; Ligands; Medical sciences; Models, Theoretical; Pharmacology. Drug treatments; Quantitative Structure-Activity Relationship; Software; Trypanocidal Agents - chemistry; Trypanocidal Agents - pharmacology; Trypanosoma cruzi; Trypanosoma cruzi - drug effects; Trypanosoma cruzi - growth & development; Trypanosomicidal; Trypanosomicidal; Amastigote susceptibility assay; Anti-epimastigote elimination; Bond-based linear indices; Trypanosoma cruzi; Nitro compound; Ligand; Lactam; Modeling; Antiprotozoal agent; Chlorine Organic compounds; Molecular model; Kinetoplastida; Protozoa; Quinoxaline derivatives; Discriminant analysis; Rodentia; Prediction; Biological activity; Vertebrata; Mammalia; Cell line; Epimastigote; Mouse; Parasiticide; Amastigote; Chemometrics; Macrophage
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2011.04.057

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. Two 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. [Display omitted] ► 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.