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Identification In Silico and In Vitro of Novel Trypanosomicidal Drug-like Compounds
* 1, 2, 3, 4 , 1 , 5 , 5 , 5 , 6 , 6 , 7 , 7 , 2, 4 , 4 , 3
1  Applied Chemistry Research Center, Faculty of Chemistry-Pharmacy, Universidad Central “Marta Abreu” de Las Villas, Santa Clara, 54830, Villa Clara, Cuba
2  Unit of Computer-Aided Molecular “Biosilico” Discovery and Bioinformatic Research (CAMD-BIR Unit), Faculty of Chemistry-Pharmacy. Universidad Central “Marta Abreu” de Las Villas, Santa Clara, 54830, Villa Clara, Cuba
3  Departament de Bioquímica i Biologia Molecular, Universitat de València, E-46100 Burjassot, Spain
4  Institut Universitari de Ciència Molecular, Universitat de València, Edifici d'Instituts de Paterna, P.O. Box 22085, E-46071, València, Spain
5  Laboratorio de Química Orgánica y Biomolecular, Escuela de Química, Universidad Industrial de Santander, Bucaramanga, Colombia
6  Centro para el Desarrollo de la Investigacion Cientifica (CEDIC), Pai Perez 265 casi Mariscal Estigarribia. Asuncion-Paraguay
7  Departamento de Parasitología, Facultad de Farmacia, UCM, Pza. Ramón y Cajal s/n, 28040 Madrid

Abstract: Atom-based bilinear indices and linear discriminant analysis (LDA) are used to discover novel trypanosomicidal compounds. The obtained LDA-based quantitative structure-activity relationship (QSAR) models, using non-stochastic and stochastic indices, provide accuracies of 89.02% (85.11%) and 89.60% (88.30%) of the chemicals in the training (test) sets, respectively. Later, both models were applied to the virtual screening of 18 in house synthesized compounds to find new pro-lead antitrypanosomal agents. The in vitro antitrypanosomal activity of this set against epimastigote forms of Trypanosoma cruzi is assayed. Predictions agree with experimental results to a great extent (16/18) of the chemicals. Sixteen compounds show more than 70% of epimastigote inhibition at a concentration 100 µg/mL. In addition, three compounds (CRIS 112, CRIS 140 and CRIS 147) present more than 70% of epimastigote inhibition at a concentration of 10 µg/mL (79.95%, 73.97% and 78.13%, respectively) with low values of cytotoxicity (19.7%, 7.44% and 20.63%, correspondingly).Taking into account all these results, we could say that these three compounds could be optimized in forthcoming works. Even though none of them resulted more active than nifurtimox, the current results constitute a step forward in the search for efficient ways to discover new lead antitrypanosomals.
Keywords: Atom-based bilinear indices, Anti-epimastigote elimination, Cytotoxicity, Trypanosoma cruzi, Trypanosomicidal, virtual screening