New Antitrichomonal Drug-like Chemicals Selected by Bond (Edge)-Based TOMOCOMD-CARDD Descriptors
Alfredo Meneses‐Marcel, Oscar Miguel Rivera-Borroto, Yovani Marrero‐Ponce, Alina Montero, Yanetsy Machado Tugores, José Antonio Escario, Alicia Gómez‐Barrio, David Montero Pereira, Juan José Nogal‐Ruiz, Vladímir V. Kouznetsov, Cristian Ochoa Puentes, Arnold R. Romero Bohórquez, Ricardo J. A. Grau, Francisco Torrens, Froylán Ibarra‐Velarde, Vicente J. Arán · SLAS DISCOVERY · 2008
Bond-based quadratic indices, new TOMOCOMD-CARDD molecular descriptors, and linear discriminant analysis (LDA) were used to discover novel lead trichomonacidals. The obtained LDA-based quantitative structure-activity relationships (QSAR) models, using nonstochastic and stochastic indices, were able to classify correctly 87.91% (87.50%) and 89.01% (84.38%) of the chemicals in training (test) sets, respectively. They showed large Matthews correlation coefficients of 0.75 (0.71) and 0.78 (0.65) for the training (test) sets, correspondingly. Later, both models were applied to the virtual screening of 21 chemicals to find new lead antitrichomonal agents. Predictions agreed with experimental results to a great extent because a correct classification for both models of 95.24% (20 of 21) of the chemicals was obtained. Of the 21 compounds that were screened and synthesized, 2 molecules (chemicals G-1, UC-245) showed high to moderate cytocidal activity at the concentration of 10 microg/ml, another 2 compounds (G-0 and CRIS-148) showed high cytocidal activity only at the concentration of 100 microg/ml, and the remaining chemicals (from CRIS-105 to CRIS-153, except CRIS-148) were inactive at these assayed concentrations. Finally, the best candidate, G-1 (cytocidal activity of 100% at 10 microg/ml) was in vivo assayed in ovariectomized Wistar rats achieving promising results as a trichomonacidal drug-like compound.