title: Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) of some benzimidazole derivatives with trichomonicidal activity.
abstract: Trichomonosis is a common sexually transmitted infectious disease linked to reproductive health complications. Recently, the benzimidazole nucleus has emerged as a promising scaffold to develop new trichomonicidal agents. Despite the fact that large amounts of experimental data have been accumulated over the past eight years, no quantitative studies have yet been reported on this class of compounds. In our effort to develop new antiparasitic benzimidazole derivatives, we report in this paper CoMFA and CoMSIA studies with an initial set of 70 benzimidazole derivatives with trichomonicidal activity. Four CoMFA models and eight CoMSIA models were generated; ten of these models had values of r(2) > 0.6 and q(2) > 0.5. The best CoMFA model had r(2) = 0.936 and q(2) = 0.634, and the best CoMSIA model had r(2) = 0.858 and q(2) = 0.642. These models were generated by using two conformer selection methodologies (minimum energy conformations and 3D similarity), and three charge types (Mulliken, Gasteiger-Hükel and electrostatic potential atomic charges). The putative active tautomers of 1H-benzimidazole derivatives were selected using 3D-QSAR calculations. All models were validated via an external test set with 13 molecules. The best models satisfied additional validation criteria. The contour maps generated show the most important features that a benzimidazole derivative should have for trichomonicidal activity; they also, suggest that substituents at the 2- and 6-positions are important in the generation of derivatives with strong activity.
authors.affiliation: Facultad de Química, Departamento de Farmacia, UNAM, México, DF 04510, Mexico.
authors.forename: Jaime
authors.initials: J
authors.lastname: Pérez-Villanueva
authors.forename: José L
authors.initials: JL
authors.lastname: Medina-Franco
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Caulfield
authors.forename: Alicia
authors.initials: A
authors.lastname: Hernández-Campos
authors.forename: Francisco
authors.initials: F
authors.lastname: Hernández-Luis
authors.forename: Lilián
authors.initials: L
authors.lastname: Yépez-Mulia
authors.forename: Rafael
authors.initials: R
authors.lastname: Castillo
mesh_terms: D000465:Algorithms; D000994:Antitrichomonal Agents / Q000737:chemistry* / Q000494:pharmacology; D001562:Benzimidazoles / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D015195:Drug Design; D004583:Electrons; D006801:Humans; D008432:Mathematical Computing; D008958:Models, Molecular; D008968:Molecular Conformation; D021281:Quantitative Structure-Activity Relationship; D013237:Stereoisomerism; D013816:Thermodynamics; D014245:Trichomonas Infections / Q000188:drug therapy / Q000469:parasitology; D014246:Trichomonas vaginalis / Q000187:drug effects* / Q000254:growth & development
chemical_list: D000994:Antitrichomonal Agents; D001562:Benzimidazoles