title: A sequential procedure for rapid and accurate identification of putative trichomonacidal agents.
abstract: In the current report, a sequential step-wise methodology based on in silico, in vitro and in vivo experimental procedures for the prompt detection of potential trichomonacidal drugs is proposed. A combinatorial of 12 QSAR (Quantitative Structure-Activity Relationship) models based on Linear Discrimination Analysis (LDA) are suggested for the rational identification of new trichomonacidal drugs from virtual screening of in house chemical libraries and drug databases. Subsequently, compounds selected as potential anti-trichomonas are screened in vitro against Trichomonas vaginalis. Finally, molecules with specific trichomonacidal activity are evaluated in vivo. Herein, different molecules were exposed to the proposed methodology. Firstly, the agents were virtually screened and two of the eight molecules (G-1 and dimetridazole) were classified as trichomonacidals by the 12 models. Subsequently both drugs were proved in vitro and in vivo following the workflow procedure. Although a remarkable in vitro activity was observed in both cases, dimetridazole achieved higher MIC100 activity than metronidazole against the resistant isolate. Furthermore, the in vivo models showed a remarkable reduction of lesions of more than 55% in both compounds. These observations support the current flowchart screening and suggest the use of dimetridazole as a promising drug-like scaffold for novel therapeutic alternatives against T. vaginalis resistant infections.
authors.affiliation: Campus of International Excellence Moncloa, Madrid, Spain; Departamento de Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid, Pza. Ramón y Cajal s/n, 28040 Madrid, Spain. Electronic address: alexandraibanez@ucm.es.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Ibáñez-Escribano
authors.affiliation: Departamento de Parasitología, Centro de Bioactivos Químicos, Universidad Central de Las Villas, Santa Clara, 54830 Villa Clara, Cuba. Electronic address: ameneses@uclv.edu.cu.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Meneses-Marcel
authors.affiliation: Unit of Computer-Aided Molecular "Biosilico" Discovery and Bioinformatic Research (CAMD-BIR Unit), Faculty of Chemistry-Pharmacy, Universidad Central de Las Villas, Santa Clara, 54830 Villa Clara, Cuba. Electronic address: yovanimp@uclv.edu.cu.
authors.forename: Yovani
authors.initials: Y
authors.lastname: Marrero-Ponce
authors.affiliation: Campus of International Excellence Moncloa, Madrid, Spain; Departamento de Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid, Pza. Ramón y Cajal s/n, 28040 Madrid, Spain. Electronic address: jjnogal@yahoo.es.
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Nogal-Ruiz
authors.affiliation: Campus of International Excellence Moncloa, Madrid, Spain; Instituto de Química Médica (IQM), CSIC, C/ Juan de la Cierva n° 3, 28006 Madrid, Spain. Electronic address: vjaran@iqm.csic.es.
authors.forename: Vicente J
authors.initials: VJ
authors.lastname: Arán
authors.affiliation: Campus of International Excellence Moncloa, Madrid, Spain; Departamento de Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid, Pza. Ramón y Cajal s/n, 28040 Madrid, Spain. Electronic address: agbarrio@ucm.es.
authors.forename: Alicia
authors.initials: A
authors.lastname: Gómez-Barrio
authors.affiliation: Campus of International Excellence Moncloa, Madrid, Spain; Departamento de Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid, Pza. Ramón y Cajal s/n, 28040 Madrid, Spain. Electronic address: escario@ucm.es.
authors.forename: José Antonio
authors.initials: JA
authors.lastname: Escario
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000302:isolation & purification* / Q000494:pharmacology* / Q000627:therapeutic use; D019295:Computational Biology; D003517:Cyclopentanes / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use; D004131:Dimetridazole / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005260:Female; D051379:Mice; D021261:Parasitic Sensitivity Tests; D021281:Quantitative Structure-Activity Relationship; D011804:Quinolines / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use; D017208:Rats, Wistar; D013997:Time Factors; D014245:Trichomonas Infections / Q000188:drug therapy; D014246:Trichomonas vaginalis / Q000187:drug effects*
chemical_list: C517943:1-(4-(6-bromobenzo(1,3)dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta(c)quinolin-8-yl)ethanone; D000981:Antiprotozoal Agents; D003517:Cyclopentanes; D011804:Quinolines; D004131:Dimetridazole
keywords: In vitro; In vivo; QSAR; TOMOCOMD-CARDD; Trichomonas vaginalis; Virtual screening