title: In vitro trichomonacidal activity and preliminary in silico chemometric studies of 5-nitroindazolin-3-one and 3-alkoxy-5-nitroindazole derivatives.
abstract: A selection of 1,2-disubstituted 5-nitroindazolin-3-ones (1-19) and 3-alkoxy-5-nitroindazoles substituted at positions 1 (20-24) or 2 (25-39) from our in-house compound library were screened in vitro against the most common curable sexually transmitted pathogen, Trichomonas vaginalis. A total of 41% of the studied molecules (16/39) achieved a significant activity of more than 85% growth inhibition at the highest concentration assayed (100 µg mL(-1)). Among these compounds, 3-alkoxy-5-nitroindazole derivatives 23, 24, 25 and 27 inhibited parasite growth by more than 50% at 10 µg mL(-1). In addition, the first two compounds (23, 24) still showed remarkable activity at the lowest dose tested (1 µg mL(-1)), inhibiting parasite growth by nearly 40%. Their specific activity towards the parasite was corroborated by the determination of their non-specific cytotoxicity against mammalian cells. The four mentioned compounds exhibited non-cytotoxic profiles at all of the concentrations assayed, showing a fair antiparasitic selectivity index (SI > 7·5). In silico studies were performed to predict pharmacokinetic properties, toxicity and drug-score using Molinspiration and OSIRIS computational tools. The current in vitro results supported by the virtual screening suggest 2-substituted and, especially, 1-substituted 3-alkoxy-5-nitroindazoles as promising starting scaffolds for further development of novel chemical compounds with the main aim of promoting highly selective trichomonacidal lead-like drugs with adequate pharmacokinetic and toxicological profiles.
authors.affiliation: Moncloa Campus of International Excellence,UCM-UPM & CSIC,Madrid,Spain.
authors.forename: Alexandra
authors.identifier: http://orcid.org/0000-0002-8687-1100
authors.initials: A
authors.lastname: Ibáñez-Escribano
authors.affiliation: Moncloa Campus of International Excellence,UCM-UPM & CSIC,Madrid,Spain.
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Nogal-Ruiz
authors.affiliation: Moncloa Campus of International Excellence,UCM-UPM & CSIC,Madrid,Spain.
authors.forename: Alicia
authors.initials: A
authors.lastname: Gómez-Barrio
authors.affiliation: Moncloa Campus of International Excellence,UCM-UPM & CSIC,Madrid,Spain.
authors.forename: Vicente J
authors.initials: VJ
authors.lastname: Arán
authors.affiliation: Moncloa Campus of International Excellence,UCM-UPM & CSIC,Madrid,Spain.
authors.forename: José Antonio
authors.initials: JA
authors.lastname: Escario
mesh_terms: D000438:Alcohols / Q000737:chemistry; D000818:Animals; D000994:Antitrichomonal Agents / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival; D002522:Chlorocebus aethiops; D003198:Computer Simulation; D007191:Indazoles / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D021261:Parasitic Sensitivity Tests; D013329:Structure-Activity Relationship; D014245:Trichomonas Infections / Q000188:drug therapy*; D014246:Trichomonas vaginalis / Q000187:drug effects*; D014709:Vero Cells
chemical_list: D000438:Alcohols; D000994:Antitrichomonal Agents; D007191:Indazoles; C059688:alkoxyl radical; C530840:5-nitroindazole
keywords: Molinspiration; OSIRIS software; Trichomonas vaginalis; chemotherapy; nitroindazoles; pharmacokinetic properties; rule of five; toxicity; trichomonosis