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In vitro trichomonacidal activity and preliminary in silico chemometric studies of 5-nitroindazolin-3-one and 3-alkoxy-5-nitroindazole derivatives

Published online by Cambridge University Press:  04 November 2015

ALEXANDRA IBÁÑEZ-ESCRIBANO Open the ORCID record for ALEXANDRA IBÁÑEZ-ESCRIBANO [Opens in a new window] ,
JUAN JOSÉ NOGAL-RUIZ ,
ALICIA GÓMEZ-BARRIO ,
VICENTE J. ARÁN  and
JOSÉ ANTONIO ESCARIO
ALEXANDRA IBÁÑEZ-ESCRIBANO*
Affiliation:
Moncloa Campus of International Excellence, UCM-UPM & CSIC, Madrid, Spain Departamento de Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), Pza. Ramón y Cajal s/n, 28040 Madrid, Spain
JUAN JOSÉ NOGAL-RUIZ
Affiliation:
Moncloa Campus of International Excellence, UCM-UPM & CSIC, Madrid, Spain Departamento de Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), Pza. Ramón y Cajal s/n, 28040 Madrid, Spain
ALICIA GÓMEZ-BARRIO
Affiliation:
Moncloa Campus of International Excellence, UCM-UPM & CSIC, Madrid, Spain Departamento de Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), Pza. Ramón y Cajal s/n, 28040 Madrid, Spain
VICENTE J. ARÁN
Affiliation:
Moncloa Campus of International Excellence, UCM-UPM & CSIC, Madrid, Spain Instituto de Química Médica (IQM), CSIC, c/ Juan de la Cierva 3, 28006 Madrid, Spain
JOSÉ ANTONIO ESCARIO*
Affiliation:
Moncloa Campus of International Excellence, UCM-UPM & CSIC, Madrid, Spain Departamento de Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), Pza. Ramón y Cajal s/n, 28040 Madrid, Spain
*
*Corresponding author. Departamento de Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid, Pza. Ramón y Cajal s/n, 28040 Madrid, Spain. E-mail: [email protected], [email protected]
*Corresponding author. Departamento de Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid, Pza. Ramón y Cajal s/n, 28040 Madrid, Spain. E-mail: [email protected], [email protected]
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Summary

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.

Keywords

Trichomonas vaginalisrule of fivenitroindazoleschemotherapytrichomonosispharmacokinetic propertiestoxicityMolinspirationOSIRIS software
Type
Research Article
Information
Parasitology , Volume 143 , Issue 1 , January 2016 , pp. 34 - 40
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Copyright
Copyright © Cambridge University Press 2015 

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