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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: alexandraibanez@ucm.es, escario@ucm.es
*Corresponding author. Departamento de Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid, Pza. Ramón y Cajal s/n, 28040 Madrid, Spain. E-mail: alexandraibanez@ucm.es, escario@ucm.es
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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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References

REFERENCES

Adagu, I. S., Nolder, D., Warhurst, D. C. and Rossignol, J.-F. (2002). In vitro activity of nitazoxanide and related compounds against isolates of Giardia intestinalis, Entamoeba histolytica and Trichomonas vaginalis . Journal of Antimicrobial Chemotherapy 49, 103–111.Google Scholar
Arán, V. J., Ochoa, C., Boiani, L., Buccino, P., Cerecetto, H., Gerpe, A., González, M., Montero, D., Nogal, J. J., Gómez-Barrio, A., Azqueta, A., López de Ceráin, A., Piro, O. E. and Castellano, E. E. (2005). Synthesis and biological properties of new 5-nitroindazole derivatives. Bioorganic & Medicinal Chemistry 13, 3197–3207.Google Scholar
Bachmann, L. H., Hobbs, M. M., Seña, A. C., Sobel, J. D., Schwebke, J. R., Krieger, J. N., Scott McClelland, R. and Workowski, K. A. (2011). Trichomonas vaginalis genital infections: progress and challenges. Clinical Infectious Diseases 53, S160–S172.Google Scholar
Cotch, M. F., Pastorek, J. G., Nugent, R. P., Hillier, S. L., Gibbs, R. S., Martin, D. H., Eschenbach, D. A., Edelman, R., Carey, J. C., Regan, J. A., Krohn, M. A., Klebanoff, M. A., Rao, A. V., Rhoads, G. G., Yaffe, S. J., Catz, C. S., McNellis, D., Berendes, H. W., Blackwelder, W. C., Kaslow, R. A., Reed, G. F., Greenberg, E. M., Williams, S. and Rettig, P. J. (1997). Trichomonas vaginalis associated with low birth weight and preterm delivery. Sexually Transmitted Diseases 24, 353–360.CrossRefGoogle ScholarPubMed
Cudmore, S. L., Delgaty, K. L., Hayward-McClelland, S. F., Petrin, D. P. and Garber, G. E. (2004). Treatment of infections caused by metronidazole-resistant Trichomonas vaginalis . Clinical Microbiology Reviews 17, 783–793.Google Scholar
Dunne, R. L., Dunn, L. A., Upcroft, P., O'Donoghue, P. J. and Upcroft, J. A. (2003). Drug resistance in the sexually transmitted protozoan Trichomonas vaginalis . Cell Research 13, 239–249.Google Scholar
El-Gayar, E. K. and Rashwan, M. F. (2007). Cervical intraepithelial neoplasia (CIN) and Trichomonas vaginalis infection as revealed by polymerase chain reaction. Journal of the Egyptian Society of Parasitology 37, 623–630.Google Scholar
Ertl, P., Rohde, B. and Selzer, P. (2000). Fast calculation of molecular polar surface area as a sum of fragment-based contributions and its application to the prediction of drug transport properties. Journal of Medicinal Chemistry 43, 3714–3717.CrossRefGoogle Scholar
Fonseca-Berzal, C., Escario, J. A., Arán, V. J. and Gómez-Barrio, A. (2014). Further insights into biological evaluation of new anti-Trypanosoma cruzi 5-nitroindazoles. Parasitology Research 113, 1049–1056.Google Scholar
Hall, B. S. and Wilkinson, S. R. (2012). Activation of benznidazole by trypanosomal type I nitroreductases results in glyoxal formation. Antimicrobial Agents and Chemotherapy 56, 115–123.Google Scholar
Hall, B. S., Bot, C. and Wilkinson, S. R. (2011). Nifurtimox activation by trypanosomal type I nitroreductases generates cytotoxic nitrile metabolites. Journal of Biological Chemistry 286, 13088–13095.Google Scholar
Helms, D. J., Mosure, D. J., Secor, W. E. and Workowski, K. A. (2008). Management of Trichomonas vaginalis in women with suspected metronidazole hypersensitivity. American Journal of Obstetrics and Gynecology 198, 370.e1–370.e7.Google Scholar
Hernández-Núñez, E., Tlahuext, H., Moo-Puc, R., Torres-Gómez, H., Reyes-Martínez, R., Cedillo-Rivera, R., Nava-Zuazo, C. and Navarrete-Vazquez, G. (2009). Synthesis and in vitro trichomonicidal, giardicidal and amebicidal activity of N-acetamide(sulfonamide)-2-methyl-4-nitro-1H-imidazoles. European Journal of Medicinal Chemistry 44, 2975–2984.Google Scholar
Ibáñez Escribano, A., Meneses Marcel, A., Machado Tugores, Y., Nogal Ruiz, J. J., Arán Redó, V. J., Garcia-Trevijano, J. A. and Gómez Barrio, A. (2012). Validation of a modified fluorimetric assay for the screening of trichomonacidal drugs. Memórias do Instituto Oswaldo Cruz 107, 637–643.CrossRefGoogle Scholar
Ibáñez-Escribano, A., Meneses-Marcel, A., Marrero-Ponce, Y., Nogal-Ruiz, J. J., Arán, V. J., Gómez-Barrio, A. and Escario, J. A. (2014). A sequential procedure for rapid and accurate identification of putative trichomonacidal agents. Journal of Microbiological Methods 105, 162–167.Google Scholar
Ibáñez-Escribano, A., Reviriego, F., Nogal-Ruiz, J. J., Meneses-Marcel, A., Gómez-Barrio, A., Escario, J. A. and Arán, V. J. (2015). Synthesis and in vitro and in vivo biological evaluation of substituted nitroquinoxalin-2-ones and 2,3-diones as novel trichomonacidal agents. European Journal of Medicinal Chemistry 94, 276–283.Google Scholar
Kissinger, P., Amedee, A., Clark, R. A., Dumestre, J., Theall, K. P., Myers, L., Hagensee, M. E., Farley, T. A. and Martin, D. H. (2009). Trichomonas vaginalis treatment reduces vaginal HIV-1 shedding. Sexually Transmitted Diseases 36, 11–16.Google Scholar
Kumar, L., Sarswat, A., Lal, N., Sharma, V. L., Jain, A., Kumar, R., Verma, V., Maikhuri, J. P., Kumar, A., Shukla, P. K. and Gupta, G. (2010). Imidazole derivatives as possible microbicides with dual protection. European Journal of Medicinal Chemistry 45, 817–824.Google Scholar
Kumar, L., Sarswat, A., Lal, N., Jain, A., Kumar, S., Kumar, S. T. V. S. K., Maikhuri, J. P., Pandey, A. K., Shukla, P. K., Gupta, G., Sharma, V. L. (2011). Design and synthesis of 3-(azol-1-yl)phenylpropanes as microbicidal spermicides for prophylactic contraception. Bioorganic & Medicinal Chemistry Letters 21, 176–181.Google Scholar
Kumar, L., Jain, A., Lal, N., Sarswat, A., Jangir, S., Kumar, L., Singh, V., Shah, P., Jain, S. K., Maikhuri, J. P., Siddiqi, M. I., Gupta, G. and Sharma, V. L. (2012). Potentiating metronidazole scaffold against resistant Trichomonas: design, synthesis, biology and 3D–QSAR analysis. ACS Medicinal Chemistry Letters 3, 83–87.Google Scholar
Lazenby, G. B., Taylor, P. T., Badman, B. S., McHaki, E., Korte, J. E., Soper, D. E. and Young Pierce, J. (2014). An association between Trichomonas vaginalis and high-risk human papillomavirus in rural Tanzanian women undergoing cervical cancer screening. Clinical Therapeutics 36, 38–45.Google Scholar
Leitsch, D., Kolarich, D., Binder, M., Stadlmann, J., Altmann, F. and Duchêne, M. (2009). Trichomonas vaginalis: metronidazole and other nitroimidazole drugs are reduced by the flavin enzyme thioredoxin reductase and disrupt the cellular redox system. Implications for nitroimidazole toxicity and resistance. Molecular Microbiology 72, 518–536.Google Scholar
Lewis, D. (2014). Trichomoniasis. Medicine (Avingdon) 42, 369–371.Google Scholar
Lipinski, C. A. (2004). Lead- and drug-like compounds: the rule-of-five revolution. Drug Discovery Today Technologies 1, 337–341.Google Scholar
Lipinski, C. A., Lombardo, F., Dominy, B. W. and Feeney, P. J. (1997). Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced Drug Delivery Reviews 23, 3–25.Google Scholar
Marrero-Ponce, Y., Machado-Tugores, Y., Montero Pereira, D., Escario, J. A., Gómez Barrio, A., Nogal-Ruiz, J. J., Ochoa, C., Arán, V. J., Martínez-Fernández, A. R., García Sánchez, R. N., Montero-Torres, A., Torrens, F. and Meneses-Marcel, A. (2005). A computer-based approach to the rational discovery of new trichomonacidal drugs by atom-type linear indices. Current Drug Discovery Technologies 2, 245–265.Google Scholar
Marrero-Ponce, Y., Meneses-Marcel, A., Castillo-Garit, J. A., Machado-Tugores, Y., Escario, J. A., Gómez Barrio, A., Montero Pereira, D., Nogal-Ruiz, J. J., Arán, V. J., Martínez-Fernández, A. R., Torrens, F., Rotondo, R., Ibarra-Velarde, F. and Alvarado, Y. J. (2006). Predicting antitrichomonal activity: a computational screening using atom-based bilinear indices and experimental proofs. Bioorganic & Medicinal Chemistry 14, 6502–6524.Google Scholar
McClelland, R. S., Sangare, L., Hassan, W. M., Lavreys, L., Mandaliya, K., Kiarie, J., Ndinya-Achola, J., Jaoko, W. and Baeten, J. M. (2007). Infection with Trichomonas vaginalis increases the risk of HIV-1 acquisition. Journal of Infectious Diseases 195, 698–702.Google Scholar
Molinspiration Cheminformatics (2014). Slovak Republic Free online molecular descriptor calculations. Available from: http://www.molinspiration.com/services/properties.html.Google Scholar
Moodley, P., Wilkinson, D., Connolly, C., Moodley, J. and Sturm, A. W. (2002). Trichomonas vaginalis is associated with pelvic inflammatory disease in women infected with human immunodeficiency virus. Clinical Infectious Diseases 34, 519–522.CrossRefGoogle ScholarPubMed
Muro, B., Reviriego, F., Navarro, P., Marín, C., Ramírez-Macías, I., Rosales, M. J., Sánchez-Moreno, M. and Arán, V. J. (2014). New perspectives on the synthesis and antichagasic activity of 3-alkoxy-1-alkyl-5-nitroindazoles. European Journal of Medicinal Chemistry 74, 124–134.Google Scholar
Navarrete-Vázquez, G., Rojano-Vilchis, M. M., Yépez-Mulia, L., Meléndez, V., Gerena, L., Hernández-Campos, A., Castillo, R. and Hernández-Luis, F. (2006). Synthesis and antiprotozoal activity of some 2-(trifluoromethyl)-1H-benzimidazole bioisosteres. European Journal of Medicinal Chemistry 41, 135–141.Google Scholar
Organic Chemistry Portal (2014). OSIRIS Property Explorer. Free online software. Available from: http://www.organic-chemistry.org/prog/peo/.Google Scholar
Palm, K., Stenberg, P., Luthman, K. and Artursson, P. (1997). Polar molecular surface properties predict the intestinal absorption of drugs in human. Pharmaceutical Research 14, 568–571.CrossRefGoogle Scholar
Sutcliffe, S., Neace, C., Magnuson, N. S., Reeves, R. and Alderete, J. F. (2012). Trichomonosis, a common curable STI, and prostate carcinogenesis – a proposed molecular mechanism. PLoS Pathogens 8, e1002801.CrossRefGoogle ScholarPubMed
Trochine, A., Creek, D. J., Faral-Tello, P., Barrett, M. P. and Robello, C. (2014). Benznidazole biotransformation and multiple targets in Trypanosoma cruzi revealed by metabolomics. PLoS Neglected Tropical Diseases 8, e2844.Google Scholar
Van der Pol, B. (2007). Trichomonas vaginalis infection: the most prevalent nonviral sexually transmitted infection receives the least public health attention. Clinical Infectious Diseases 44, 23–25.Google Scholar
Veber, D. F., Johnson, S. R., Cheng, H. Y., Smith, B. R., Ward, K. W. and Kopple, K. D. (2002). Molecular properties that influence the oral bioavailability of drug candidates. Journal of Medicinal Chemistry 45, 2615–2623.Google Scholar
Vega, M. C., Rolón, M., Montero-Torres, A., Fonseca-Berzal, C., Escario, J. A., Gómez-Barrio, A., Gálvez, J., Marrero-Ponce, Y. and Arán, V. J. (2012). Synthesis, biological evaluation and chemometric analysis of indazole derivatives. 1,2-Disubstituted 5-nitroindazolinones, new prototypes of antichagasic drug. European Journal of Medicinal Chemistry 58, 214–227.CrossRefGoogle Scholar
Wang, C. C., McClelland, R. S., Reilly, M., Overbaugh, J., Emery, S. R., Mandaliya, K., Chohan, B., Ndinya-Achola, J., Bwayo, J. and Kreiss, J. K. (2001). The effect of treatment of vaginal infections on shedding of human immunodeficiency virus type 1. Journal of Infectious Diseases 183, 1017–1022.Google Scholar
WHO (World Health Organization) (2007). Global Strategy for the Prevention and Control of Sexually Transmitted Infections: 2006–2015, Geneva, Switzerland.Google Scholar
WHO (World Health Organization) (2012). Global Incidence and Prevalence of Selected Curable Sexually Transmitted Infections-2008, Geneva, Switzerland.Google Scholar
Zhao, Y. H., Abraham, M. H., Le, J., Hersey, A., Luscombe, C. N., Beck, G., Sherborne, B. and Cooper, I. (2002). Rate-limited steps of human oral absorption and QSAR studies. Pharmaceutical Research 19, 1446–1457.Google Scholar
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