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17 October 2017

Activity of 2-benzyl-1-(2-hydroxyethyl)-5-nitroindazolin-3-one on Trypanosoma cruzi Bloodstream Trypomastigotes (Y strain): In Vitro and In Vivo Studies †

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1
Departamento de Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid (CEI Campus Moncloa UCM-UPM and CSIC), Pza. Ramón y Cajal s/n, 28040 Madrid, Spain
2
Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fiocruz, Av. Brasil 4365, 21040-900 Rio de Janeiro, Brazil
3
Instituto de Química Médica (IQM), CSIC, Calle Juan de la Cierva 3, 28006 Madrid, Spain
*
Author to whom correspondence should be addressed.
Proceedings2017, 1(6), 655;https://doi.org/10.3390/proceedings1060655
This article belongs to the Proceedings Proceedings of the 1st Molecules Medicinal Chemistry Symposium, Barcelona, Spain
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Benznidazole and nifurtimox, the currently available drugs for the specific treatment of Chagas disease, show limited effectiveness and high toxicity that prompt the identification of therapeutic alternatives. In this context, our group has proposed 5-nitroindazole derivatives as antichagasic prototypes, according to their activity in vitro and in vivo [1,2,3,4,5]. The lack of cytotoxicity and outstanding activity on the replicative forms of Trypanosoma cruzi (i.e., epimastigotes and intracellular amastigotes) previously shown by 2-benzyl-1-(2-hydroxyethyl)-5-nitroindazolin-3-one [5], encouraged assaying this compound in vitro on bloodstream trypomastigotes of Y strain (DTU TcII) and then, moved it to murine models of toxicity and infection. After confirming NOAEL >25 mg/kg and no signs of acute toxicity (i.e., normal weight, organs appearance, hemogram and biochemistry), infected mice were treated on the 5th and 8th dpi with doses of 25, 12.5 or 6.25 mg/kg/day. The results obtained in this acute model of T. cruzi infection in mice showed that this compound achieved ca. 30% of parasitemia reduction on the 8th dpi when administered either at 25 mg/kg/day p.o. or 6.25 mg/kg/day ip. Accordingly, new treatment schemes and molecule optimization are now considered for further analysis in vivo, aiming to contribute to the identification of novel alternative therapies for Chagas disease.

Author Contributions

C.F.-B., C.F.d.S. and M.d.N.C.S. have conceived and designed the experiments. V.J.A. has designed and synthesized the compound here evaluated. C.F.-B., C.F.d.S., M.M.B., F.H.G.-d.-S., M.V. and K.C.D. have performed the experiments. C.F.-B., C.F.d.S., J.A.E., V.J.A., M.d.N.C.S. and A.G.-B. have analyzed the data. C.F.-B., J.A.E., V.J.A., M.d.N.C.S. and A.G.-B. have written this abstract. All authors have read and agreed to the published version of the manuscript.

Acknowledgments

The authors thank the Spanish Ministry of Economy, Industry and Competitiveness (MINEICO, ref. SAF2015-66690-R), the PICATA Program of CEI Campus Moncloa (UCM-UPM & CSIC), the 911120 UCM-CEI Moncloa Research Group, CNPq, FAPERJ and FIOCRUZ.

Conflicts of Interest

The authors declare no conflict of interest.

References

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