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Design, Synthesis and Antileishmanial Activity of Naphthotriazolyl-4- Oxoquinolines

[ Vol. 18 , Issue. 17 ]

Author(s):

Vanessa G. Oliveira, Viviane dos Santos Faiões, Gabrieli B.R. Gonçalves, Miriam F.O. Lima, Fernanda C.S. Boechat, Anna C. Cunha, Valter V. de Andrade-Neto, Fernando de C. da Silva, Eduardo C. Torres-Santos* and Maria Cecília B.V. de Souza*   Pages 1454 - 1464 ( 11 )

Abstract:


Background: Leishmaniasis is a neglected public health problem caused by several protozoanspecies of the genus Leishmania. The therapeutic arsenal for treating leishmaniasis is quite limited, raising concerns about the occurrence of resistant strains. Furthermore, most of these drugs were developed more than 70 years ago and suffer from poor efficacy and safety and are not well adapted to the needs of patients. Therefore, research on novel natural or synthetic compounds with antiparasitic activity is urgently needed. In this paper, we evaluated the effect and the mechanism of action of naphthotriazolyl-4-oxoquinolines on promastigotes and intracellular amastigotes of Leishmania amazonensis.

Materials and Methods: The naphthotriazolyl-4-oxoquinoline derivatives were obtained in good to moderate yields via the [3+2] cycloaddition reaction between 1,4-naphtoquinone and azido-4- oxoquinoline derivatives. HMPA at 100°C was established as the best solvent and temperature condition for this reaction. The structures of the compounds were confirmed by spectral analyses (infrared spectroscopy, one- and two-dimensional ¹H and ¹³C NMR spectroscopy, and high-resolution mass spectrometry). The compounds exhibited promising activities with IC50 values ranging from 0.7 to 2.0 µM against intracellular amastigotes of Leishmania amazonensis. The most selective compound was the Npentyl- substituted derivative, which showed a Selectivity Index (SI) of 8.6, making it less toxic than pentamidine (SI 4.5).

Results: Our results demonstrated that all compounds, except the N-propyl-substituted derivative, induce ROS production by parasites early in the culture. As a proof of concept, we demonstrated that the most selective compound was able to interfere with sterol biosynthesis in L. amazonensis.

Conclusion: The naphthotriazolyl-4-oxoquinoline derivatives were obtained in good to moderate yields. These conjugates have potent in vitro antileishmanial activity involving at least two different mechanisms of action, making them promising lead compounds for the development of new therapeutic alternatives for leishmaniasis.

Keywords:

Leishmania, Quinone, Free radicals, 1, 2, 3-triazole, [3+2] cycloaddition, Reactive Oxygen Species (ROS).

Affiliation:

Programa de Pos-Graduacao em Ciencias Aplicadas a Produtos para Saude, Faculdade de Farmacia, Universidade Federal Fluminense, Niteroi, RJ, Fundacao Oswaldo Cruz, Laboratorio de Bioquimica de Tripanosomatídeos, Instituto Oswaldo Cruz, Rio de Janeiro, RJ, Programa de Pos-Graduacao em Quimica, Instituto de Quimica, Universidade Federal Fluminense, Niteroi, RJ, Programa de Pos-Graduacao em Quimica, Instituto de Quimica, Universidade Federal Fluminense, Niteroi, RJ, Programa de Pos-Graduacao em Quimica, Instituto de Quimica, Universidade Federal Fluminense, Niteroi, RJ, Programa de Pos-Graduacao em Quimica, Instituto de Quimica, Universidade Federal Fluminense, Niteroi, RJ, Fundacao Oswaldo Cruz, Laboratorio de Bioquimica de Tripanosomatídeos, Instituto Oswaldo Cruz, Rio de Janeiro, RJ, Programa de Pos-Graduacao em Quimica, Instituto de Quimica, Universidade Federal Fluminense, Niteroi, RJ, Fundacao Oswaldo Cruz, Laboratorio de Bioquimica de Tripanosomatídeos, Instituto Oswaldo Cruz, Rio de Janeiro, RJ, Programa de Pos-Graduacao em Quimica, Instituto de Quimica, Universidade Federal Fluminense, Niteroi, RJ

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