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Molecules 2018, 23(7), 1626; https://doi.org/10.3390/molecules23071626

Development of Thiophene Compounds as Potent Chemotherapies for the Treatment of Cutaneous Leishmaniasis Caused by Leishmania major

1
Department of Biological Sciences, Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX 79968, USA
2
Department of Chemistry, Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX 79968, USA
3
Centro de Desenvolvimento Tecnológico em Saúde, Fundação Oswaldo Cruz, Rio de Janeiro, RJ 21040-361, Brazil
4
Instituto de Tecnologia em Fármacos-Farmanguinhos, Fundação Oswaldo Cruz, Rio de Janeiro, RJ 22775-903, Brazil
5
Department of Biology, University of Massachusetts, Amherst, MA 01003-9297, USA
*
Authors to whom correspondence should be addressed.
Received: 29 May 2018 / Revised: 1 July 2018 / Accepted: 3 July 2018 / Published: 4 July 2018
(This article belongs to the Special Issue Directed Drug Design and Molecular Therapy)
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Abstract

Leishmania major (L. major) is a protozoan parasite that causes cutaneous leishmaniasis. About 12 million people are currently infected with an annual incidence of 1.3 million cases. The purpose of this study was to synthesize a small library of novel thiophene derivatives, and evaluate its parasitic activity, and potential mechanism of action (MOA). We developed a structure–activity relationship (SAR) study of the thiophene molecule 5A. Overall, eight thiophene derivatives of 5A were synthesized and purified by silica gel column chromatography. Of these eight analogs, the molecule 5D showed the highest in vitro activity against Leishmania major promastigotes (EC50 0.09 ± 0.02 µM), with an inhibition of the proliferation of intracellular amastigotes higher than 75% at only 0.63 µM and an excellent selective index. Moreover, the effect of 5D on L. major promastigotes was associated with generation of reactive oxygen species (ROS), and in silico docking studies suggested that 5D may play a role in inhibiting trypanothione reductase. In summary, the combined SAR study and the in vitro evaluation of 5A derivatives allowed the identification of the novel molecule 5D, which exhibited potent in vitro anti-leishmanial activity resulting in ROS production leading to cell death with no significant cytotoxicity towards mammalian cells. View Full-Text
Keywords: thiophene compounds; Leishmania major; cutaneous leishmaniasis; drug screening; chemotherapy; structure–activity relationship (SAR); in silico docking; reactive oxygen species thiophene compounds; Leishmania major; cutaneous leishmaniasis; drug screening; chemotherapy; structure–activity relationship (SAR); in silico docking; reactive oxygen species
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).
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Rodriguez, F.; Iniguez, E.; Pena Contreras, G.; Ahmed, H.; Costa, T.E.M.M.; Skouta, R.; Maldonado, R.A. Development of Thiophene Compounds as Potent Chemotherapies for the Treatment of Cutaneous Leishmaniasis Caused by Leishmania major. Molecules 2018, 23, 1626.

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