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

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.

Thiophene derivatives activity against the protozoan parasite Leishmania infantum

“…The 2,2,6,6-tetramethyl piperidine derivatives were synthesized in two steps synthesis as we described previously ( Rodriguez et al, 2018 ). We expanded our synthesis design and created the synthesis of the 2,2,6,6-tetramethyl-tetrahydro-pyran derivatives.…”

“…A number of thiophene derivatives (e.g. amino-thiophene, benzothiophenes, thiophene carboxaldehydes) were shown to be active against various Leishmania species ( Savornin et al, 1991 ; Rodrigues et al, 2015 ; Navin et al, 2017 ; Rodriguez et al, 2018 ; Borsari et al, 2019 ; Pacheco et al, 2021 ). However, the mode of action of thiophene derivatives is not clearly defined and no specific cellular target has yet been identified ( Borsari et al, 2019 ).…”

“…However, the mode of action of thiophene derivatives is not clearly defined and no specific cellular target has yet been identified ( Borsari et al, 2019 ). Some thiophene derivatives used against Leishmania were shown to produce reactive oxygen species (ROS) ( Rodriguez et al, 2018 ) but other derivatives did not ( Pacheco et al, 2021 ). Therefore, further work is warranted to decipher how thiophene derivatives are active against Leishmania .…”

“…Recently we synthesized a series of 2,2,6,6 tetramethylpiperidine thiophene derivatives that were active against Leishmania major ( Rodriguez et al, 2018 ). We expanded our search for active thiophenes by synthesizing and testing against Leishmania infantum , a parasite responsible for VL, 16 different 2,2,6,6 tetramethylpiperidine thiophene derivatives and 22 distinct 2,2,6,6 tetramethylpyran thiophene derivatives using structure activity relationship studies.…”

Toward New Antileishmanial Compounds: Molecular Targets for Leishmaniasis Treatment

“…Various chemical structures were reported with TR inhibitor activity and leishmaniacidal activity to the literature: Ag(0) nanoparticles encapsulated by ferritin molecules [89], Cu(II) diketonates [90], oxabicyclo[3.3.1]nonanones [73], azole-based compounds -e. pyrrole [91], β-carboline-quinazolinone hybrid [92], phenothiazine and phenoxazine derived chloroacetamides [93], selenocyanates and diselenide compounds [94,95], iminodibenzyl derivatives with ethylenediamine, ethanolamine and diethylenetriamine and their copper(II) complexes [96], diaryl sulfide derivatives [97], ammonium trichloro [1,2-ethanediolato-O,O′]-tellurat [98], all-hydrocarbon stapled peptides [99] chalcone derivatives [100], thiophene derivatives [101], imidazole-phenyl-thiazole compounds [102], isothiocyanate derivatives [103], (phenylthio)pyrimidin-4-amine derivatives [104], ferrocenylquinoline derivatives [105], triazole-phenyl-thiazoles derivatives [106], fluorene derivatives [107], adamantan derivatives, and their gold complexes [108] and natural products [109,110] (Figure 6).…”