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

() 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 . Overall, eight thiophene derivatives of were synthesized and purified by silica gel column chromatography. Of these eight analogs, the molecule showed the highest in vitro activity against promastigotes (EC 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 on promastigotes was associated with generation of reactive oxygen species (ROS), and in silico docking studies suggested that may play a role in inhibiting trypanothione reductase. In summary, the combined SAR study and the in vitro evaluation of derivatives allowed the identification of the novel molecule , which exhibited potent in vitro anti-leishmanial activity resulting in ROS production leading to cell death with no significant cytotoxicity towards mammalian cells.