Thiophene derivatives activity against the protozoan parasite Leishmania infantum

作者：Sophia Bigot, Philippe Leprohon, Abimael Vasquez, Rohit Bhadoria, Rachid Skouta, Marc Ouellette · 发表于：International Journal for Parasitology Drugs and Drug Resistance · 年份：2022 · DOI：10.1016/j.ijpddr.2022.11.004 · 被引用次数：18 · 研究领域：Research on Leishmaniasis Studies、Trypanosoma species research and implications、Synthesis and Biological Evaluation

Treatments against leishmaniasis are limited and the development of new molecules is crucial. One class of developmental drug that has shown activity against the parasite Leishmania are thiophene derivatives. Here we synthetized thirty-eight novel thiophene compounds and characterized their activity and potential for resistance against L. infantum. Half of the molecules had an EC50 in the low micromolar range, the piperidine derivatives being more potent than the tetramethylpyran derivatives. Resistance was challenging to select for, and resistant cells could only be raised against one (GC1-19) of the four most active compounds. Using chemogenomic screens we show that a gene conversion event at the ABCG2 locus as well as the overexpression of a tryparedoxin peroxidase are responsible for a weak but significant resistance to the GC1-19 drug candidate. Together, our results suggest that thiophene is a scaffold of interest for further drug development against leishmaniasis.