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Human American trypanosomiasis, called Chagas disease, caused by <i>T. cruzi</i> protozoan infection, represents a major public health problem, with about 7000 annual deaths in Latin America. As part of the search for new and safe anti-<i>Trypanosoma cruzi</i> derivatives involving nitroheterocycles, we report herein the synthesis of ten 1-substituted 2-nitropyrrole compounds and their biological evaluation. After an optimization phase, a convergent synthesis methodology was used to obtain these new final compounds in two steps from the 2-nitropyrrole starting product. All the designed derivatives follow Lipinski’s rule of five. The cytotoxicity evaluation on CHO cells showed no significant cytotoxicity, except for compound <b>3</b> (CC₅₀ = 24.3 µM). Compound <b>18</b> appeared to show activity against <i>T. cruzi</i> intracellular amastigotes form (EC₅₀ = 3.6 ± 1.8 µM) and good selectivity over the vero host cells. Unfortunately, this compound <b>18</b> showed an insufficient maximum effect compared to the reference drug (nifurtimox). Whether longer duration treatments may eliminate all parasites remains to be explored.