Synthesis and Anti-Trypanosoma cruzi Biological Evaluation of Novel 2-Nitropyrrole Derivatives

Abstract

Human American trypanosomiasis, called Chagas disease, caused by T. cruzi 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-Trypanosoma cruzi 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 3 (CC50 = 24.3 µM). Compound 18 appeared to show activity against T. cruzi intracellular amastigotes form (EC50 = 3.6 ± 1.8 µM) and good selectivity over the vero host cells. Unfortunately, this compound 18 showed an insufficient maximum effect compared to the reference drug (nifurtimox). Whether longer duration treatments may eliminate all parasites remains to be explored.

Studies on Methylpyrazole-Substituted Benzimidazoles to Target Helicobacter pylori Infection through HpIMPDH Inhibition

“…All the 2-bromo N -arylacetamide linkers 3a – s were synthesized using the previously reported procedures and wherever required, using slight modifications in previously reported procedures. ,− The aryl amines 1a – s (80–200 mg, 0.69 mmol, 1 equiv) were taken in a round-bottom flask equipped with a magnetic stir bar and dissolved in anhydrous dichloromethane. One among the basespotassium carbonate (143 mg, 1.035 mmol, 1.5 equiv) or triethylamine (0.14 mL, 1.035 mmol, 1.5 equiv)was then added in the flask and stirred for a few minutes in ice.…”

Alternative Approaches for the Treatment of Chagas Disease

“…Mathias et al . (2022) synthesized novel nitropyrrole analogs, with compound 14 identified as a standout candidate, exhibiting an EC 50 value of 3.6±1.8 μM against the amastigote form of Vero host cells [158] …”

“…[157] Mathias et al (2022) synthesized novel nitropyrrole analogs, with compound 14 identified as a standout candidate, exhibiting an EC 50 value of 3.6 � 1.8 μM against the amastigote form of Vero host cells. [158] In 2023, Souza et al delved into Metal-BZN complexes, surpassing the efficacy of BZN alone against T. cruzi. Notably, compound 15 from the metal complexes exhibited significant activity with an IC 50 of 3.6, 2.7, and 2.4 μM for epimastigotes at 24 h, 48 h, and 72 h, respectively, and 0.23 μM against the amastigote form.…”