10.1016/j.bmcl.2015.08.018
The research focuses on the synthesis and biological activity of a series of 14 benzimidazole derivatives designed to target the enzyme triosephosphate isomerase (TcTIM) of Trypanosoma cruzi, the parasite responsible for Chagas disease. The study aims to develop new drugs to treat this neglected tropical disease, as existing treatments are not ideal due to side effects and variable efficacy. The researchers synthesized the benzimidazole derivatives by reacting methyl 6-chloro-2-mercapto-1H-benzimidazole-5-carboxylate with various 2-chloroacetamides. The synthesized compounds were then tested for their ability to inhibit TcTIM, with four compounds showing moderate inhibitory activity and no inhibitory activity against human TIM (HsTIM). Among these, compound 10 (pyrazin-2-yl) and compound 14 (5-nitrothiazol-2-yl) exhibited the highest TcTIM inhibition and were further tested for their trypanocidal activity against T. cruzi epimastigotes. Compound 10 showed better inhibitory activity than the reference drug nifurtimox and had a favorable cytotoxicity profile in mouse macrophages. The study highlights the potential of these benzimidazole derivatives as selective TcTIM inhibitors and as a basis for the development of new treatments for Chagas disease.
10.1016/j.bioorg.2019.103269
The research focuses on the structure-activity relationship study of Forkhead Domain Inhibitors (FDI), specifically examining the importance of halogen binding interactions with the FOXM1 protein, a transcription factor overexpressed in various cancers. The study hypothesizes that the 4-fluorophenyl group in FDI-6 interacts with an Arg297 residue within the FOXM1-DNA binding domain (DBD). To test this, the researchers synthesized ten FDI-6 derivatives with different groups at the 4-fluorophenyl position. They found that derivatives with 4-chlorophenyl, 4-bromophenyl, or 4-iodophenyl groups were as potent as the original 4-fluorophenyl group in FDI-6, while those without this halogen moiety were inactive. The study concludes that a 4-halophenyl bonding interaction with Arg297 is essential for inhibiting FOXM1's transcriptional activity. Chemicals used in the synthesis process included various chloroacetamides, K2CO3, and ethanol, among others, with the final products being novel FDI derivatives such as 3-Amino-N-(4-bromophenyl)-6-(thiophen-2-yl)-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxamide (7d) and 3-Amino-N-(4-iodophenyl)-6-(thiophen-2-yl)-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxamide (7e).
T
