Abstract
Di(hetero) aryl and alicyclic amine derivatives of thieno[2,3-b]pyridine were synthesized in good to high yields (45–76%) via palladium-catalyzed Buchwald–Hartwig amination. The reactions were performed using methyl 5-bromothieno[2,3-b]pyridine-2-carboxylate, prepared in this work, and a variety of substituted anilines bearing either electron-donating groups (EDGs) or electron-withdrawing groups (EWGs), as well as pyridinyl amines, and saturated heterocyclic amines such as morpholine and piperidine. For most substrates, the optimal conditions involved Pd(OAc)(2), rac-BINAP, and Cs(2)CO(3) in toluene at 100 °C under argon. Substrate bearing EWGs and electron-deficient pyridinyl amines required Xantphos as the ligand, while reactions with piperidine were only successful using Pd(2)(dba)(3) as a palladium (0) source. The antiparasitic activity of the synthesized compounds was evaluated against Trypanosoma brucei (T. brucei) and Leishmania infantum (L. infantum) in both promastigote and amastigote forms. Most compounds exhibited no significant cytotoxicity (CC(50) > 100 μM) in PMA-differentiated THP-1 derived macrophage cells. Analysis of substituent effects focusing on the nature of amino substitution at position C(5) revealed distinct trends in antiparasitic activity. Notably, one compound exhibited activity against Leishmania infantum promastigotes that was nearly four times higher than that of the reference drug miltefosine, and its selectivity index was also approximately fourfold higher.