Design and synthesis of 4-quinolinone 2-carboxamides as calpain inhibitors

Calpains are involved in a variety of calcium-regulated cellular processes, such as signal transduction, cell proliferation, differentiation, and apoptosis. Excessive calpain activation contributes to serious cellular damage and has been reported in many pathological conditions. 4-Quinolinone 2-carboxamide derivatives were prepared and evaluated for μ-calpain inhibitory activities. Of the compounds synthesized, 3a and 3k, which possess a primary amide and 4-methoxyphenethyl amide at P1′ region, were found to most potently inhibit μ-calpain with IC50 values of 0.71 ± 0.07 and 0.73 ± 0.23 μM, respectively. On the other hand, the incorporation of pyridine-containing amides decreased inhibitory activity.

Graphical abstract4-Quinolinone 2-carboxamide derivatives were prepared and evaluated for μ-calpain inhibition. Of the derivatives synthesized, compound 3a and 3k, which have a primary amide and 4-methoxyphenethy amide at P1′ region, were the most potent μ-calpain inhibitor with an IC50 values of 0.71 and 0.73 μM, respectively.Figure optionsDownload full-size imageDownload as PowerPoint slide