Synthesis of chromone carboxamide derivatives with antioxidative and calpain inhibitory properties

The overactivation of μ-calpain can cause serious cell damage in several diseases. Furthermore, cell death in a number of neurodegenerative disorders is linked to the overproduction of reactive oxygen species. Therefore, antioxidants and μ-calpain inhibitors could have the therapeutic potentials to treat cell death related diseases. New chromone carboxamide derivatives 3 were synthesized to provide alternative μ-calpain inhibitors to compound 2, a conformationally constrained structural variant of MDL 28,170. Compounds 3h and 3l exhibited the most potent μ-calpain inhibitory activities (IC50 = 0.09–0.10 μM), and were comparable to 2 in this respect (IC50 = 0.07 μM). Compound 3i showed both potent μ-calpain inhibitory activity (IC50 = 0.28 μM) and antioxidant activities in DPPH scavenging and lipid peroxidation inhibition assays.

New chromone carboxamide derivatives 3 were prepared as a conformationally constrained structural variant of MDL 28,170. Compounds 3i showed potent μ-calpain inhibitory (IC50 = 0.28 μM) and antioxidant activities.Figure optionsDownload as PowerPoint slideHighlights
► Both calpain overactivation and reactive oxygen species can cause serious cell death.
► Primary amide-substituted chromone derivatives were unstable in acidic conditions.
► 4-Methoxyphenethyl-substituted derivatives could be prepared in acidic conditions and showed potent calpain inhibition.
► Compound 3i showed potent calpain inhibitory as well as antioxidant activities.