Excessive calpain activations contribute to serious cellular damage and have been found in many pathological conditions. Novel chromone carboxamides derived from ketoamides were prepared and evaluated for mu-calpain inhibition. Among synthesized, compound 2i was the most potent calpain inhibitor with an IC(50) value of 0.24 +/- 0.11 microM comparable to the activity of peptide aldehyde calpain inhibitor MDL 28,170. Furthermore, compound 2i showed higher selectivity for mu-calpain over two related cysteine proteases cathepsin B and cathepsin L, suggesting the chromone ring as a good scaffold for selective mu-calpain inhibitors.