A series of tetra- and pentasubstituted polyfunctional dihydropyrroles 5 and 6 were synthesized via practical multicomponent reactions (MCRs) for research on their structure-activity relationship as caspase-3 inhibitors. Among 39 compounds evaluated, 14 of them exhibited inhibition against caspase-3 with IC(50) ranging from 5 to 20 μM. The inhibitory activities of 5 and 6 depend on the nature of substituents on different positions. 5 and 6 possess a different scaffold from those previously reported and are the first caspase-3 inhibitors prepared via MCRs. The most active compounds 5k (IC(50) = 5.27 μM) could therefore be used as a lead for the development of highly potent caspase-3 inhibitors as drug candidates for therapeutic agents by taking advantage of MCRs.
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