N-benzylisatin sulfonamide analogues as potent caspase-3 inhibitors: synthesis, in vitro activity, and molecular modeling studies

A number of isatin sulfonamide analogues were prepared and their potencies for inhibiting Caspase-1, -3, -6, -7, and -8 were evaluated in vitro. Several compounds displaying a nanomolar potency for inhibiting the executioner caspases, Caspase-3 and caspase-7, were identified. These compounds were also observed to have a low potency for inhibiting the initiator caspases, Caspase-1 and Caspase-8, and caspase-6. Molecular modeling studies provided further insight into the interaction of this class of compounds with activated Caspase-3. The results of the current study revealed a number of non-peptide-based Caspase inhibitors that may be useful in assessing the role of inhibiting the executioner caspases in minimizing tissue damage in disease conditions characterized by unregulated Apoptosis.