Design and Synthesis of Ketenimine Sulfonamide Conjugates through Multicomponent Reactions; A Combined Cytotoxic Analysis and Computational Exploration

[Image: see text] Multicomponent reactions involving zwitterion generated from dimethyl acetylenedicarboxylate, aryl sulfonamide, and isocyanide to generate sulfonamide-conjugated ketenimines is reported. The synthetic strategy adopted is highly atom economical and stereoselective. Ketenimine sulfonamide analogues are key intermediates for further synthetic conversions to generate a combinatorial library of compounds. Furthermore, sulfonamide compounds are known to possess a broad spectrum of biological applications. All the novel molecules synthesized exhibit the potential to target the nonhomologous DNA end-joining (NHEJ) pathway with cytotoxic ability. Computational studies compliment the in vitro biological assays of the 8 small-molecule inhibitors. DNA double-strand breaks (DSBs) are considered as the most lethal among different DNA damages. NHEJ repairs about 70% of the DSBs generated in cells within mammals. The DNA-dependent protein kinase catalytic subunit is one of the PI3 kinases associated with NHEJ. Compounds DK01–DK08 were investigated for their ability to induce cancer cell death by treating with two leukemic cell lines where NHEJ is high. Results showed that bromoaryl (DK04)- and nitroaryl (DK05)-conjugated molecules showed excellent biological activity, having IC(50) values of ∼2 μM in Nalm6 cell lines.