Structure-based design and synthesis of novel pseudosaccharine derivatives as antiproliferative agents and kinase inhibitors

This study is concerned with the implementation of structure-based techniques for the design of new heterocyclic compounds based on pseudosaccharine scaffold with protein kinase inhibition activity. This nucleus was exploited based on the well-known quinazoline core and its interactions with several protein kinases. Two series of compounds employing this new scaffold were synthesized and evaluated at enzymatic and cellular levels. Compound 9b displayed broad spectrum antiproliferative activity on NCI 60-cell lines panel with mean GI50 of 5.4 μM. Investigation of the molecular mechanism showed probable inhibitory activity against Src kinase.

Novel pseudosaccharine derivatives were designed, synthesized and evaluated at enzymatic and cellular levels. Compound 9b displayed broad antiproliferative and inhibitory activity against Src kinase.Figure optionsDownload as PowerPoint slideHighlights
► Novel benzo[d]isothiazole 1,1-dioxide derivatives were designed and synthesized.
► The antiproliferative activity of 7 compounds was evaluated against NCI 60 cell lines.
► Compound 9b showed very promising antiproliferative activity against various cell lines.
► Investigation of the mechanism of action of compound 9b revealed its good inhibition of Src kinase.
► The binding mode of 9b in Src was predicted using molecular docking.