Novel 9-oxo-thiazolo[5,4-f]quinazoline-2-carbonitrile derivatives as dual cyclin-dependent kinase 1 (CDK1)/glycogen synthase kinase-3 (GSK-3) inhibitors: Synthesis, biological evaluation and molecular modeling studies

Continuous efforts in microwave-assisted synthesis and the structure–activity relationships' (SARs) studies of novel modified 9-oxo-thiazolo[5,4-f]quinazoline-2-carbonitriles, allowed identification of new amidine and imidate derivatives as potent and dual CDK1/GSK-3 inhibitors. Combination of lead optimization and molecular modeling studies allowed identification of a dual CDK1/GSK-3 inhibitor (compound 13d) with submicromolar values.

The dual CDK1/GSK-3 imidate inhibitors 12c–e and 13c,d make hydrogen bond with residue Val135 into the ATP-binding site of GSK-3β and form polar interactions with the side-chain amino group of conserved Lys85.Figure optionsDownload as PowerPoint slide