Design and synthesis of novel quinazolinone-pyrazole derivatives as potential α-glucosidase inhibitors: Structure-activity relationship, molecular modeling and kinetic study.

[Display omitted] • Based on pharmacophore hybridization strategy, a novel series of quinazolinone-pyrazole derivatives were designed and synthesized. • All the title compounds displayed significant α-glucosidase inhibition with IC 50 values of 60.5 ± 0.3–186.6 ± 20 µM comparing with acarbose as the standard drug (IC 50 = 750.0 ± 10.0 µM). • Compound 9i was found to be the most active compound (IC 50 = 60.5 ± 0.3 µM). • Compound 9i was a competitive inhibitor against α-glucosidase (K i = 56 μM). • The molecular dynamic simulation and MM-GBSA calculation was performed to investigate the difference in structural perturbation and dynamic behavior. In this study, a new series of quinazolinone-pyrazole hybrids were designed, synthesized and screened for their α-glucosidase inhibitory activity. The results of the in vitro screening indicated that all the molecular hybrids exhibited more inhibitory activity (IC 50 values ranging from 60.5 ± 0.3 µM-186.6 ± 20 μM) in comparison to standard acarbose (IC 50 = 750.0 ± 10.0 µM). Limited structure–activity relationship suggested that the variation in the inhibitory activities of the compounds affected by different substitutions on phenyl rings of diphenyl pyrazole moiety. The enzyme kinetic studies of the most potent compound 9i revealed that it inhibited α-glucosidase in a competitive mode with a Ki of 56 μM. Molecular docking study was performed to predict the putative binding interaction. As expected, all pharmacophoric moieties used in the initial structure design playing a pivotal role in the interaction with the binding site of the enzyme. In addition, by performing molecular dynamic investigation and MM-GBSA calculation, we investigated the difference in structural perturbation and dynamic behavior that is observed over α-glycosidase in complex with the most active compound and acarbose relative to unbound α-glycosidase enzyme. [ABSTRACT FROM AUTHOR]