Design, synthesis, in vitro α-glucosidase inhibition, docking, and molecular dynamics of new phthalimide-benzenesulfonamide hybrids for targeting type 2 diabetes

In the present work, a new series of 14 novel phthalimide-benzenesulfonamide derivatives 4a-n were synthesized, and their inhibitory activity against yeast alpha-glucosidase was screened. The obtained results indicated that most of the newly synthesized compounds showed prominent inhibitory activity against alpha-glucosidase. Among them, 4-phenylpiperazin derivative 4m exhibited the strongest inhibition with the IC50 value of 52.2 +/- 0.1 mu M. Enzyme kinetic study of compound 4m proved that its inhibition mode was competitive and K-i value of this compound was calculated to be 52.7 mu M. In silico induced fit docking and molecular dynamics studies were performed to further investigate the interaction, orientation, and conformation of the target compounds over the active site of alpha-glucosidase. Obtained date of these studies demonstrated that our new compounds interacted as well with the alpha-glucosidase active site with the acceptable binding energies. Furthermore, in silico druglikeness/ADME/Toxicity studies of compound 4m were performed and predicted that this compound is druglikeness and has good ADME and toxicity profiles.

Automated summary

A series of novel phthalimide-benzenesulfonamide derivatives were synthesized and their inhibitory activity against yeast alpha-glucosidase was evaluated. Most of the compounds showed significant inhibitory activity, with 4-phenylpiperazin derivative exhibiting the strongest inhibition. In silico studies confirmed the interaction between the compounds and the active site of alpha-glucosidase, and predicted good druglikeness, ADME, and toxicity profiles for compound 4m.