Novel hexahydrocyclopentapyrrol-indolemethanimine as highly potent α-glucosidase inhibitors; design, biological evaluation, and computational insights.

A series of novel hexahydrocyclopentapyrrol-indolemethanimine derivatives were synthesized and evaluated for their α-glucosidase inhibitory activity. All compounds demonstrated promising inhibition with IC50 values in the range of 1.05 to 95.60 μM, which compounds 9i, 9l, and 9o demonstrated the best potential anti-α-glucosidase activity (IC50 of 1.05, 14.45, and 17.13 μM, respectively), surpassing the efficacy of the positive control, acarbose (IC50 = 750.0 ± 2.0 μM). The kinetic studies showed that the most potent derivative (compound 9i) inhibits competitively, which suggests its direct interaction at the active site of α-glucosidase (Kᵢ value of 0.39 μM). Molecular docking studies demonstrated that compound 9i effectively forms hydrogen bonds and hydrophobic interactions with the enzyme active-site catalytic residues. Molecular docking studies also corroborated this idea by demonstrating that compound 9i effectively formed hydrogen bonds and hydrophobic interactions with the enzyme active-site catalytic residues. Molecular dynamics simulations further highlighted the formation and stable nature of the enzyme-inhibitor complex over a 100-ns trajectory with minimum fluctuation, suggesting strong and stable binding. These results are indicative of the fact that this new scaffold could be considered as a lead for further development of α-glucosidase inhibitors in the management of type 2 diabetes.