Synthesis, biological evaluation, and molecular docking study of chromen-linked hydrazine carbothioamides as potent -glucosidase inhibitors

Inhibiting alpha-glucosidase is a reliable method for reducing blood sugar levels in diabetic individuals. Several novel chromen-linked hydrazine carbothioamide (3a-r) were designed and synthesized by condensation of chromone-3-carbaldehyde with a variety of substituted thiosemicarbazides. The structures of these new analogues were elucidated through various advanced spectroscopic techniques (H-1 NMR, C-13 NMR, and ESI-MS). The resulted compounds were screened for alpha-glucosidase inhibitory potential and all the compounds (3a-r) exhibited potent inhibition of a-glucosidase with IC50 values ranging 0.29-53.70 mu M. Among them compounds 3c, 3f, 3h, and 3r displayed the highest a-glucosidase inhibitor capability with IC50 values of 1.50, 1.28, 1.08, and 0.29 mu M, respectively. Structure-activity relationship showed that different substituted groups are responsible for the variation in the alpha-glucosidase inhibition. The kinetics studies of the most active inhibitor (3r) were performed, to investigate the mode of inhibition and dissociation constants (Ki), that indicated a competitive inhibitor with Ki value of 1.47 +/- 0.31 mu M. Furthermore, molecular docking studies was performed to reveal the possible interactions, such as H-bonding, or Pi-Pi stacking, with the key residues of alpha-glucosidase. Docking analysis revealed the importance of hydrazine carbothioamide moiety of compounds in the attachment of ligands with the crucial residues of alpha-glucosidase. The estimated pharmacokinetic, physicochemical, and drug likeness properties of compounds 3a-r reflects that these molecules have acceptable range of these properties.