Abstract
The current study describes the discovery of novel inhibitors of alpha-glucosidase and a-amylase enzymes. For that purpose, new hybrid analogs of N-hydrazinecarbothioamide substituted indazoles 4-18 were synthesized and fully characterized by EI-MS, FAB-MS, HRFAB-MS, H-1-, and C-13 NMR spectroscopic techniques. Stereochemistry of the imine double bond was established by NOESY measurements. All derivatives 4-18 with their intermediates 1-3, were evaluated for in vitro alpha-glucosidase and a-amylase enzyme inhibition. It is worth mentioning that all synthetic compounds showed good inhibition potential in the range of 1.54 +/- 0.02-4.89 +/- 0.02 mu M for alpha-glucosidase and for alpha-amylase 1.42 +/- 0.04-4.5 +/- 0.18 mu M in comparison with the standard acarbose (IC50 value of 1.36 +/- 0.01 mu M). In silico studies were carried out to rationalize the mode of binding interaction of ligands with the active site of enzymes. Moreover, enzyme inhibitory kinetic characterization was also performed to understand the mechanism of enzyme inhibition.