Discovery of triazole tethered thymol/carvacrol-coumarin hybrids as new class of -glucosidase inhibitors with potent in vivo antihyperglycemic activities

Keeping in view the inhibitory potential of monoterpenes thymol and carvacrol as well as coumarin nucleus against alpha-glucosidase, novel series of thymol/carvacrol-coumarin hybrids was designed, synthesized and evaluated for alpha-glucosidase inhibitory potential. Among the series of hybrid molecules, AS14 with IC50 value of 4.32 +/- 0.11 mu M was selective alpha-glucosidase inhibitor over alpha-amylase (IC50 = 37.36 +/- 0.84 mu M). AS14 was non-toxic toward mouse normal fibroblast cells (L929: IC50 > 100 mu M). Molecular docking and dynamic simulation studies confirmed desired interactions of AS14 with alpha-glucosidase responsible for the inhibition of its catalysis capabilities. Acute oral toxicity study confirmed AS14 as safer molecule for in vivo pharmacological investigations with LD50 value of 300 mg/kg. AS14 also showed acute hypoglycaemic effects [reduction in blood glucose levels at 1 h of administration in maltose loading test (at 10 and 20 mg/kg by 62.65 % and 70.12 %) and sucrose loading test (at 10 and 20 mg/kg by 59.65 % and 60.23 %), respectively] as well as long term (28 days) fasting blood glucose reduction (At day 28: 10 mg/kg = 54.69 % and 20 mg/kg = 62.23 % reduction in fasting blood glucose levels) capabilities in streptozotocin induced diabetic rats. Overall study represents, AS14 as potential alpha-glucosidase inhibitor with adequate efficacy and safety profile and act as an effective hit lead for the further development of potent and safer alpha-glucosidase inhibitors for the management of postprandial hyperglycemia in diabetic patients.