Synthesis of thymol derivatives and their inhibitory effects on alpha-glucosidase and tyrosinase

Diabetes is a chronic disease all over the world. More than 90% of patients have diabetes of type II and require effective methods to control their blood glucose. A promising treatment for diabetes mellitus is to reduce postprandial hyperglycemia by using α-glucosidase inhibitors to prevent carbohydrate digestion. Thymol is a naturally occurring monoterpene. Thymol motifs have a wide range of biological activities, including anti-cancer, antibacterial, antimalarial, antifungal and antioxidant. In this study, thymol-esters AS01-AS04, piperazine-containing thymols AS15-AS17 and thymol acetohydrazones AS21-AS49 were synthesized and subjected to α-glucosidase inhibitory activities. AS21-AS49 were obtained as a mixture of geometrical isomers (E/Z). All compounds displayed low-to-good inhibitions. Amongst them, AS29, AS43, AS44, AS45 and AS46 were the most active compounds, with IC50 values of 2.80, 5.10, 10.54, 2.77 and 1.45 µM, respectively. Kinetic analysis of AS29 and AS46 showed non-competitive and competitive modes of inhibition. Molecular docking study of these compounds possessed lower binding energies could form several interactions with key amino acids to stabilize the inhibitor/a-glucosidase complex or inhibitor/a-glucosidase-substrate complex.