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This study aims to synthesize and evaluate the inhibitory activity of thymol derivatives targeting ?-glucosidase using in vitro and in silico studies. Ten thymol derivatives (2-11) including five new thymol-fused chalcones (7-11) were successfully synthesized. Among them, four compounds (4, 8, 9, 11) showed the best inhibitory activity with IC50 values of 18.45, 13.75, 8.86, and 10.67µM compared with acarbose (IC50 = 832.82 µM), respectively. The kinetic study of three new thymol-fused chalcones (8, 9, 11) exhibited a competitive inhibition. Molecular docking demonstrated the predicted interactions between ligand (8, 9, 11) and ?-glucosidase, which are responsible for inhibiting the enzyme's catalytic abilities. Furthermore, molecular dynamics simulation of the enzyme-ligand 9 complex indicated that this complex was stable in aqueous condition. This research contributes significantly to the understanding of thymol-fused chalcones that may have therapeutic potential and their possible application in the treatment of type 2 diabetes mellitus (T2DM) for further study.

Abstract Thirty-five 9-O-berberrubine carboxylate derivatives were synthesized and evaluated for yeast α-glucosidase inhibitory activity. All compounds demonstrated better inhibitory activities than the parent compounds berberine (BBR) and berberrubine (BBRB), and a positive control, acarbose. The structure–activity correlation study indicated that most of the substituents on the benzoate moiety such as methoxy, hydroxy, methylenedioxy, benzyloxy, halogen, trifluoromethyl, nitro and alkyl can contribute to the activities except multi-methoxy, fluoro and cyano. In addition, replacing benzoate with naphthoate, cinnamate, piperate or diphenylacetate also led to an increase in inhibitory activities except with phenyl acetate. 9, 26, 27, 28 and 33 exhibited the most potent α-glucosidase inhibitory activities with the IC50 values in the range of 1.61–2.67 μM. Kinetic study revealed that 9, 26, 28 and 33 interacted with the enzyme via competitive mode. These four compounds were also proved to be not cytotoxic at their IC50 values. The competitive inhibition mechanism of these four compounds against yeast α-glucosidase was investigated using molecular docking and molecular dynamics simulations. The binding free energy calculations suggest that 26 exhibited the strongest binding affinity, and its binding stability is supported by hydrophobic interactions with D68, F157, F158 and F177. Therefore, 9, 26, 28 and 33 would be promising candidates for further studies of antidiabetic activity.

Tyrosinase is a crucial enzyme in melanin production to protect the skin from ultraviolet, leading to skin cancers. This study synthesized eight compounds of acyl resorcinol with long-chain carbon (1-8) and structurally elucidated by 1H and 13C NMR. The in vitro evaluation of eight synthesized compounds against tyrosinase enzyme showed that 4-heptanoyl resorcinol (6) exhibited high inhibitory activity compared with the kojic acid as standard. In addition, the molecular docking study demonstrated that 6 showed lower binding energy (-7.3 kcal/mol) than kojic acid (-6.9 kcal/mol) and possessed interaction with crucial residues in the active site.