Synthesis and biological evaluation of esculetin derivatives as antidiabetic agents

•The α-glucosidase and α-amylase inhibitory activities of 4a-4j were investigated.•Compound 4d showed promising hypoglycaemic and antioxidant activities.•The enzyme inhibition mechanism of compound 4d was investigated.•Compound 4d had good biosafety, which can serves as a lead compound for diabetes. Esculetin derivatives 4a-4j (including six novel hydroxylated/halogenated derivatives 4a, 4d, 4e, 4f, 4g, 4h) were synthesized through Perkin reaction with 2,4,5-trihydroxybenzaldehyde and appropriate phenylacetic acid as raw materials, and screened for α-glucosidase and α-amylase inhibitory activities. Among these compounds, compound 3-(3-iodophenyl)-6,7-dihydroxy-2H-chromen-2-one (4d) showed promising hypoglycaemic activity with half maximal inhibitory concentration (IC50) values of 0.18±0.03 mM and 1.82±0.18 mM against α-glucosidase and α-amylase, respectively, classifying it as a mixed-type inhibitor. Compound 4d could statically quench the intrinsic fluorescence of enzymes, which bound to enzymes mainly through hydrogen bonding and hydrophobic interactions affecting the microenvironment of proteins. Compound 4d also exhibited antioxidant activity, which demonstrated good scavenging effects for 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2, 2’-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) free radicals. Furthermore, compound 4d still maintained a certain degree of hypoglycemic and antioxidant activities after simulated gastrointestinal digestion. The oral toxicity study showed that compound 4d had no significant effect on the serum biochemical indices and organs of mice, indicating its safety profile. This study suggests that esculetin may be a potential skeleton to the development of hypoglycaemic drugs. [Display omitted] Esculetin derivatives 4a-4j (including six novel hydroxylated/halogenated derivatives 4a, 4d, 4e, 4f, 4g, 4h) were synthesized through Perkin reaction and screened for α-glucosidase and α-amylase inhibitory activities. Among these compounds, compound 4d showed promising hypoglycaemic activity against α-glucosidase and α-amylase. Compound 4d also exhibited antioxidant activity, demonstrating good scavenging effects for DPPH and ABTS free radicals. Furthermore, compound 4d still maintained a certain degree of hypoglycemic and antioxidant activities after gastrointestinal digestion. The oral toxicity study showed the biosafety of compound 4d. This study suggests that esculetin may be a potential skeleton to the development of hypogly