Discovery and synthesis of novel phenoxyacetate ester Schiff base α-glucosidase inhibitors

A phenoxyacetate ester Schiff base lead compound 4a (ZINC20073984) was firstly discovered through molecular docking screening and molecular dynamics (MD) simulation, which could be used as an α-glucosidase (PDB: 3A4A) inhibitor. Then a series of α-glucosidase inhibitors 4b-4r with novel structures were designed and synthesized with the lead ZINC20073984 as a template. The results of in vitro α-glucosidase inhibitory activity show that the synthesized phenoxyacetate ester Schiff base compounds 4e, 4o-4r (IC₅₀ values range from 5.44 ± 0.52 μM to 33.67 ± 9.1 μM) exhibit good activity. Among them, ethyl (Z)-2-(2,4-dinitro-5-(2-(1-(2,4,6-trimethoxyphenyl) ethylidene) hydrazineyl) phenoxy) acetate (4r) and ethyl (Z)-2-(2,4-dinitro-5-(2-(1-(1-(4-ethoxyphenyl) ethylidene) hydrazineyl) phenoxy) acetate (4p) exert the best inhibitory activity, with IC₅₀ values of 5.44 ± 0.52 μM and 5.80 ± 1.4 μM, respectively, which are superior to the standard drug acarbose (IC₅₀ = 8.36 ± 0.02 μM). Molecular docking results indicate that the good inhibitory activity of 4r and 4p may be attributed to multiple hydrogen-bonding interactions with the α-glucosidase. Furthermore, the drug-likeness of all synthesized compounds was evaluated using the pkCSM tool, and ADMET predictions were conducted for compound 4r. The results demonstrated that all compounds follow Lipinski's rules, and 4r possesses favorable pharmaceutical properties. In an in vitro cytotoxicity assay, the most potent 4r shows non-cytotoxicity to the 3T3 cells with an CC50 value > 40 µM. In both antioxidant and anti-cancer capacity assays, compound 4r has demonstrated promising potential. The results of this study might be helpful in the discovery of new drugs for the treatment of diabetes mellitus type-2 and bladder cancer.