Novel acetic acid derivatives containing quinazolin-4(3H)-one ring: Synthesis, in vitro, and in silico evaluation of potent aldose reductase inhibitors

Abstract

Aldose reductase (AR) is a crucial enzyme of the polyol pathway through whichglucose is metabolized under conditions of hyperglycemia related to diabetes. Aseries of novel acetic acid derivatives containing quinazolin‐4(3H)‐one ring (1–22)was synthesized and tested for in vitro AR inhibitory effect. All the targetcompounds exhibited nanomolar activity against the target enzyme, and allcompounds displayed higher activity as compared to the reference drug epalrestat.Among them, Compound19, named 2‐(4‐[(2‐[(4‐methylpiperazin‐1‐yl)methyl]‐4‐oxoquinazolin‐3(4H)‐ylimino)methyl]phenoxy)acetic acid, displayed the strongestinhibitory effect with aKIvalue of 61.20 ± 10.18 nM. Additionally, these compoundswere investigated for activity against L929, nontumoral fibroblast cells, and MCF‐7,breast cancer cells using the MTT assay. Compounds16and19showed lowertoxicity against the normal L929 cells. The synthesized compounds’(1–22)absorption, distribution, metabolism, and excretion properties were also evaluated.Molecular docking simulations were used to look into the possible bindingmechanisms of these inhibitors against AR.