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Aldose reductase (AR) is a crucial enzyme of the polyol pathway through which glucose is metabolized under conditions of hyperglycemia related to diabetes. A series 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 target compounds exhibited nanomolar activity against the target enzyme, and all compounds displayed higher activity as compared to the reference drug epalrestat. Among them, Compound 19, named 2‐(4‐[(2‐[(4‐methylpiperazin‐1‐yl)methyl]‐4‐oxoquinazolin‐3(4H)‐ylimino)methyl]phenoxy)acetic acid, displayed the strongest inhibitory effect with a KI value of 61.20 ± 10.18 nM. Additionally, these compounds were investigated for activity against L929, nontumoral fibroblast cells, and MCF‐7, breast cancer cells using the MTT assay. Compounds 16 and 19 showed lower toxicity 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 binding mechanisms of these inhibitors against AR. [ABSTRACT FROM AUTHOR]

A series of novel sulfonates containing quinazolin‐4(3H)‐one ring derivatives was designed to inhibit aldose reductase (ALR2, EC 1.1.1.21). Novel quinazolinone derivatives (1–21) were synthesized from the reaction of sulfonated aldehydes with 3‐amino‐2‐alkylquinazolin‐4(3H)‐ones in glacial acetic acid with good yields (85%–94%). The structures of the novel molecules were characterized using IR, 1H‐NMR, 13C‐NMR, and HRMS. All the novel quinazolinones (1–21) demonstrated nanomolar levels of inhibitory activity against ALR2 (KIs are in the range of 101.50–2066.00 nM). Besides, 4‐[(2‐isopropyl‐4‐oxoquinazolin‐3[4H]‐ylimino)methyl]phenyl benzenesulfonate (15) showed higher inhibitor activity inhibited ALR2 up to 7.7‐fold compared to epalrestat, a standard inhibitor. Binding interactions between ALR2 and quinazolinones have been investigated using Schrödinger Small‐Molecule Drug Discovery Suite 2021–1, reported possible inhibitor‐ALR2 interactions. Both in vitro and in silico study results suggest that these quinazolin‐4(3H)‐one ring derivatives (1–21) require further molecular modification to improve their drug nominee potency as an ALR2 inhibitor. [ABSTRACT FROM AUTHOR]