Synthesis, biological evaluation, and in silico study of novel library sulfonates containing quinazolin‐4(3H)‐one derivatives as potential aldose reductase inhibitors

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.