Synthesis and Evaluation of Quinazolin-4(3H)-one Derivatives as Multitarget Metabolic Enzyme Inhibitors: A Biochemistry-Oriented Drug Design

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Abstract In this study, imines bearing quinazolin‐4(3 H )‐one were synthesized and their inhibitory properties were investigated against some metabolic enzymes including Acetylcholinesterase (AChE), Butyrylcholinesterase (BChE), α‐Glycosidase (α‐Gly), and human Carbonic Anhydrase I–II (hCA I–II). All compounds had inhibitory strength with K i values in the range of 38.55±4.08–159.05±10.68 nM and 41.04±6.73–177.12±8.06 nM against hCA I and hCA‐II, respectively in comparison to the standard acetazolamide (AZA) K i =125.15±0.78 nM (for hCA‐I) and K i =148.75±0.92 nM (for hCA‐II). The compounds showed potent inhibitory activity against α ‐Gly enzyme with IC 50 value 0.34–2.28 nM (standard inhibitor acarbose (ACR): 3.18 nM). Also, these analogs had potent inhibitory strength with K i values in the range of 4.20±0.15–26.10±2.36 nM against AChE and 1.22±0.05–16.09±0.88 nM against BChE in comparison to the standard tacrine (TAC) K i =37.62±6.86 nM (for AChE) and K i =26.75±5.79 nM (for BChE). Additionally, the molecular docking and molecular dynamics simulation study was carried out for the determination of ligand‐enzyme interactions. The docking scores of the most active compound were calculated as −7.31, −7.59, −6.66, −6.93 and −7.11 kcal/mol for AChE, BChE, hCA I, hCA II, and α‐Gly, respectively.