2026-10-18T23:56:50Zhttps://ebyu-rdlopen.rawdatalibrary.net/oai/request

oai:ebyu-rdlopen.rawdatalibrary.net:ebyu/109032026-10-18T21:13:11Zopenairedrivercom_ebyu_10000col_ebyu_10001

Phthalimide–benzoic acid hybrids as potent aldose reductase inhibitors: Synthesis, enzymatic kinetics, and in silico characterizationHoti, DafinaNixha, Arleta RifatiDuran, Hatice EsraArslan, MustafaYıldıztekin, GizemEce, AbdulilahTürkeş, CüneytADME/Tox predictionAldose reductase inhibitors (ALR2 AKR1B1)Diabetic complications / polyol pathwayEnzyme kinetics (competitive inhibition)MM-GBSA binding energyMolecular dockingPhthalimide–benzoic acid hybridsStructure–activity relationship (SAR)Aldehyde ReductaseAnimalsBenzoic AcidDose-Response Relationship, DrugEnzyme InhibitorsHumansKineticsMolecular Docking SimulationMolecular StructurePhthalimidesStructure-Activity Relationship2 ethoxy 2 oxoethyl 1,3 dioxo 2 (4 sulfamoylphenyl)isoindoline 5 carboxylate2 ethoxy 2 oxoethyl 1,3 dioxo 2 phenylisoindoline 5 carboxylate2 ethoxy 2 oxoethyl 2 (2 chlorophenyl) 1,3 dioxoisoindoline 5 carboxylate2 ethoxy 2 oxoethyl 2 (2,6 dimethylphenyl) 1,3 dioxoisoindoline 5 carboxylate2 ethoxy 2 oxoethyl 2 (3 iodophenyl) 1,3 dioxoisoindoline 5 carboxylate2 ethoxy 2 oxoethyl 2 (3,4 dimethoxyphenethyl) 1,3 dioxoisoindoline 5 carboxylate2 ethoxy 2 oxoethyl 2 (4 acetylphenyl) 1,3 dioxoisoindoline 5 carboxylate2 ethoxy 2 oxoethyl 2 (4 bromophenyl) 1,3 dioxoisoindoline 5 carboxylate2 ethoxy 2 oxoethyl 2 (4 chlorophenyl) 1,3 dioxoisoindoline 5 carboxylate2 ethoxy 2 oxoethyl 2 (4 cyanophenyl) 1,3 dioxoisoindoline 5 carboxylate2 ethoxy 2 oxoethyl 2 (4 fluorophenyl) 1,3 dioxoisoindoline 5 carboxylateAldose reductase (ALR2; AKR1B1) is implicated in hyperglycemia-driven tissue injury and remains a tractable enzymatic target. We developed a concise, chromatography-free two-step route to phthalimide–benzoic acid hybrids ( 5a–5m) and profiled their biochemical activity against human ALR2. Across the series, halogenated analogs were most active, with the para-bromophenyl derivative5demerging as the top hit (KI = 7.56 nM). Steady-state kinetic analysis indicated a competitive inhibition mechanism. Molecular docking to the ALR2 active site (PDB4JIR), supported by MM-GBSA rescoring, yielded a catalytically consistent binding mode featuring hydrogen-bonding within the anion-binding region (Tyr48, His110) and complementary hydrophobic contacts (Trp111, Trp219), with Cys298 contributing as a proximal hydrophobic contact. In cell-based assays (A549, Hep3B, L929), the compounds generally showed low intrinsic cytotoxicity at the tested concentrations, suggesting a favorable preliminary safety margin aligned with their ALR2-directed pharmacology. In silico ADME/Tox assessments further supported oral drug-likeness. Overall, these results identify phthalimide–benzoic acid hybrids as tractable ALR2 inhibitor scaffolds that combine potent biochemical inhibition with a competitive kinetic profile and encouraging early safety signals, warranting in vivo evaluation and SAR-guided optimization. © 2025 Elsevier Ltd. All rights are reserved, including those for text and data mining, AI training, and similar technologies.Elsevier Ltd2025Articlehttps://rdlopen.rawdatalibrary.net/r/ebyu/10903https://doi.org/10.1016/j.bmc.2025.1184160968-0896enBioorganic and Medicinal Chemistryinfo:eu-repo/semantics/openAccessinfo:eu-repo/semantics/articlehttps://ebyu-rdlopen.rawdatalibrary.net/tr/items/ebyu/10903