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N-substituted phthalimide–carboxylic acid hybrids as dual-targeted aldose reductase inhibitors: Synthesis, mechanistic insights, and cancer-relevant profilingZognjani, BlineraNixha, Arleta RifatiDuran, Hatice EsraArslan, MustafaYıldıztekin, GizemEce, AbdulilahTürkeş, CüneytAldose reductase inhibitorsLead optimizationMolecular docking and MM-GBSAN-substituted phthalimidesPolyol pathway modulationProtein-protein interactionStructure-activity-energy relationshipAldehyde ReductaseAnimalsAntineoplastic AgentsCell Line, TumorCell ProliferationDose-Response Relationship, DrugDrug Screening Assays, AntitumorEnzyme InhibitorsHumansMolecular Docking SimulationMolecular StructurePhthalimidesStructure-Activity Relationship2 ethoxy 2 oxoethyl 4 (1,3 dioxo 1,3,3a,4,7,7a hexahydro 2h isoindol 2 yl)benzoate2 ethoxy 2 oxoethyl 4 (1,3 dioxoisoindolin 2 yl)benzoate2 ethoxy 2 oxoethyl 4 (1,3 dioxooctahydro 2h isoindol 2 yl)benzoate2 ethoxy 2 oxoethyl 4 (2,5 dioxo 2,5 dihydro 1h pyrrol 1 yl)benzoate2 ethoxy 2 oxoethyl 4 (4 fluoro 1,3 dioxoisoindolin 2 yl)benzoate2 ethoxy 2 oxoethyl 4 (4,5,6,7 tetrabromo 1,3 dioxoisoindolin 2 yl)benzoate2 ethoxy 2 oxoethyl 4 (4,5,6,7 tetrachloro 1,3 dioxoisoindolin 2 yl)benzoate2 ethoxy 2 oxoethyl 4 (5 fluoro 1,3 dioxoisoindolin 2 yl)benzoate2 ethoxy 2 oxoethyl 4 (5 nitro 1,3 dioxoisoindolin 2 yl)benzoate2 [4 [(2 ethoxy 2 oxoethoxy)carbonyl]phenyl] 1,3 dioxoisoindoline 5 carboxylicAldose reductase (ALR2; AKR1B1), a NADPH-dependent cytosolic oxidoreductase, plays a central role in the polyol pathway and is implicated in hyperglycemia-induced tissue injury. Beyond its metabolic function, elevated ALR2 expression has been reported in several malignancies, including hepatocellular and pulmonary carcinomas, highlighting its potential as a therapeutic target in metabolic-oncologic interface. In this study, a novel set of eleven N-substituted phthalimide–carboxylic acid derivatives (5a–5k) was synthesized and evaluated for ALR2 inhibition, pharmacokinetic characteristics, and cancer-selective safety. Among the series, compound 5f demonstrated the highest inhibitory potency (KI = 7.34 nM), outperforming epalrestat (KI = 232.1 nM). Glide docking positioned 5f within the ALR2 active site (GlideScore: −6.71 kcal/mol), stabilized via key contacts with Tyr48, His110, and Cys298, along with π–π stacking at Trp219. MM-GBSA analysis corroborated strong binding affinity (ΔG = −64.86 kcal/mol). DFT-derived quantum descriptors, logP, TPSA, and solvation energies supported its favorable interaction profile. ADME/Tox predictions indicated high GI absorption, no P-gp or CYP liabilities, and acceptable bioavailability. In vitro cytotoxicity assays showed negligible activity of 5f against A549 and Hep3B cancer cell lines (IC₅₀ > 160 μM) and no toxicity toward L929 fibroblasts, reflecting safety for long-term use. Transcriptomic data from CCLE and DepMap confirmed AKR1B1 overexpression in these cancer models. Network analysis linked ALR2 to redox imbalance and inflammation, suggesting its broader role in tumorigenesis. © 2025 Elsevier Inc.Academic Press Inc.2025Articlehttps://rdlopen.rawdatalibrary.net/r/ebyu/10910https://doi.org/10.1016/j.bioorg.2025.1087880045-2068enBioorganic Chemistryinfo:eu-repo/semantics/openAccessinfo:eu-repo/semantics/articlehttps://ebyu-rdlopen.rawdatalibrary.net/tr/items/ebyu/10910