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Fluorenyl-phthalimide hybrids as potent aldose reductase inhibitors with selective anticancer activity: Rational design, synthesis, and molecular insightsGundogdu, SalihaDuran, Hatice EsraArslan, MustafaÇetinkaya, Büşra DemirTürkeş, CüneytAldose reductase inhibitorsFluorenyl-phthalimide hybridsMachine learningPrecision oncologyRational drug designSelective cytotoxicityTargeted therapyAldehyde ReductaseAntineoplastic AgentsCell ProliferationDose-Response Relationship, DrugDrug DesignDrug Screening Assays, AntitumorEnzyme InhibitorsHumansMolecular Docking SimulationMolecular StructurePhthalimidesStructure-Activity Relationship2 [(9h fluoren 2 yl)carbamoyl] 3,4,5,6 tetrabromobenzoic acid2 [(9h fluoren 2 yl)carbamoyl] 3,4,5,6 tetrachlorobenzoic acid2 [(9h fluoren 2 yl)carbamoyl] 5 fluorobenzoic acid2 [(9h fluoren 2 yl)carbamoyl] 6 fluorobenzoic acid2 [(9h fluoren 2 yl)carbamoyl] 6 nitrobenzoic acid2 [(9h fluoren 2 yl)carbamoyl]benzoic acid2 [(9h fluoren 2 yl)carbamoyl]c 5 methylcyclohexane 1 carboxylic acid2 [(9h fluoren 2 yl)carbamoyl]cyclohexane 1 carboxylic acid4 [(9h fluoren 2 yl)amino] 3 methyl 4 oxobutanoic acid4 [(9h fluoren 2 yl)amino] 4 oxobut 2 enoic acid4 [(9h fluoren 2 yl)amino] 4 oxobutanoic acidMetabolic reprogramming in cancer cells creates actionable vulnerabilities for precision oncology. Aldose reductase (ALR2, AKR1B1; EC 1.1.1.21), a cytosolic NADPH-dependent oxidoreductase, has emerged as a multifunctional player in tumor progression, drug resistance, and oxidative stress modulation, yet remains underexploited as a cancer target. In this study, we report the rational design, synthesis, and biological evaluation of a focused series of fluorenyl-phthalimide carboxylic-acid hybrids (5a-5l) as dual-acting agents with selective anticancer potential and potent ALR2 inhibition. Among them, compound 5a exhibited the strongest ALR2 inhibition with a KI of 8.71 ± 0.81 nM, far surpassing the clinical comparator epalrestat (KI = 232.10 ± 14.42 nM). In MCF-7 and A549 carcinoma cells, 5a demonstrated moderate antiproliferative activity (IC50 = 52.04 μM and 192.91 μM, respectively) while sparing normal bronchial epithelial cells, indicating tumor selectivity. Molecular docking and MM-GBSA calculations (ΔGbind = −44.02 kcal/mol) revealed a consistent bidentate hydrogen bonding network supporting high-affinity binding involving Tyr48, His110, and Trp111, further stabilized by crystallographic water molecules. To explore structure-activity relationships, a Random Forest regression model was developed using 24 descriptors derived from QikProp. The model achieved strong predictive performance (Q2CV = 0.71), and SHAP analysis identified water/gas partition coefficient, skin permeability, and human oral absorption as the most influential features shaping inhibitory potency. In silico ADME/Tox profiling supported the drug-like nature of compound 5a, with no major CYP or hERG liabilities predicted. Collectively, these findings position 5a as a first-in-class ALR2-targeted anticancer lead, introducing a chemically novel and mechanistically validated chemotype for further development within the framework of metabolically targeted precision therapies. © 2025 Elsevier Inc.Academic Press Inc.2025Articlehttps://rdlopen.rawdatalibrary.net/r/ebyu/10699https://doi.org/10.1016/j.bioorg.2025.1086890045-2068enBioorganic Chemistryinfo:eu-repo/semantics/openAccessinfo:eu-repo/semantics/articlehttps://ebyu-rdlopen.rawdatalibrary.net/tr/items/ebyu/10699