Chalcone-inspired indole, carbazole, and phenothiazine hybrids as potent aldose reductase inhibitors with selective anticancer potential: Rational design, synthesis, and multi-level characterization.

Aldose reductase (ALR2) has emerged as a dual-function therapeutic target, critically involved in diabetic complications and cancer-related redox adaptation. In this study, a novel series of 15 chalcone-inspired heteroaryl-dihydronaphthalenone hybrids bearing indole, carbazole, or phenothiazine motifs (4a-4f, 8a-8e, 12a-12d) were rationally designed, synthesized, and systematically evaluated for their ALR2 inhibitory and anticancer properties. Enzymatic inhibition assays revealed low-nanomolar to low-nanomolar KI values, with compound 8b (KI = 3.59 nM, pKI = 8.44) emerging as the most potent inhibitor, outperforming the reference drug Epalrestat. SAR analysis highlighted the critical role of flexible alkyl side chains and polycyclic aromatic scaffolds in optimizing hydrophobic anchoring. Complementary in silico studies, including MM-GBSA binding energy calculations (ΔGbind = -56.37 kcal/mol), quantum descriptors (HOMO-LUMO gap, solvation energy), and ADME/Tox profiling (SwissADME, QikProp, ADMETlab), provided further mechanistic insight into selectivity and drug-likeness. Lead compound 8b also demonstrated selective antiproliferative activity toward A549 lung carcinoma cells (IC₅₀ = 197.6 μM), with no observed cytotoxicity in Hep3B hepatoma or L929 fibroblast lines. Molecular dynamics simulations confirmed binding stability, while target prediction analyses suggested low off-target risk. This multi-parametric evaluation underscores the translational potential of scaffold-tuned ALR2 inhibitors as oxidative stress-modulating agents with cancer-selective properties.