Phenothiazine-rhodanine derivatives targeting aldose reductase: Synthesis, kinetic characterization, and molecular modeling.

Abstract

Twenty-one phenothiazine-rhodanine derivatives (6a-g and 7a-n) were synthesized, characterized, and evaluated for aldose reductase (ALR2, AKR1B1) inhibition. Cellular effects were examined in HUVEC, A549, and Hep3B cells, alongside electronic-descriptor, ADME, and molecular-modeling analyses. Compound 7i showed the strongest ALR2 inhibition, with an apparent KI of 98.91 ± 9.58 nM, approximately 8.9-fold lower than that of epalrestat (877.80 ± 44.25 nM); this comparison requires independent confirmation. Matched-series analysis associated the highest potency with the combination of phenothiazine N-ethyl substitution and a 2-(diethylamino)-2-oxoethyl ester group. Cellular activity against A549 and Hep3B was generally limited, with no established mechanistic relationship to ALR2 inhibition. Docking reproduced the crystallographic ligand pose with an RMSD of 0.34 Å and suggested a plausible binding mode for 7i. MM-GBSA provided a protocol-dependent binding-energy estimate, while a single 500 ns molecular dynamics trajectory identified persistent protein-ligand contacts. Electronic descriptors did not show a robust, series-independent relationship with potency. Overall, 7i represents a potent biochemical hit requiring further validation and optimization. Its enzyme selectivity and normal-cell safety profile require further investigation, while high predicted lipophilicity and poor aqueous solubility indicate developability challenges.

Abstract as supplied by the indexing source. © the authors / publisher.