Synthesis and evaluation of aldose reductase inhibition of new thiazolidine-quinazoline hybrids through in vitro and in silico approaches.

In this study, eleven novel quinazolin-4(3H)-one-thiazolidine-4-one hybrid compounds (1-11) were synthesized and evaluated for their in vitro aldose reductase (AR) inhibitory activity as potential therapeutics for diabetic complications. Structural characterization was performed using FT-IR, NMR, and HRMS techniques. The biological activity evaluation revealed that the nature of the substituents at the C2 position of the quinazoline ring significantly influenced AR inhibition. Compounds with aromatic or alicyclic groups (8-11) exhibited superior inhibitory potency, with compound 11, containing a thiophene ring, showing the strongest inhibition (IC = 10.19 µM), comparable to the standard quercetin. Molecular docking studies identified key interactions between the compounds and AR enzyme, including hydrogen bonds with Cys-298 and His-110, and π-π stacking with Trp-111. Notably, compound 11 demonstrated enhanced binding through additional π-π stacking with Phe-122. Molecular dynamics simulations confirmed the stability of these interactions, with residues such as Trp-111, Ala-299, and Tyr-209 playing crucial roles in ligand binding stability. ADME predictions for compounds 9-11 indicated favorable pharmacokinetic profiles, including strong oral bioavailability, absorption, and permeability, making them promising drug candidates. Overall, compounds 9-11 present significant AR inhibitory activity and pharmacokinetic properties, positioning them as strong candidates for further development in treating diabetic complications.