Repositioning of rhodanine-thiazole hybrids as aldose reductase inhibitors

Abstract

This study investigates the aldose reductase (AR) inhibitory potential of a series of synthesized rhodanine-thiazole hybrids (7a–7 l) through a combination of biological assays and computational modeling. The derivatives were divided into two categories: rhodanine (7a–7f) and rhodanine acetic acid derivatives (7g–7l). Biological evaluation revealed that rhodanine acetic acid derivatives demonstrated superior AR inhibition, with IC₅₀ values ranging from 6.87 to 9.07 µM, compared to rhodanine derivatives (11.79–15.90 µM). Among them, compound 7i (4-fluoro rhodanine acetic acid) exhibited the highest potency (IC₅₀ = 6.87 ± 1.22 µM), outperforming the standard Quercetin. Kinetic studies confirmed 7i as a reversible, non-competitive inhibitor (Ki = 6.87 µM), indicating interaction at an allosteric site of AR. Molecular docking using Schrödinger’s Glide XP mode against AKR1B1 (PDB ID: 4JIR) revealed that 7i had the most favorable docking score (−10.02) and binding energy (−67.51 kcal/mol), surpassing the standard inhibitor Epalrestat. Molecular dynamics simulations (200 ns) for 7 h and 7i indicated stable binding within the active site, with TRP111 identified as a key interacting residue. Interaction profiling revealed consistent hydrogen bonding and hydrophobic interactions, especially for 7i. Further, Principal Component Analysis (PCA) and Free Energy Landscape (FEL) analysis confirmed the stability of the 7i-bound complex, showing a dominant low-energy conformation. Dynamic Cross-Correlation Matrix (DCCM) analysis suggested that 7i enhances protein stability by modulating internal dynamics. Overall, 7i emerges as a promising AR inhibitor with potential therapeutic relevance for diabetic complications.