Novel Spiroindoline Derivatives Targeting Aldose Reductase Against Diabetic Complications: Bioactivity, Cytotoxicity, and Molecular Modeling Studies

Abstract

Despite significant developments in therapeutic strategies, Diabetes Mellitus remains an increasing concern, leading to various complications, e.g., cataracts, neuropathy, retinopathy, nephropathy, and several cardiovascular diseases. The polyol pathway, which involves Aldose reductase (AR) as a critical enzyme, has been focused on by many researchers as a target for intervention. On the other hand, spiroindoline-based compounds possess remarkable biological properties. This guided us to synthesize novel spiroindoline oxadiazolyl-based acetate derivatives and investigate their biological activities. The synthesized molecules' structures were confirmed herein, using IR, NMR (1H and 13C), and Mass spectroscopy. All compounds were potent inhibitors with KI constants spanning from 0.186 +/- 0.020 mu M to 0.662 +/- 0.042 mu M versus AR and appeared as better inhibitors than the clinically used drug, Epalrestat (EPR, KI: 0.841 +/- 0.051 mu M). Besides its remarkable inhibitory profile compared to EPR, compound 6k (KI: 0.186 +/- 0.020 mu M) was also determined to have an unusual pharmacokinetic profile. The results showed that 6k had less cytotoxic effect on normal mouse fibroblast (L929) cells (IC50 of 569.58 +/- 0.80 mu M) and reduced the viability of human breast adenocarcinoma (MCF-7) cells (IC50 of 110.87 +/- 0.42 mu M) more than the reference drug Doxorubicin (IC50s of 98.26 +/- 0.45 mu M and 158.49 +/- 2.73 mu M, respectively), thus exhibiting more potent anticancer activity. Moreover, molecular dynamic simulations for 200 ns were conducted to predict the docked complex's stability and reveal significant amino acid residues that 6k interacts with throughout the simulation.