Rational design and synthesis of novel N-benzylindole-based epalrestat analogs as selective aldose reductase inhibitors: An unexpected discovery of a new glucose-lowering agent (AK-4) acting as a mitochondrial uncoupler

Eur J Med Chem. 2025 Jan 5:281:117035. doi: 10.1016/j.ejmech.2024.117035. Epub 2024 Nov 8.

Abstract

Diabetes mellitus is one of the most frequent metabolic diseases associated with hyperglycemia. Although antidiabetic drugs reduce hyperglycemia, diabetic patients suffer from abnormal fluctuations in blood glucose levels leading to the onset of long-term complications. Aldose reductase inhibitors are considered a promising strategy for regulating the occurrence of diabetic-specific comorbidities. So far, epalrestat is the only drug being approved in Asian countries. In this paper, we ground our research in discovering novel epalrestat analogs that prevent chronic complications and normalize hyperglycemia. Herein, we describe the rational design and synthesis of four novel 4-thiazolidinone acetic acid derivatives (AK-1-4) being evaluated for their efficacy against aldose reductase from rat lenses and their specificity over the homologous enzyme from rat kidneys. AK-1-4 were also tested against human recombinant protein tyrosine phosphatase 1B as a key target in insulin sensitization and towards the closely related T-cell-derived enzyme. Docking analyses suggested possible binding modes on examined targets. The promising inhibitory profile of AK-4 sparked our interest in exploring its effect on the insulin-receptor signaling pathway and its ability to stimulate glucose uptake under ex vivo conditions. We further investigated the ability of AK-4 to target mitochondria acting as an uncoupling agent and impairing mitochondrial membrane potential. Herein, we report for the first time a new glucose-lowering agent (AK-4) that can combine alleviation for chronic diabetic complications without off-target adverse effects and antihyperglycemic efficacy through controlled mitochondrial uncoupling activity. Pharmacokinetic and toxicity studies in silico revealed optimal properties of AK-4 for oral administration without potential side effects.

Keywords: ADMET; Aldose reductase; Diabetes mellitus; Epalrestat analogs; Indole-thiazolidinediones; Mitochondrial uncoupling; Protein tyrosine phosphatase 1B.

MeSH terms

  • Aldehyde Reductase* / antagonists & inhibitors
  • Aldehyde Reductase* / metabolism
  • Animals
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Drug Discovery
  • Enzyme Inhibitors* / chemical synthesis
  • Enzyme Inhibitors* / chemistry
  • Enzyme Inhibitors* / pharmacology
  • Humans
  • Hypoglycemic Agents* / chemical synthesis
  • Hypoglycemic Agents* / chemistry
  • Hypoglycemic Agents* / pharmacology
  • Indoles / chemical synthesis
  • Indoles / chemistry
  • Indoles / pharmacology
  • Male
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Molecular Docking Simulation
  • Molecular Structure
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / antagonists & inhibitors
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / metabolism
  • Rats
  • Rhodanine* / analogs & derivatives
  • Rhodanine* / chemical synthesis
  • Rhodanine* / chemistry
  • Rhodanine* / pharmacology
  • Structure-Activity Relationship
  • Thiazolidines / chemical synthesis
  • Thiazolidines / chemistry
  • Thiazolidines / pharmacology

Substances

  • Aldehyde Reductase
  • Hypoglycemic Agents
  • Enzyme Inhibitors
  • epalrestat
  • Rhodanine
  • Indoles
  • Thiazolidines
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1