Development and exploration of novel substituted thiosemicarbazones as inhibitors of aldose reductase via in vitro analysis and computational study

Aqeel Imran, Muhammad Tariq Shehzad, Syed Jawad Ali Shah, Taha al Adhami, Mark Laws, Khondaker Miraz Rahman, Rima D. Alharthy, Imtiaz Ali Khan, Zahid Shafiq, Jamshed Iqbal*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)

Abstract

The role of aldose reductase (ALR2) in causing diabetic complications is well-studied, with overactivity of ALR2 in the hyperglycemic state leading to an accumulation of intracellular sorbitol, depletion of cytoplasmic NADPH and oxidative stress and causing a variety of different conditions including retinopathy, nephropathy, neuropathy and cardiovascular disorders. While previous efforts have sought to develop inhibitors of this enzyme in order to combat diabetic complications, non-selective inhibition of both ALR2 and the homologous enzyme aldehyde reductase (ALR1) has led to poor toxicity profiles, with no drugs targeting ALR2 currently approved for therapeutic use in the Western world. In the current study, we have synthesized a series of N-substituted thiosemicarbazones with added phenolic moieties, of which compound 3m displayed strong and selective ALR2 inhibitory activity in vitro (IC50 1.18 µM) as well as promising antioxidant activity (75.95% free radical scavenging activity). The target binding modes of 3m were studied via molecular docking studies and stable interactions with ALR2 were inferred through molecular dynamics simulations. We thus report the N-substituted thiosemicarbazones as promising drug candidates for selective inhibition of ALR2 and possible treatment of diabetic complications.

Original languageEnglish
Article number5734
JournalScientific Reports
Volume12
Issue number1
Early online date6 Apr 2022
DOIs
Publication statusPublished - Dec 2022

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