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

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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

Original languageEnglish
Article number5734
JournalScientific Reports
Volume12
Issue number1
Early online date6 Apr 2022
DOIs
E-pub ahead of print6 Apr 2022
PublishedDec 2022

Bibliographical note

Funding Information: This research work was funded by the Institutional Fund Projects under grant no. (IFPIP: 54-665-1442). Therefore, authors gratefully acknowledge technical and financial support from the Ministry of Education and King Abdulaziz University, DSR, Jeddah, Saudi Arabia. Funding Information: This research work was funded by the Institutional Fund Projects under grant no. (IFPIP: 54-665-1442). Therefore, authors gratefully acknowledge technical and financial support from the Ministry of Education and King Abdulaziz University, DSR, Jeddah, Saudi Arabia. Publisher Copyright: © 2022, The Author(s).

King's Authors

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.

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