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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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Development and exploration of novel substituted thiosemicarbazones as inhibitors of aldose reductase via in vitro analysis and computational study. / Imran, Aqeel; Shehzad, Muhammad Tariq; Shah, Syed Jawad Ali et al.

In: Scientific Reports, Vol. 12, No. 1, 5734, 12.2022.

Research output: Contribution to journalArticlepeer-review

Harvard

Imran, A, Shehzad, MT, Shah, SJA, al Adhami, T, Laws, M, Rahman, KM, Alharthy, RD, Khan, IA, Shafiq, Z & Iqbal, J 2022, 'Development and exploration of novel substituted thiosemicarbazones as inhibitors of aldose reductase via in vitro analysis and computational study', Scientific Reports, vol. 12, no. 1, 5734. https://doi.org/10.1038/s41598-022-09658-z

APA

Imran, A., Shehzad, M. T., Shah, S. J. A., al Adhami, T., Laws, M., Rahman, K. M., Alharthy, R. D., Khan, I. A., Shafiq, Z., & Iqbal, J. (2022). Development and exploration of novel substituted thiosemicarbazones as inhibitors of aldose reductase via in vitro analysis and computational study. Scientific Reports, 12(1), [5734]. https://doi.org/10.1038/s41598-022-09658-z

Vancouver

Imran A, Shehzad MT, Shah SJA, al Adhami T, Laws M, Rahman KM et al. Development and exploration of novel substituted thiosemicarbazones as inhibitors of aldose reductase via in vitro analysis and computational study. Scientific Reports. 2022 Dec;12(1). 5734. https://doi.org/10.1038/s41598-022-09658-z

Author

Imran, Aqeel ; Shehzad, Muhammad Tariq ; Shah, Syed Jawad Ali et al. / Development and exploration of novel substituted thiosemicarbazones as inhibitors of aldose reductase via in vitro analysis and computational study. In: Scientific Reports. 2022 ; Vol. 12, No. 1.

Bibtex Download

@article{bbcc8520b1be494ba8c2bb3199f7da8f,
title = "Development and exploration of novel substituted thiosemicarbazones as inhibitors of aldose reductase via in vitro analysis and computational study",
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.",
author = "Aqeel Imran and Shehzad, {Muhammad Tariq} and Shah, {Syed Jawad Ali} and {al Adhami}, Taha and Mark Laws and Rahman, {Khondaker Miraz} and Alharthy, {Rima D.} and Khan, {Imtiaz Ali} and Zahid Shafiq and Jamshed Iqbal",
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: {\textcopyright} 2022, The Author(s).",
year = "2022",
month = dec,
doi = "10.1038/s41598-022-09658-z",
language = "English",
volume = "12",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",
number = "1",

}

RIS (suitable for import to EndNote) Download

TY - JOUR

T1 - Development and exploration of novel substituted thiosemicarbazones as inhibitors of aldose reductase via in vitro analysis and computational study

AU - Imran, Aqeel

AU - Shehzad, Muhammad Tariq

AU - Shah, Syed Jawad Ali

AU - al Adhami, Taha

AU - Laws, Mark

AU - Rahman, Khondaker Miraz

AU - Alharthy, Rima D.

AU - Khan, Imtiaz Ali

AU - Shafiq, Zahid

AU - Iqbal, Jamshed

N1 - 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).

PY - 2022/12

Y1 - 2022/12

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85127658964&partnerID=8YFLogxK

U2 - 10.1038/s41598-022-09658-z

DO - 10.1038/s41598-022-09658-z

M3 - Article

C2 - 35388067

AN - SCOPUS:85127658964

VL - 12

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

IS - 1

M1 - 5734

ER -

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