Exploring antidiabetic potential of adamantyl-thiosemicarbazones via aldose reductase (ALR2) inhibition

Shehzad MT 1 , Hameed A 2 , Al-Rashida M 2 , Imran A 3 , Uroos M 4 , Asari A 5 Show all authors , Mohamad H 6 , Islam M 1 , Iftikhar S 7 , Shafiq Z 8 , Iqbal J 9

Affiliations 

  • 1 Institute of Chemical Sciences, Bahauddin Zakariya University, Multan 60800, Pakistan
  • 2 Department of Chemistry, Forman Christian College (A Chartered University), Ferozepur Road, Lahore 54600, Pakistan
  • 3 Centre for Advanced Drug Research, COMSATS University Islamabad, Abbottabad Campus, Abbottabad 22060, Pakistan
  • 4 Institute of Chemistry, University of The Punjab, Lahore 54590, Pakistan
  • 5 Faculty of Science and Marine Environment, Universiti Malaysia Terengganu, 21030 Kuala Nerus, Terengganu, Malaysia
  • 6 Institute of Marine Biotechnology, Universiti Malaysia Terengganu, 21030 Kuala Nerus, Terengganu, Malaysia
  • 7 Department of Chemistry, The University of Lahore, Lahore Pakistan
  • 8 Institute of Chemical Sciences, Bahauddin Zakariya University, Multan 60800, Pakistan. Electronic address: zahidshafiq@bzu.edu.pk
  • 9 Centre for Advanced Drug Research, COMSATS University Islamabad, Abbottabad Campus, Abbottabad 22060, Pakistan. Electronic address: drjamshed@ciit.net.pk
Bioorg Chem, 2019 11;92:103244.
PMID: 31541804 DOI: 10.1016/j.bioorg.2019.103244

Abstract

The role of aldose reductase (ALR2) in diabetes mellitus is well-established. Our interest in finding ALR2 inhibitors led us to explore the inhibitory potential of new thiosemicarbazones. In this study, we have synthesized adamantyl-thiosemicarbazones and screened them as aldehyde reductase (ALR1) and aldose reductase (ALR2) inhibitors. The compounds bearing phenyl 3a, 2-methylphenyl 3g and 2,6-dimethylphenyl 3m have been identified as most potent ALR2 inhibitors with IC50 values of 3.99 ± 0.38, 3.55 ± 0.26 and 1.37 ± 0.92 µM, respectively, compared with sorbinil (IC50 = 3.14 ± 0.02 μM). The compounds 3a, 3g, and 3m also inhibit ALR1 with IC50 value of 7.75 ± 0.28, 7.26 ± 0.39 and 7.04 ± 2.23 µM, respectively. Molecular docking was also performed for putative binding of potent inhibitors with target enzyme ALR2. The most potent 2,6-dimethylphenyl bearing thiosemicarbazone 3m (IC50 = 1.37 ± 0.92 µM for ALR2) and other two compound 3a and 3g could potentially lead for the development of new therapeutic agents.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

MeSH terms
Similar publications