2. Academic Validation
  3. Synthesis, characterization and biological evaluation of thiadiazole amide derivatives as nucleoside triphosphate diphosphohydrolases (NTPDases) inhibitors

Synthesis, characterization and biological evaluation of thiadiazole amide derivatives as nucleoside triphosphate diphosphohydrolases (NTPDases) inhibitors

  • Bioorg Chem. 2022 Jan;118:105456. doi: 10.1016/j.bioorg.2021.105456.
Sadia Abbas 1,  Saira Afzal 2,  Humaira Nadeem 3,  Dilawar Hussain 2,  Peter Langer 4,  Jean Sévigny 5,  Zaman Ashraf 6,  Jamshed Iqbal 7
Affiliations

Affiliations

  • 1 Department of Chemistry, Allama Iqbal Open University, Islamabad 44000, Pakistan.
  • 2 Centre for Advanced Drug Research, COMSATS University Islamabad, Abbottabad Campus, Abbottabad 22060, Pakistan.
  • 3 Department of Pharmaceutical Chemistry, Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan.
  • 4 Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany; Leibniz Institut für Katalyse an der Universität Rostock e.V. (LIKAT), Albert-Einstein-Str. 29a, 18059 Rostock, Germany.
  • 5 Centre de Recherche du CHU de Québec - Université Laval, Québec, QC G1V 4G2, Canada; Département de microbiologie-infectiologie et d'immunologie, Faculté de Médecine, Université Laval, Québec, QC G1V 0A6, Canada.
  • 6 Department of Chemistry, Allama Iqbal Open University, Islamabad 44000, Pakistan. Electronic address: zaman.ashraf@aiou.edu.pk.
  • 7 Centre for Advanced Drug Research, COMSATS University Islamabad, Abbottabad Campus, Abbottabad 22060, Pakistan. Electronic address: drjamshed@cuiatd.edu.pk.
PMID: 34800887 DOI: 10.1016/j.bioorg.2021.105456
Abstract

Importance of extracellular nucleotides is widely understood. These nucleotides act as ligand for P2X and P2Y receptors and modulate a variety of biological functions. However, their extracellular concentration is maintained by a chain of Enzymes termed as ecto-nucleotidases. Amongst them, nucleoside triphosphate diphosphohydrolases (NTPDases) is an important Enzyme family responsible for the dephosphorylation of these nucleotides. Overexpression of NTPDases leads to many pathological conditions such as Cancer and thrombosis. So far, only a few NTPDase inhibitors have been reported. Considering this scarcity of (NTPDase) inhibitors, a number of thiadiazole amide derivatives were synthesized and screened against human (h)-NTPDases. Several compounds showed promising inhibitory activity; compound 5a (IC50 (µM); 0.05 ± 0.008) and 5g (IC50 (µM); 0.04 ± 0.006) appeared to be the most distinguished molecules corresponding to h-NTPDase1 and -2. However, h-NTPDase3 was the least susceptible isozyme and only three compounds (5d, 5e, 5j) strongly inhibited h-NTPDase3. Interestingly, compound 5e was recognized as the most active compound that showed dual inhibition against h-NTPDase3 as well as against h-NTPDase8. For better comprehension of binding mode of these inhibitors, most potent inhibitors were docked with their respective isozyme.

Keywords

Amide; Ectonucleotidases; Molecular docking; Nucleoside triphosphate diphosphohydrolases; Thiadiazole.

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