Saira Afzal, Sumera Zaib, Behzad Jafari, Peter Langer, Joanna Lecka, Jean Sévigny and Jamshed Iqbal* Pages 1 - 14 ( 14 )
Background: The ecto-nucleoside triphosphate diphosphohydrolases (NTPDases) terminates nucleotide signaling via the hydrolysis of extracellular nucleoside–5'–triphosphate and nucleoside-5'-diphosphate, to nucleoside–5'– monophosphate and composed of eight Ca2+/Mg2+ dependent ectonucleotidases (NTPDase1-8). Extracellular nucleotides are involved in a variety of physiological mechanisms. However, they are rapidly inactivated by ectonucleotidases that are involved in the sequential removal of phosphate group form nucleotides with the release of inorganic phosphate and their respective nucleoside. As ectonucleoside triphosphate diphosphohydrolases (NTPDases) represents the key enzymes responsible for nucleotides hydrolysis, and its overexpression has been related to certain pathological conditions. Therefore, the inhibitors of NTPDases are of particular importance in order to investigate their potential to treat various diseases e.g., cancer, ischemia and other disorders of the cardiovascular and immune system.
Methods: Keeping in view the importance of NTPDase inhibitors, a series of thiadiazolopyrimidones was evaluated for their potential inhibitory activity towards NTPDases by the malachite green assay.
Results: The results suggested that some of the compounds were found as non-selective inhibitors of isozyme of NTPDases, however, most of the compounds act as potent and selective inhibitors. In case of substituted amino derivatives (4c-m), the compounds 4m (IC50 = 1.13 ± 0.09 μM) and 4g (IC50 = 1.72 ± 0.08 μM) were found to be the most potent inhibitors of h-NTPDase1 and 2, respectively. Whereas, compound 4d showed the best inhibitory potential for both h-NTPDase3 (IC50 = 1.25 ± 0.06 μM) and h-NTPDase8 (0.21 ± 0.02 μM). Among 5a-t derivatives, compounds 5e (IC50 = 2.52 ± 0.15 μM), 5p (IC50 = 3.17 ± 0.05 μM), 5n (IC50 = 1.22 ± 0.06 μM) and 5b (IC50 = 0.35 ± 0.001 μM) were found to be the most potent inhibitors of h-NTPDase1, 2, 3 and 8, respectively. Interestingly, the inhibitory concentration values of above-mentioned inhibitors were several folds greater than suramin, a reference control. In order to determine the binding interactions, molecular docking studies of the most potent inhibitors were conducted into the homology models of NTPDases and the putative binding analysis further confirmed that selective and potent compounds bind deep inside the active pocket of the respective enzymes.
Conclusions: The docking analysis proposed that the inhibitory activity correlates with the hydrogen bonds inside the binding pocket. Thus, these derivatives are of interest and may further be investigated for their importance in medicinal chemistry.Highly, Potent, and, Selective, Ectonucleoside, Triphosphate, Diphosphohydrolase, (ENTPDase1,, 2,, 3, and, 8), Inhibitors, Having, 2-substituted-7-, trifluoromethyl-thiadiazolopyrimidones, Scaffold
Centre for Advanced Drug Research, COMSATS University Islamabad, Abbottabad Campus, Abbottabad-22060, Centre for Advanced Drug Research, COMSATS University Islamabad, Abbottabad Campus, Abbottabad-22060, Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Département de microbiologie-infectiologie et d'immunologie, Faculté de Médecine, Université Laval, Québec, QC, G1V 0A6, Département de microbiologie-infectiologie et d'immunologie, Faculté de Médecine, Université Laval, Québec, QC, G1V 0A6, Centre for Advanced Drug Research, COMSATS University Islamabad, Abbottabad Campus, Abbottabad-22060