Background: The ecto-nucleoside triphosphate diphosphohydrolases (NTPDases) terminate
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 from nucleotides with the release of inorganic
phosphate and their respective nucleoside. Ectonucleoside triphosphate diphosphohydrolases
(NTPDases) represent the key enzymes responsible for nucleotides hydrolysis and their 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
were evaluated for their potential inhibitory activity towards NTPDases by the malachite green
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.
Conclusion: 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.