1,3,4-Oxadiazole-2(3H)-thione and its analogues: a new class of non-competitive nucleotide pyrophosphatases/phosphodiesterases 1 inhibitors.
A series of 1,3,4-oxadiazole-2 (3H)-thiones and 1,3,4-thiadiazole-2 (3H)-thiones were synthesized and evaluated for their inhibitory activities against the two nucleotide pyrophosphatase phosphodiesterase 1 enzymes. Dixon, as well as Lineweaver-Burk plots, and their secondary replots have indicated that the inhibition was of pure non-competitive type, against both snake venom and pure human recombinant enzymes as the V(max) values decreases without affecting the K(m) values. 5-[4-(t-Butyldimethylsilyloxy)-phenyl]-1,3,4-thiadiazole-2 (3H)-thione (17) and [4-(t-butyldimethylsilyloxy)-phenyl]-1,3,4-oxadiazole-2 (3H)-thione (1) were found to be the most active compounds with IC(50) values 66.47 and 368microM, respectively. The K(i) values were 100microM and 360microM against the snake venom and human recombinant NPP1 enzyme, respectively. Most active compounds were found to be non-toxic in neutrophil viability assay.
Khan
Khalid M
KM
H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan. hassaan2@super.net.pk
Fatima
Naheed
N
Rasheed
Maimona
M
Jalil
Saima
S
Ambreen
Nida
N
Perveen
Shahnaz
S
Choudhary
M Iqbal
MI
D002460:Cell Line; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D043264:Phosphodiesterase I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011755:Pyrophosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D013830:Thiadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013871:Thiones / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D011994:Recombinant Proteins; D013830:Thiadiazoles; D013871:Thiones; D043264:Phosphodiesterase I; C470790:phosphodiesterase I, snake venom; D011755:Pyrophosphatases; C021899:nucleotide pyrophosphatase