ABSTRACT
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.
Subject(s)
Enzyme Inhibitors/pharmacology , Oxadiazoles/pharmacology , Phosphodiesterase I/antagonists & inhibitors , Pyrophosphatases/antagonists & inhibitors , Thiadiazoles/pharmacology , Thiones/pharmacology , Cell Line , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/metabolism , Humans , Inhibitory Concentration 50 , Kinetics , Neutrophils/drug effects , Neutrophils/enzymology , Oxadiazoles/chemical synthesis , Oxadiazoles/metabolism , Phosphodiesterase I/metabolism , Pyrophosphatases/metabolism , Recombinant Proteins/chemistry , Recombinant Proteins/metabolism , Thiadiazoles/chemical synthesis , Thiadiazoles/chemistry , Thiones/chemical synthesis , Thiones/metabolismABSTRACT
Twenty-one hydrazides were synthesized by treating different esters with hydrazine hydrate. Substituted hydrazides were obtained by treating hydrazides with alkyl/aryl/acyl halides. Some of these compounds exhibit potential in vitro leishmanicidal activity. The structures of all the synthesized compounds were confirmed by spectroscopic analysis.
