Oxadiazoles and thiadiazoles: Novel α-glucosidase inhibitors

Published on Oct 1, 2014in Bioorganic & Medicinal Chemistry2.802
· DOI :10.1016/j.bmc.2014.07.032
Hamdy Kashtoh3
Estimated H-index: 3
(KAU: King Abdulaziz University),
Shafqat Hussain9
Estimated H-index: 9
(KU: University of Karachi)
+ 5 AuthorsM. Iqbal Choudhary49
Estimated H-index: 49
(KAU: King Abdulaziz University)
Abstract Oxadiazoles and thiadiazoles 1 – 37 were synthesized and evaluated for the first time for their α-glucosidase inhibitory activities. As a result, fifteen of them 1 , 4 , 5 , 7 , 8 , 13 , 17 , 23 , 25 , 30 , 32 , 33 , 35 , 36 and 37 were identified as potent inhibitors of the enzyme. Kinetic studies of the most active compounds (oxadiazoles 1 , 23 and 25 , and thiadiazoles 35 and 37 ) were carried out to determine their mode of inhibition and dissociation constants K i . The most potent compound of the oxadiazole series (compound 23 ) was found to be a non-competitive inhibitor ( K i  = 4.36 ± 0.017 μM), while most potent thiadiazole 35 was identified as a competitive inhibitor ( K i  = 6.0 ± 0.059 μM). The selectivity and toxicity of these compounds were also studied by evaluating their potential against other enzymes, such as carbonic anhydrase-II and phosphodiesterase-I. Cytotoxicity was evaluated against rat fibroblast 3T3 cell line. Interestingly, these compounds were found to be inactive against other enzymes, exhibiting their selectivity towards α-glucosidase. Inhibition of α-glucosidase is an effective strategy for controlling post-prandial hyperglycemia in diabetic patients. α-Glucosidase inhibitors can also be used as anti-obesity and anti-viral drugs. Our study identifies two novel series of potent α-glucosidase inhibitors for further investigation.
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