Abstract
A new series of thiobarbituric (thiopyrimidine trione) enamine derivatives and its analogues barbituric acid derivatives was synthesised, characterised, and screen for in vitro evaluation of α-glucosidase enzyme inhibition and anti-glycation activity. This series of compounds were found to inhibit α-glucosidase activity in a reversible mixed-type manner with IC50 between 264.07 ± 1.87 and 448.63 ± 2.46 µM. Molecular docking studies indicated that compounds of 3g, 3i, 3j, and 5 are located close to the active site of α-glucosidase, which may cover the active pocket, thereby inhibiting the binding of the substrate to the enzyme. Thiopyrimidine trione derivatives also inhibited the generation of advanced glycation end-products (AGEs), which cause long-term complications in diabetes. While, compounds 3a–k, 5, and 6 showed significant to moderate anti-glycation activity (IC50 = 31.5 ± 0.81 to 554.76 ± 9.1 µM).
Highlights
Diabetes mellitus (DM) is a disease which caused by a breakdown of carbohydrate metabolism, which plays a significant role in the development of long-term diabetic complications
The results reveal that the four monomeric compounds 4a–d derived from N,N0-dimethylbarbituric enamine derivatives showed no anti-glycation activity, while compounds derived from N,N0-diethylthiobarbituric enamine derivatives 3a–k exhibited moderate activity against protein glycation with IC50 in the range 70–550 mM
The most potent anti-glycation activity was showed by the dimeric product from N,N0diethylthiobarbituric enamine 6 with an IC50 of 31.5 mM, while the dimeric analogue of N,N0-dimethylbarbituric enamine 5 showed less activity with an IC50 of 554.8 mM
Summary
Diabetes mellitus (DM) is a disease which caused by a breakdown of carbohydrate metabolism, which plays a significant role in the development of long-term diabetic complications. They catalyse the breaking down long-chain polysaccharides into absorbable monosaccharide units Of these enzymes, a-glucosidases, which play a key role in the digestion and absorption of complex carbohydrates, and has emerged as target to maintain postprandial blood glucose control. A-Glucosidase inhibitors currently used to treat T2DM include acarbose (Precose), voglibose, and miglitol[8]. These drugs are associated with several side effects, such as flatulence, stomach-ache, diarrhoea, and liver damage[9]. Barbituric acid (BA) derivatives have been reported to have potential anti-hypertensive[13], anti-cancer[14], anti-convulsant[15], antiinflammatory[16], anti-psychotic[17], and antitumor properties[18,19,20,21]. Synthetic route for the synthesis of 3a–k, 4a–d, 5, and 6
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