Abstract
In an attempt to find novel, potent α-glucosidase inhibitors, a library of poly-substituted 3-amino-2,4-diarylbenzo[4,5]imidazo[1,2-a]pyrimidines 3a–ag have been synthesized through heating a mixture of 2-aminobenzimidazoles 1 and α-azidochalcone 2 under the mild conditions. This efficient, facile protocol has been resulted into the desirable compounds with a wide substrate scope in good to excellent yields. Afterwards, their inhibitory activities against yeast α-glucosidase enzyme were investigated. Showing IC50 values ranging from 16.4 ± 0.36 µM to 297.0 ± 1.2 µM confirmed their excellent potency to inhibit α-glucosidase which encouraged us to perform further studies on α-glucosidase enzymes obtained from rat as a mammal source. Among various synthesized 3-amino-2,4-diarylbenzo[4,5]imidazo[1,2-a]pyrimidines, compound 3k exhibited the highest potency against both Saccharomyces cerevisiae α-glucosidase (IC50 = 16.4 ± 0.36 μM) and rat small intestine α-glucosidase (IC50 = 45.0 ± 8.2 μM). Moreover, the role of amine moiety on the observed activity was studied through substituting with chlorine and hydrogen resulted into a considerable deterioration on the inhibitory activity. Kinetic study and molecular docking study have confirmed the in-vitro results.
Highlights
Diabetes mellitus is a common, chronic disease mainly characterized by the body’s lack of ability to control blood sugar resulted into chronic hyperglycemia
Design and synthesis of these targeted compounds which are anticipated to possess potent α-glucosidase inhibitory activity could be an interesting challenge in medicinal chemistry
Some noticeable examples include the reaction of this starting material with α,β-unsaturated compounds44, 1,2-diphenylethanones, alkynes, or 1,3-bis electrophilic compounds and aromatic a ldehydes45–50, acrylamides bearing a leaving group like ethoxy in the β-position51, domino reaction with N-methyl-1-(methylthio)-2-nitroprop-1-en-1-amine and aromatic aldehydes52, as well as four-component reaction with amines, diketene, and aromatic a ldehydes53
Summary
Diabetes mellitus is a common, chronic disease mainly characterized by the body’s lack of ability to control blood sugar resulted into chronic hyperglycemia Progression in this metabolic disorder may bring subsequent severe health problems, including abnormally great thrust, excessive appetite, overweight, blindness, excessive urination, leg amputation, cardiovascular complications, as well as renal and neurodegenerative diseases. Carbohydrate digestive enzymes, found in the brush border of the intestine, play the catalyzing role in breaking down the long-chain polysaccharides into absorbable monosaccharide units Among these enzymes, α-glucosidase has received considerable attention regarding their noticeable role in the lysis of α-glucopyranoside bond in oligosaccharides and disaccharides. There are several reports concerning α-glucosidase inhibitors having benzimidazole and pyrimidine skeletons separately, compounds bearing both of these heterocycles, benzo[4,5]imidazo[1,2-a]pyrimidine, in particular, as anti-diabetic agents have not been proposed yet (Fig. 1). Some noticeable examples include the reaction of this starting material with α,β-unsaturated compounds44, 1,2-diphenylethanones, alkynes, or 1,3-bis electrophilic compounds and aromatic a ldehydes, acrylamides bearing a leaving group like ethoxy in the β-position, domino reaction with N-methyl-1-(methylthio)-2-nitroprop-1-en-1-amine and aromatic aldehydes, as well as four-component reaction with amines, diketene, and aromatic a ldehydes
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