An efficient and targeted synthetic approach towards new highly substituted 6-amino-pyrazolo[1,5-a]pyrimidines with α-glucosidase inhibitory activity

Abstract

In an attempt to find novel α-glucosidase inhibitors, an efficient, straightforward reaction to synthesize a library of fully substituted 6-amino-pyrazolo[1,5-a]pyrimidines 3 has been investigated. Heating a mixture of α-azidochalcones 1 and 3-aminopyrazoles 2 under the mild condition afforded desired compounds with a large substrate scope in good to excellent yields. All obtained products were evaluated as α-glucosidase inhibitors and exhibited excellent potency with IC 50 values ranging from 15.2 ± 0.4 µM to 201.3 ± 4.2 µM. Among them, compound 3d was around 50-fold more potent than acarbose (IC 50 = 750.0 ± 1.5 µM) as standard inhibitor. Regarding product structures, kinetic study and molecular docking were carried out for two of the most potent ones. Recently, the world health organization (WHO) has identified the diabetes mellitus (DM) as a critical health challenge in the 21st century. The prevalence of diabetes has been increasing at alarming rate over the past three decades. This metabolic disorder, characterized by chronic hyperglycemia, leads to further severe damages like abnormally great thrust, excessive appetite, overweigh, blindness, excessive urination, cardiovascular complications, as well as renal and neurodegenerative diseases 1-6. There are three main diabetes types among which type 2 or non-insulin dependent (T2DM) is the most common one, mainly treated by controlling the digestive enzyme activities such as α-glucosidase 7-9. α-Glucosidase, found in the brush-border surface membrane of intestinal cells, plays catalyzing role in the carbohydrate digestion process by which the postprandial blood glucose levels increases. Preventing the glucose release in the bloodstream, the α-glucosidase inhibitors control T2DM 10. Additionally, this enzyme has a pivotal role in the biosynthesis of glycoprotein, therefore, its inhibitors have possessed anticancer, antitumor, antiviral, and immunoregulatory properties 11-15. Acrabose, miglitol, voglibose, and deoxynojirimycin have clinically been used to restrict the α-glucosidase activity 16. Considering the side effects and absorption problems associated with these drugs, new scaffolds should be synthesized and evaluated by medicinal chemists to extend the library of compounds 17-25. Pyrazoles are common structural motif in numerous drugs 26 and biologically active compounds showing activities such as anti-cancer 27,28 , anti-inflammatory 29 , anti-hypertensive 30 , cannabinoid receptor antagonist 31 , dopaminergic receptor antagonist 32 , and α-glucosidase inhibitors 33. Pyrazoles have been used to synthesize

Pyrazole scaffold‐based derivatives: A glimpse of α‐glucosidase inhibitory activity, SAR, and route of synthesis

“…Numerous hydrophobic interactions between Ala 326, His 239, Arg 312, and Pro 309 were also identified in the active site. [ 59 ]…”

BF3-Mediated Acetylation of Pyrazolo[1,5-a]pyrimidines and Other π-Excedent (N-Hetero)arenes

“…In particular, pyrazolo­[1,5- a ]­pyrimidine (PP) derivatives have been identified as privileged N -heterocyclic compounds (NHCs) with those frequent applications. − For example, numerous derivatives have biological activities such as anticancer, − anti-inflammatory, and anti-infectious, among others. Some 3-acylpyrazolo­[1,5- a ]­pyrimidine derivatives are approved and commercialized as active pharmaceutical ingredients (APIs) in some health disorder treatments, , involving drugs such as Lorediplon, Ocinaplon, and Indiplon . Alternatively, more recent research has highlighted the use of the PP core in photophysical applications as molecular sensors for cyanide recognition , (Figure ).…”

Copper-based glass-ceramic as an efficient catalyst in the synthesis of pyrazolo[1,5-a] pyrimidineunder solvent-free condition with docking validation as Covid-19 main protease (Mpro) inhibitor

“…Pyrazolo [1,5-a]pyrimidines have diverse biological activities [6][7][8][9][10][11][12] such as compound A, pyrazolo [1,5-a]pyrimidine benzoic acid derivative, act as an antimicrobial agent [13]. Compound B, N 1 -(2,5-dimethyl-3-p-tolylpyrazolo [1,5-a]pyrimidin-7-yl)-1,3-diamine derivative, act as a potent hepatitis C virus inhibitor [14].…”