An efficient and targeted synthetic approach towards new highly substituted 6-amino-pyrazolo[1,5-a]pyrimidines with \u03b1-glucosidase inhibitory activity

Fariba Peytam,Mohammad Mahdavi,Loghman Firoozpour,Alireza Foroumadi,Mohammad Ali Faramarzi,Mahmoud Rahmanian-Jazi,Somayeh Mojtabavi,Kouros Divsalar,Fatemeh Safari,Setareh Moghimi,Mehdi Adib,Reihaneh Shourgeshty,Mehdi Jahani

doi:10.1038/s41598-020-59079-z

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 IC50 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 (IC50 = 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.

Highlights

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
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[17,18,19,20,21,22,23,24,25]
We described a targeted reaction for the synthesis of a series of novel poly functionalized 6-amino-pyrazolo[1,5-a]pyrimidines 3 by Michael-addition-cyclization of α-azidochalcones 1 with 3-aminopyrazoles 2 (Scheme 1)

Summary

Introduction

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. 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[7,8,9]. Preventing the glucose release in the bloodstream, the α-glucosidase inhibitors control T2DM10. This enzyme has a pivotal role in the biosynthesis of glycoprotein, its inhibitors have possessed anticancer, antitumor, antiviral, and immunoregulatory properties[11,12,13,14,15]. Different synthetic routes towards pyrazolo[1,5-a]pyrimidines have been reported These methods have been mainly included the condensation of 3-aminopyrazoles with 1,3-bis electrophilic substrates51–59, 1,2-allenic lactones[60], β-halovinyl aldehyde[61], and activated alkynes[62,63]

Methods

Results

Conclusion