Malononitrile-activated synthesis and anti-cholinesterase activity of styrylquinoxalin-2(1H)-ones.

Sheena Mahajan,Kamal K Kapoor,Vijay K Nuthakki,Sandip B Bharate,Nancy Slathia

doi:10.1039/d0ra02816a

Abstract

Herein, we report a base-free malononitrile activated condensation of 3-methylquinoxaline-2(1H)-one (3MQ) 1 with aryl aldehydes 3a–3ad for synthesis of styrylquinoxalin-2(1H)-ones (SQs) 4a–4ad with excellent yields. In this reaction, malononitrile activates the aldehyde via Knoevenagel condensation towards reaction with 3MQ 1 and gets liberated during the course of reaction to yield the desired SQs 4a–4ad. The SQs were evaluated for in vitro cholinesterase inhibition and 4n was found to display a mixed type of inhibition of AChE, which was supported by molecular modelling studies. This study has led to the discovery of a new chemotype for cholinesterase inhibition which might be useful in finding a remedy for Alzheimer's disease.

Highlights

Styrylquinoxalin-2(1H)-ones (SQs) are hybrid molecules of styryl and quinoxalinone. These are promising sources of bioactive scaffolds in the treatment of diverse physiological and pathophysiological events.[1]. Their derivatives serve as useful rigid subunits in the glucagon receptor antagonist1b (I), macrocyclic receptors in molecular recognition1c (II), anticancer agents1d–f (III, IV), VEGFR-2 inhibitor1g (V), aldose reductase inhibition, antioxidants1h,i (VI, VII) and are used as uorescent probes for amyloid-beta brils (Fig. 1).[2]
A er 15 min, thin layer chromatography (TLC) observation reveals the complete disappearance of reactants
Malononitrile was best amongst all active methylenes investigated, yielding desired compound 4a, in 92% yield only in 15 min of reaction time, suggesting that malononitrile acts as best activator in the reaction

Summary

Introduction

Styrylquinoxalin-2(1H)-ones (SQs) are hybrid molecules of styryl and quinoxalinone. These are promising sources of bioactive scaffolds in the treatment of diverse physiological and pathophysiological events.[1] Their derivatives serve as useful rigid subunits in the glucagon receptor antagonist1b (I), macrocyclic receptors in molecular recognition1c (II), anticancer agents1d–f (III, IV), VEGFR-2 inhibitor1g (V), aldose reductase inhibition, antioxidants1h,i (VI, VII) and are used as uorescent probes for amyloid-beta brils (Fig. 1).[2] SQs have an interesting architecture composed of quinoxalinone, a polarized olefenic bond and the presence of H-bond donors and acceptors. Various approaches and the present method are summarized in Scheme 1

Methods

Results

Conclusion