Functionalized quinoxalinones as privileged structures with broad-ranging pharmacological activities
Graphical abstract
Introduction
Heterocyclic compounds have been extensively concerned in the field of organic synthesis and novel drug development for several decades, among which quinoxalinone is one of the most promising heterocycles [1]. Quinoxalinone belongs to benzodiazine heterocyclic class with nitrogen atoms located at 1- and 4-position, and a ketone carbonyl group located at 2-position [2]. Quinoxalinediones can also be obtained by introducing another ketone carbonyl group at 3-position.
The direct functionalization of the quinoxalinone parent nucleus is mainly focused on expanding quinoxalinone derivatives and performing structural modification. Several novel, mild, efficient and sustainable synthesis strategies and methods have been reported, including arylation [3], alkylation [4], olefination [5], alkoxylation [6], fluoroalkylation [7], acylation [8], alkoxycarbonylation [9], amination [10], amidation [11], phosphonation [12], thiolation [13], silylation [14] and annulation [15] via transition metal catalysis, photocatalysis, electrocatalysis or radical oxidative coupling reactions. Most of substituted quinoxalinones and their derivatives have showed interesting biological properties [1,16,17], such as anti-tumor [18], anticonvulsant [19], antidepression [20], antibacterial [21], antiviral [22], anti-inflammatory [23], anti-allergy [24], antithrombosis [25], anti-diabetes [26], anti-oxidation [27], etc (Fig. 1).
Although a series of effective methods for functionalizing quinoxalinones have been widely established through organic synthesis, the developments of organic synthesis methodology toward the optimization of quinoxalinone lead compounds is rarely reported. This review initially presents an overview of the design principles, then describes the different pharmacological activities of quinoxalinones based on different targets or different modification sites, focusing on the modification process of the optimal compounds and their SARs. Finally, a brief summary of SARs study and a perspective on the connection between synthetic methodological studies and pharmacological applications of quinoxalinone derivatives were outlined. We hope that it could promote the development of quinoxalinone derivatives in the field of drug discovery and give more inspiration to chemists. We also expect that our readers would like to point out some careless errors and we will append these very import works in future.
Section snippets
RTK inhibitors
Receptor tyrosine kinases (RTKs), including hepatocyte growth factor receptor (HGFR) c-Met, vascular endothelial growth factor receptor-2 (VEGFR-2), fibroblast growth factor receptor (FGFR) and epidermal growth factor receptor (EGFR), etc., regulate many signal transduction pathways and cellular processes in normal cells. However, they are overexpressed or mutated in many tumor cells, playing an important role in the development and progression of cancer [28].
Liu et al. found that the moieties
Conclusions and perspectives
Quinoxalinones have been widely reported to be continuously modified through different synthetic strategies because of their excellent reactivity and easily modified structures. More importantly, as a privileged structure, functionalized quinoxalinones can bind with various targets with high affinity, possessing a wide range of biological characteristics. They are most commonly used in cancer, central nervous system (CNS) diseases, infections and cardiovascular diseases.
Based on the SARs study,
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
This project was supported by the National Natural Science Foundation of China, NSFC (Grant No. 22178078, 21773311, 21972169, 81803340), the Hunan Provincial Science and Technology Project (No. 2019TP1001), the Natural Science Foundation of Zhejiang Province (LY20H300004), and the Scientific Research Foundation for Scholars of HZNU (2021QDL026).
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