Synthesis and biological evaluation of chromanone-based derivatives as potential anti-neuroinflammatory agents

Guoxun Li; Xiaoqing Feng; Wenqian Wang; Jian Li; Yeye Shi; Lin Wang; Caijuan Hu

doi:10.1016/j.bioorg.2023.106767

Synthesis and biological evaluation of chromanone-based derivatives as potential anti-neuroinflammatory agents

Bioorg Chem. 2023 Oct:139:106767. doi: 10.1016/j.bioorg.2023.106767. Epub 2023 Aug 5.

Authors

Guoxun Li¹, Xiaoqing Feng¹, Wenqian Wang¹, Jian Li², Yeye Shi¹, Lin Wang³, Caijuan Hu⁴

Affiliations

¹ School of Pharmacy, Changzhou University, Changzhou, Jiangsu 213164, China.
² School of Pharmacy, Changzhou University, Changzhou, Jiangsu 213164, China; Analysis and Testing Center, NERC Biomass of Changzhou University, Jiangsu Key Laboratory of Advanced Catalytic Materials and Technology, Changzhou University, Changzhou, Jiangsu 213164, China.
³ College of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: wanglin66@syphu.edu.cn.
⁴ School of Pharmacy, Changzhou University, Changzhou, Jiangsu 213164, China. Electronic address: hcj@cczu.edu.cn.

PMID: 37552914
DOI: 10.1016/j.bioorg.2023.106767

Abstract

As a privileged scaffold, chromanone has been extensively introduced in the design of drug leads with diverse pharmacological features, particularly in the area of inflammatory diseases. Herein, the preparation of chromanone-based derivatives (4a-4i) was smoothly achieved, and their structures were characterized using ¹H NMR, ¹³C NMR, and ESI-HRMS spectroscopy techniques. Out of them, analogue 4e exhibited the most potent inhibitory capacity against the NO release and iNOS expression, without apparent cytotoxicity. Our observations showed that 4e could dramatically prevent the translocation of NF-κB from the cytoplasm to nucleus, and decrease the production of proinflammatory cytokines TNF-α, IL-6 and IL-1β in LPS-induced BV-2 cells. Mechanistically, 4e significantly deactivated NF-κB by disturbing TLR4-mediated TAK1/NF-κB and PI3K/Akt signaling cascades. Consistent with the in vitro study, 4e could effectively mitigate the inflammation response of hippocampal tissue in LPS-induced mouse model by inhibiting microglial activation. Collectively, these results revealed 4e as a prospective neuroprotective candidate for the therapy of neuroinflammation-related disorders.

Keywords: Chromanone analogues; NF-κB activation; Neuroinflammation; Proinflammatory cytokines; TLR4-mediated pathway.