Chen Shuxia, Yang Jichen, Wang Xiangyu, Liu Xiaochun, Li Xiuxue, Ye Yansheng, Wang Pingyuan, Liu Zhiqing, Wang Chang-Yun
Key Laboratory of Marine Drugs and Key Laboratory of Evolution and Marine Biodiversity (Ministry of Education), School of Medicine and Pharmacy, Institute of Evolution & Marine Biodiversity, Ocean University of China, Qingdao, 266003, China; Laboratory for Marine Drugs and Bioproducts, Qingdao Marine Science and Technology Center, Qingdao, 266237, China.
Key Laboratory of Marine Drugs of Ministry of Education & Qingdao Marine Biomedical Research Institute, Ocean University of China, Qingdao, 266003, China.
Eur J Med Chem. 2025 Feb 15;284:117193. doi: 10.1016/j.ejmech.2024.117193. Epub 2024 Dec 24.
Bromodomain-containing protein 4 (BRD4) has been identified as a promising target in drug discovery, and the development of novel specific BRD4 bromodomain inhibitors will benefit anti-inflammatory drug discovery as well as bromodomain function role disclose. Herein, inspired by marine quinazolinone alkaloid penipanoid C, we designed and synthesized a series of quinazolin-4(3H)-ones with diverse linkers between two aromatic ring systems. Among them, compound 25 possessed good in vitro BRD4 inhibitory activities (IC = 3.64 μM for BRD4 BD1 and IC = 0.12 μM for BRD4 BD2) and anti-inflammatory activity (IC = 1.98 μM for NO production assay). Meantime, 25 obviously suppressed the expression of TNF-α and IL-6 in LPS-stimulated Raw 264.7 and THP-1 cells. Notablely, 25 displayed in vivo therapeutic efficacies in an acute inflammation model without obvious cytotoxicity. These findings suggest that 25 is a selective BRD4 BD2 inhibitor which is a promising anti-inflammatory lead compound worthy for further investigation.
