Discovery of novel danshensu derivatives bearing pyrazolone moiety as potential anti-ischemic stroke agents with antioxidant activity

被引：17

作者：

Li, Yi ^{[1
]}

Luo, Yunchun ^{[1
]}

Wang, Jing ^{[2
]}

Shi, Hao ^{[1
]}

Liao, Jun ^{[1
]}

Wang, Yan ^{[3
]}

Chen, Zhesheng ^{[4
]}

Xiong, Liyan ^{[1
]}

Zhang, Chuan ^{[1
]}

Wang, Tingfang ^{[1
]}

机构：

[1] Shanghai Univ, Shanghai Engn Res Ctr Organ Repair, Sch Med, Shanghai 200444, Peoples R China

[2] Fudan Univ, Zhongshan Hosp, Dept Pharm, Qingpu Branch, Shanghai 201700, Peoples R China

[3] Zhaohui Pharmaceut, Baoshan Zhaohui New Drug R&D & Transformat Funct P, Shanghai 201908, Peoples R China

[4] St Johns Univ, Coll Pharm & Hlth Sci, Dept Pharmaceut Sci, New York, NY 11439 USA

来源：

BIOORGANIC CHEMISTRY | 2023年 / 131卷

基金：

上海市自然科学基金;

关键词：

Ischemic stroke; Oxidative stress; Dual -antioxidant mechanism; Danshensu derivative; Pyrazolone moiety; ENDOTHELIAL PROGENITOR CELLS; OXIDATIVE STRESS; ASYMMETRIC-SYNTHESIS; ISCHEMIC-STROKE; INJURY; ACID; EDARAVONE; INHIBITION; MECHANISM;

D O I：

10.1016/j.bioorg.2022.106283

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Neuroprotective agents with attenuation of oxidative stress by directly scavenging ROS and indirectly through Keap1-Nrf2 signal pathway activation may be a promising cerebral ischemic stroke therapeutic strategy. In this study, a series of novel danshensu derivatives bearing pyrazolone moieties with dual antioxidant effects were synthesized for the treatment of ischemic stroke. Most compounds exhibited considerable DPPH free radical scavenging ability and neuroprotective activity against H2O2-induced oxidative injury in PC12 neuronal cells, without cytotoxicity. Among these target compounds, Del03 displayed the strongest dose-dependent neuroprotective activity in vitro, directly downregulated intracellular ROS levels, and improved the oxidative stress parameters MDA, SOD, and LDH. Del03 also promoted Nrf2 translocation to the nucleus, subsequently increasing the expression of the Nrf2 downstream target HO-1. Molecular docking analysis revealed that Del03 could anchor to the key site of Keap1. Del03 possessed the ability to penetrate blood-brain barrier and displayed good ability on pharmacokinetic properties in rats Del03 possessed good BBB penetration efficiency, suitable pharmacokinetic properties in vivo. Del03 reduced cerebral infarction volume and promoted neurological function in a middle cerebral artery occlusion (MCAO) mouse model at a dose of 20 mg/kg by intravenous injection. The characteristics of Del03 detailed in this study demonstrate its potential as a therapeutic agent in the treatment of ischemic stroke.

引用

页数：19

共 27 条

[21] Discovery of 3-n-butyl-2,3-dihydro-1H-isoindol-1-one as a potential anti-ischemic stroke agent [J].

Lan, Zujian ;

Xu, Xiaoyu ;

Xu, Wenkai ;

Li, Jin ;

Liang, Zengrong ;

Zhang, Xuefei ;

Lei, Ming ;

Zhao, Chunshun .

DRUG DESIGN DEVELOPMENT AND THERAPY, 2015, 9 :3377-3391

[22] Synthesis and evaluation of novel hesperidin selenium- enriched derivatives as potential anti-inflammatory and antioxidant agents [J].

Zhang, Peipei ;

Zhang, Shanshan ;

Hu, Haijuan ;

Hu, Tan ;

Shi, Kaixin ;

Xu, Yang ;

Xu, Gang ;

Hu, Hao ;

Pan, Siyi .

FOOD BIOSCIENCE, 2024, 58

[23] Design, Synthesis, Antioxidant, Anti-inflammatory Activity and Molecular Docking Studies of Novel 3,4,5-Trisubstituted-1,2,4-Triazole Derivatives Bearing Benzimidazole Moiety [J].

Katikireddy, Ramamurthy ;

Kakkerla, Ramu ;

Krishna, M. P. S. Murali ;

Durgaiah, Gandamalla ;

Yellu, Narasimha Reddy .

LETTERS IN ORGANIC CHEMISTRY, 2021, 18 (09) :694-702

[24] Discovery of Novel Antibacterial Agents against Plant Pathogens: Design, Synthesis, Antibacterial Activity, and Mechanism of Action of 1,2,4-Thiadiazole Derivatives Containing a Sulfone Moiety [J].

Zou, Yue ;

Zhu, Mei ;

Zhu, Zongnan ;

Du, Tingting ;

Liu, Xing ;

Jiang, Yaojia ;

Chen, Jixiang .

JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY, 2025, 73 (08) :4534-4543

[25] Novel 1,3-diaryl pyrazole derivatives bearing methylsulfonyl moiety: Design, synthesis, molecular docking and dynamics, with dual activities as anti-inflammatory and anticancer agents through selectively targeting COX-2 [J].

Shaker, Ahmed M. M. ;

Shahin, Mai I. ;

AboulMagd, Asmaa M. ;

Aleem, Seham A. Abdel ;

Abdel-Rahman, Hamdy M. ;

Ella, Dalal A. Abou El .

BIOORGANIC CHEMISTRY, 2022, 129

[26] Synthesis and biological evaluation of hybrids from optically active ring-opened 3-N-butylphthalide derivatives and 4-fluro-edaravone as potential anti-acute ischemic stroke agents [J].

Jia, Jian ;

Wu, Jianbing ;

Ji, Duorui ;

Jiao, Weijie ;

Wang, Xiaoli ;

Huang, Zhangjian ;

Zhang, Yihua .

BIOORGANIC & MEDICINAL CHEMISTRY, 2022, 69

[27] Synthesis of some novel pyrazolo[3,4-b]pyridine and pyrazolo[3,4-d]pyrimidine derivatives bearing 5,6-diphenyl-1,2,4-triazine moiety as potential antimicrobial agents [J].

Ali, Tarik El-Sayed .

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2009, 44 (11) :4385-4392

← 1 2 3 →