2. Academic Validation
  3. Design, synthesis, and biological evaluation of novel iNOS inhibitors as potent neuroprotective agents for ischemic stroke

Design, synthesis, and biological evaluation of novel iNOS inhibitors as potent neuroprotective agents for ischemic stroke

  • Eur J Med Chem. 2024 Sep 24:280:116907. doi: 10.1016/j.ejmech.2024.116907.
Duorui Ji 1,  Chengbin Jin 1,  Mingshu Tao 1,  Yuze Sun 1,  Huiqin Chen 2,  Hongyu Li 1,  Xiaohan Qu 1,  Hui Ye 1,  Libang Zhang 1,  Zhangjian Huang 3,  Yihua Zhang 4,  Tiantian Kong 5,  Jianbing Wu 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, PR China.
  • 2 School of Pharmacy, Xinjiang Key Laboratory of Biopharmaceuticals and Medical Devices, Key Laboratory of Active Components of Xinjiang Natural Medicine and Drug Release Technology, Engineering Research Center of Xinjiang and Central Asian Medicine Resources, Xinjiang Medical University, Urumqi, 830054, PR China.
  • 3 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, PR China; School of Pharmacy, Xinjiang Key Laboratory of Biopharmaceuticals and Medical Devices, Key Laboratory of Active Components of Xinjiang Natural Medicine and Drug Release Technology, Engineering Research Center of Xinjiang and Central Asian Medicine Resources, Xinjiang Medical University, Urumqi, 830054, PR China. Electronic address: zhangjianhuang@cpu.edu.cn.
  • 4 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, PR China. Electronic address: zyhtgd@163.com.
  • 5 The Second Affiliated Hospital of Xinjiang Medical University, Urumqi 830028, PR China. Electronic address: 123457417@qq.com.
  • 6 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, PR China. Electronic address: jwu@cpu.edu.cn.
PMID: 39368264 DOI: 10.1016/j.ejmech.2024.116907
Abstract

Ischemic stroke (IS) is characterized by intricate pathophysiological mechanisms, where single-target treatments have often proven insufficient. Thus, multi-target therapeutic approaches are essential for effective IS management. In this study, we employed a molecular hybridization strategy, merging the structures of the iNOS Inhibitor 1400W and the multi-target neuroprotective agent NBP, to develop a series of novel iNOS inhibitors BN-1 ∼ BN-4 with neuroprotective properties. Among these, BN-4 exhibited the most potent cell protective activity in OGD/R-induced SH-SY5Y and BV-2 cells. BN-4 not only reduced ROS levels induced by OGD/R in SH-SY5Y cells but also mitigated necrosis and Apoptosis. By binding to iNOS in a manner similar to 1400W, BN-4 significantly inhibited iNOS activity. Furthermore, BN-4 demonstrated high stability, excellent blood-brain barrier permeability, and more than 100-fold increase in aqueous solubility compared to NBP. Additionally, BN-4 notably decreased infarct size and showed neuroprotective effects in tMCAO rats. These findings indicate that BN-4 holds promise as a novel candidate for treatment IS, offering enhanced therapeutic efficacy due to its superior pharmacokinetic and pharmacodynamic properties.

Keywords

Ischemic stroke; Multi-target therapy; Neuroprotection; Nitric oxide; iNOS inhibitor.

Figures
Products