Drug Design, Development and Therapy (Sep 2022)
Synthesis and Bioactivity Evaluation of a Novel 1,2,4-Oxadiazole Derivative in vitro and in 3×Tg Mice
Abstract
Zhuohui Luo,1 Yongcheng Wang,2 Shuo Pang,1 Shan Gao,1 Ning Liu,1 Xiang Gao,1 Li Zhang,1,3 Xiaolong Qi,1,3 Yajun Yang,2 Lianfeng Zhang1,3 1Key Laboratory of Human Disease Comparative Medicine, National Health Commission of China (NHC), Institute of Laboratory Animal Science, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100021, People’s Republic of China; 2Beijing Key Laboratory of Active Substance Discovery and Drug Ability Evaluation, Institute of Material Medical, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100050, People’s Republic of China; 3Neuroscience Center, Chinese Academy of Medical Sciences, Beijing, 100730, People’s Republic of ChinaCorrespondence: Yajun Yang, Institute of Material Medical, Peking Union Medical College, Chinese Academy of Medical Sciences, Nanwei Road, Xicheng District, Beijing, 100050, People’s Republic of China, Email [email protected] Lianfeng Zhang, Institute of Laboratory Animal Science, Peking Union Medical College, Chinese Academy of Medical Sciences, Panjiayuan Nanli, Chaoyang District, Beijing, 100021, People’s Republic of China, Tel +86 10-87778442, Fax +86 10-67776394, Email [email protected]: Alzheimer’s disease (AD) is the most common neurodegenerative disease whose patients suffered from cognitive impairments. In our study, a novel 1,2,4-Oxadiazole derivative wyc-7-20 was synthesized, which showed low cytotoxicity and potent neuroprotective effect at the cellular level. Improved cognitive impairments, β-amyloid (Aβ) clearance, and tau pathological phenotypes were detected in transgenic animal models after wyc-7-20 treatment. Reversed expressions in AD-related genes were also detected. The results demonstrated wyc-7-20 was potent in AD therapy.Purpose: The pathological complexity of AD increased difficulties in medical research. To explore a new potential medical treatment for AD, a novel 1,2,4-Oxadiazole derivative (wyc-7-20) was designed, synthesized to explore the application in this study.Materials and Methods: Human neuroblastoma (SH-SY5Y) cells and human hepatocellular carcinoma (HepG2) cells were used to detect median lethal dose (LD50). H2O2 and Aβ1– 42 oligomers (AβOs) were respectively, added into SH-SY5Y cells to detect anti-ROS (reactive oxygen species) and anti-AβOs effects of wyc-7-20. 3×Tg mice were administered with wyc-7-20, and then Y maze test and Morris water maze (MWM) test were applied to detect cognitive improvements. Brain tissue samples were subsequently collected and analyzed using different techniques.Results: wyc-7-20 showed low cytotoxicity and potent neuroprotective effect at the cellular level. Improved cognitive impairments, Aβ clearance, and tau pathological phenotypes were detected in transgenic animal models after wyc-7-20 treatment. Reversed expressions in AD-related genes were also detected.Conclusion: wyc-7-20 was potent in AD therapy.Graphical abstract: Keywords: 1,2,4-oxadiazole, Alzheimer’s disease, animal model, neuroprotective effect
