Development of sertraline analogues as potential anti-ischemic stroke agents.

Autor: Chen X; Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China., Liu HY; Department of Pharmaceutical Chemistry, Third Military Medical University, Chongqing, 400038, China., Niu SL; Department of Pharmaceutical Chemistry, Third Military Medical University, Chongqing, 400038, China., Zhou T; Department of Neurology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400038, China., Yuan W; Department of Pharmaceutical Chemistry, Third Military Medical University, Chongqing, 400038, China., Zheng PF; Department of Pharmaceutical Chemistry, Third Military Medical University, Chongqing, 400038, China., Chen Q; Department of Neurology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400038, China., Luo SL; Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China; Medical College, Guangxi University, Nanning, 530004, China., Gu J; Department of Pharmaceutical Chemistry, Third Military Medical University, Chongqing, 400038, China. Electronic address: gujing_1020@126.com., Zhangsun DT; Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China. Electronic address: zhangsundt@163.com., Ouyang Q; Department of Pharmaceutical Chemistry, Third Military Medical University, Chongqing, 400038, China. Electronic address: ouyangq@tmmu.edu.cn.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2023 Apr 05; Vol. 252, pp. 115273. Date of Electronic Publication: 2023 Mar 15.
DOI: 10.1016/j.ejmech.2023.115273
Abstrakt: Ischemic stroke (IS) is harmful to human health and social development, and there is no medicine available at present. To find the hit compound for treating ischemic stroke, we screened 28 FDA approved nervous system drugs by using an in vitro OGD-induced stroke model. Notably, our in vitro and in vivo studies demonstrated that low-dose sertraline had good neuroprotective activities, while high-dose sertraline showed significant toxicity. Interestingly, the same high-dose sertraline in the control group did not exhibit any obvious toxic effect. Therefore, it is important to modify the structure of sertraline to improve the activity and reduce the toxicity. Stereoisomers of sertraline were first investigated to analyze the influence of stereochemistry on the neuroprotective activities, which showed no obvious difference. Then we evaluated the activity of our previously reported sertraline analogues and found that introducing amide or alkane groups to the amino moiety might be beneficial to enhance the activity and reduce the toxicity. Thus, 10 new analogues were designed, synthesized, and evaluated. Among them, compound OY-201 showed the best safety and neuroprotective activity in both in vitro and in vivo models. Moreover, it exhibited good blood-brain barrier (BBB) permeability, indicating its potential for the development of anti-ischemic stroke drugs.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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Databáze: MEDLINE
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