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Discovery of a ring-opened derivative of 3-n-butylphthalide bearing NO/H2S-donating moieties as a potential anti-ischemic stroke agent

2016; Elsevier BV; Volume: 115; Linguagem: Inglês

10.1016/j.ejmech.2016.03.044

1768-3254

Wei Yin, Lan Li, Zhangjian Huang, Jing Ji, Jiangen Fang, Xiaoli Wang, Hui Ji, Sixun Peng, Jinyi Xu, Yihua Zhang,

Advanced Glycation End Products research

To search for novel anti-ischemic stroke agents with higher potency than a known drug 3-n-butylphthalide (NBP), a series of ring-opened derivatives of NBP bearing both nitric oxide (NO) and hydrogen sulfide (H2S)-donating moieties (NO/H2S-NBP) (8a-8o) were designed, synthesized, and biologically evaluated. The most active compound 8d was more potent than NBP and the corresponding H2S-NBP 10 or NO-NBP 13 in inhibition of the ADP-induced platelet aggregation in vitro. In addition, 8d produced moderate levels of NO and H2S, which could be beneficial for improving cardiovascular and cerebral circulation. More importantly, in a rat model of transient focal cerebral ischemia, oral treatment with 8d improved neurobehavioral function, reduced the infarct brain size and brain-water content, and enhanced the levels of brain antioxidant SOD, GSH and GSH-Px but diminished the level of oxidant MDA. These protective effects of 8d against the ischemia/reperfusion (I/R)-related brain damage were greater than that of NBP, suggesting that 8d may be a promising agent for further investigation.