Studies on the enantiomers of ZJM-289: synthesis and biological evaluation of antiplatelet, antithrombotic and neuroprotective activities

Abstract

ZJM-289 is a potent racemic agent which inhibits both platelet aggregation and thrombosis superior to a known anti-ischemic stroke drug 3-n-butylphthalide (NBP). Herein, the enantiomers of ZJM-289, (S)-ZJM-289 and (R)-ZJM-289, were synthesized and evaluated for their biological activities. It was observed that the two enantiomers appeared to be almost as effective as ZJM-289 in inhibiting platelet aggregation in vitro and thrombus formation in vivo. Moreover, like ZJM-289, its enantiomers could regulate the ratio of thromboxane B₂ (TXB₂) and 6-keto-prostaglandin F_1α, and enhanced levels of nitric oxide (NO), cAMP and cGMP, suggesting that the anti-platelet and antithrombotic activities of the enantiomers and ZJM-289 are associated with both the arachidonic acid cascade and cGMP–NO signal pathway. Furthermore, it was found that oral administration of the enantiomers and ZJM-289 for three days significantly reduced the infarct size, brain water content and neurological deficit in rats after cerebral ischemia reperfusion. Importantly, the two enantiomers equally improved blood flow in the ischemic stroke model and modulated endothelial function through releasing moderate levels of NO, which might, at least partially, contribute to their neuroprotection. Collectively, the present study demonstrates that the two enantiomers are as potent as ZJM-289 in inhibition of platelet aggregation and thrombosis and in neuroprotection, and (S)-ZJM-289 shows somewhat better effects than (R)-ZJM-289 and ZJM-289 in a few cases. These findings may provide new insights into the development of therapeutic agents like ZJM-289 for the intervention of thrombosis-related ischemic stroke.