Design, synthesis and evaluation of nitric oxide releasing derivatives of 3-n-butylphthalide as antiplatelet and antithrombotic agents

Abstract

Novel nitric oxide (NO) releasing derivatives (7a-7l) of 3-n-butylphthalide (NBP) were designed and synthesized. Compound 7e inhibited the adenosine diphosphate (ADP), thrombin (TH) and arachidonic acid (AA)-induced in vitro platelet aggregation, superior to NBP and aspirin, released moderate levels of NO, and improved aqueous solubility relative to NBP. Furthermore, 7e exhibited greater antithrombotic activity than NBP and aspirin in rats, and protected against collagen and adrenaline-induced thrombosis in mice. Therefore, NO-releasing NBP derivatives possessed potent antiplatelet aggregation and antithrombotic activity. Our findings may aid in the design of new therapeutic agents for the treatment of thrombosis-related ischemic stroke.

DL-3-n-Butylphthalide, an Anti-Oxidant Agent, Prevents Neurological Deficits and Cerebral Injury Following Stroke per Functional Analysis, Magnetic Resonance Imaging and Histological Assessment

“…7). NBP possesses a multiplicity of important biological properties, including anti-inflammatory [12], anti-apoptotic [3,7], anti-platelet and anti-thrombotic [13], and antioxidative [10,11] properties. These attributes, acting alone or in unison, confer effective neuroprotection in a variety of brain injuries.…”

“…In cellular model of Parkinson's disease, NBP reduced mitochondrial dysfunction and oxidative damage [10], and death of dopaminergic neurons [11]. It was suggested that these neuroprotective effects of NBP were mediated by its anti-inflammatory [12], anti-apoptotic [3,7], anti-platelet and anti-thrombotic [13], and anti-oxidative [10,11] properties. NBP was approved by the State Food and Drug Administration of China for clinical use in ischemic stroke patients in 2002.…”

5d, a novel analogue of 3-n-butylphthalide, decreases NADPH oxidase activity through the positive regulation of CK2 after ischemia/reperfusion injury

“…Its molecular structure was shown in previous studies [9, 29] and was dissolved in normal saline. Membrane and cytosol protein extraction kit and Lactate dehydrogenase (LDH) kit were obtained from Beyotime Institute of Biotechnology (Haimen, China).…”

Synthesis and biological evaluation of nitric oxide releasing derivatives of 6-amino-3-n-butylphthalide as potential antiplatelet agents

“…1) as potent anti-ischemic stroke agents which showed excellent antiplatelet and antithrombotic activities. 11,12 In the present study, to obtain new agents with stronger potency, we employed 1 as the lead compound to design and synthesize a novel class of NO-releasing derivatives (10a-l, Fig. 2).…”