Discovery of a Potential Anti-Ischemic Stroke Agent: 3-Pentylbenzo[c]thiophen-1(3H)-one

Abstract

The development of novel antithrombotic agents with strong free radical scavenging activity is of great significance for the treatment of ischemic stroke. In the present study, 3-alkyl/arylalkyl-substituted benzo[c]thiophen-1(3H)-ones (5a-h) were designed and synthesized. The most active compound 5d significantly inhibited the adenosine diphosphate (ADP) induced and arachidonic acid (AA) induced in vitro platelet aggregation, superior to clinically used antiplatelet drug aspirin (ASP) and anti-ischemic stroke drugs 3-n-butylphthalide (NBP) and edaravone (Eda). More importantly, in comparison with both NBP and Eda, 5d exhibited stronger antithrombotic and free radical scavenging activities and better or comparable neuroprotective effects against ischemia/reperfusion (I/R) in rats by ameliorating neurobehavioral function, reducing infarct size and brain-water content, attenuating cerebral damage, and normalizing the levels of oxidative enzymes. Overall, our findings may provide an alternative strategy for the design of novel anti-ischemic stroke agents more potent than drugs like NBP and Eda.

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

“…Thus, use of antioxidants might possibly limit oxidative damage so as to ameliorate disease progression [20–22]. We recently reported the free radical scavenging potential of 5d, coupled with the neuroprotective effect on cerebral ischemia [9]. However, further study is required to elucidate the possible mechanism(s) of 5d against ischemic stroke.…”

“…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).…”

“…To improve its therapeutic effect, NBP is often administered with anti-platelet and/or antioxidant drug(s) [8]. Interestingly, it has been recently reported the actions of 5d against free radicals, platelet aggregation, thrombosis and cerebral ischemia [9]. Nevertheless, the mechanism of 5d against cerebral ischemia is still unknown.…”

An HPLC method for the quantitation of 3‐pentylbenzo[c]thiophen‐1(3H)‐one in dog plasma and its application to a pharmacokinetic study

“…Our previous studies have shown that the antiplatelet aggregation, antithrombosis and free radical scavenging activities of S 5 are all superior to those of NBP. Furthermore, S 5 could improve neurobehavioral function, reduce the infarct brain size and brainwater content, and cerebral damage in a rat model of middle cerebral artery occlusion (MCAO), and the effect of S 5 on inhibiting the brain Ischemia/Reperfusion (I/R) injury was greater than that of NBP (Wu et al, 2012). NBP is often administered with antioxidant and/or antiplatelet drug(s) to improve its therapeutic effect.…”

Novel hybrids of 3-n-butylphthalide and edaravone: Design, synthesis and evaluations as potential anti-ischemic stroke agents

“…Since these hybrids are the precursors of edaravone or its trifluoromethyl analogue, which act as radical scavengers generating protection activity, 17 we established the hydrogen peroxide induced PC12 cells injury model in vitro, and preliminarily investigated the protective effects of all target compounds on nerve cells injury caused by the treatment of H 2 O 2 , using Ticlid, ASP, NBP, Eda and NBP together with Eda as positive controls. 18,19 As shown in Figure 4, the protective effects of 10b (86.02%), 10f (85.22%), 10g (93.33%), 11e (82.95%) and 11f (87.31%) were superior to those of all positive controls, Ticlid (67.22%), ASP (77.37%), NBP (71.01%), Eda (76.89%) and NBP together with Eda (76.60%) at the same concentration, and 10g exhibited the greatest protective effects in all test compounds. All these results supported us in selecting 10g as the candidate compound for further investigation.…”