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Discovery of 3-n-butyl-2,3-dihydro-1H-isoindol-1-one as a potential anti-ischemic stroke agent.

Lan Z, Xu X, Xu W, Li J, Liang Z, Zhang X, Lei M, Zhao C - Drug Des Devel Ther (2015)

Bottom Line: This activity is superior to that of 3-n-butylphthalide and comparable with aspirin and edaravone.Meanwhile, 3d not only exhibited a potent activity in scavenging free radicals and improving the survival of HT22 cells against the reactive oxygen species-mediated cytotoxicity in vitro but also significantly attenuated the ischemia/reperfusion-induced oxidative stress in ischemic rat brains.In conclusion, our findings suggest that 3-alkyl-2,3-dihydro-1H-isoindol-1-ones, a novel series of compounds, might be candidate drugs for the treatment of acute ischemic strokes, and 3d may be a promising therapeutic agent for the primary and secondary prevention of ischemic stroke.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, People's Republic of China.

ABSTRACT
To develop novel anti-ischemic stroke agents with better therapeutic efficacy and bioavailability, we designed and synthesized a series of 3-alkyl-2,3-dihydro-1H-isoindol-1-ones compounds (3a-i) derivatives, one of which (3d) exhibited the strongest inhibitory activity for the adenosine diphosphate-induced and arachidonic acid-induced platelet aggregation. This activity is superior to that of 3-n-butylphthalide and comparable with aspirin and edaravone. Meanwhile, 3d not only exhibited a potent activity in scavenging free radicals and improving the survival of HT22 cells against the reactive oxygen species-mediated cytotoxicity in vitro but also significantly attenuated the ischemia/reperfusion-induced oxidative stress in ischemic rat brains. Results from transient middle cerebral artery occlusion and permanent middle cerebral artery occlusion model, indicated that 3d could significantly reduce infarct size, improve neurobehavioral deficits, and prominently decrease attenuation of cerebral damage. Most importantly, 3d possessed a very high absolute bioavailability and was rapidly distributed in brain tissue to keep high plasma drug concentration for the treatment of ischemic strokes. In conclusion, our findings suggest that 3-alkyl-2,3-dihydro-1H-isoindol-1-ones, a novel series of compounds, might be candidate drugs for the treatment of acute ischemic strokes, and 3d may be a promising therapeutic agent for the primary and secondary prevention of ischemic stroke.

No MeSH data available.


Related in: MedlinePlus

Representative photographs of the infarcted tails of rats 48 hours after carrageenan was injected for the induction of thrombosis.Abbreviations: ASP, aspirin; Eda, edaravone; NBP, 3-n-butylphthalide.
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f4-dddt-9-3377: Representative photographs of the infarcted tails of rats 48 hours after carrageenan was injected for the induction of thrombosis.Abbreviations: ASP, aspirin; Eda, edaravone; NBP, 3-n-butylphthalide.

Mentions: A red wine-colored section appeared in the tail tip of the rodent in the carrageenan-induced group, tail-thrombosis length increased and experienced typical dry necrosis. Our results indicated that 3d could inhibit thrombus formation in vivo; as shown in Table 2 and Figure 4, 3d (20 and 50 mg/kg) decreased the black tail occurrence and tail-thrombosis length, comparable with NBP (50 mg/kg) group and lower than ASP (50 mg/kg). However, Eda (3 mg/kg) did not decrease the black tail occurrence and tail-thrombosis length.


Discovery of 3-n-butyl-2,3-dihydro-1H-isoindol-1-one as a potential anti-ischemic stroke agent.

Lan Z, Xu X, Xu W, Li J, Liang Z, Zhang X, Lei M, Zhao C - Drug Des Devel Ther (2015)

Representative photographs of the infarcted tails of rats 48 hours after carrageenan was injected for the induction of thrombosis.Abbreviations: ASP, aspirin; Eda, edaravone; NBP, 3-n-butylphthalide.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492651&req=5

f4-dddt-9-3377: Representative photographs of the infarcted tails of rats 48 hours after carrageenan was injected for the induction of thrombosis.Abbreviations: ASP, aspirin; Eda, edaravone; NBP, 3-n-butylphthalide.
Mentions: A red wine-colored section appeared in the tail tip of the rodent in the carrageenan-induced group, tail-thrombosis length increased and experienced typical dry necrosis. Our results indicated that 3d could inhibit thrombus formation in vivo; as shown in Table 2 and Figure 4, 3d (20 and 50 mg/kg) decreased the black tail occurrence and tail-thrombosis length, comparable with NBP (50 mg/kg) group and lower than ASP (50 mg/kg). However, Eda (3 mg/kg) did not decrease the black tail occurrence and tail-thrombosis length.

Bottom Line: This activity is superior to that of 3-n-butylphthalide and comparable with aspirin and edaravone.Meanwhile, 3d not only exhibited a potent activity in scavenging free radicals and improving the survival of HT22 cells against the reactive oxygen species-mediated cytotoxicity in vitro but also significantly attenuated the ischemia/reperfusion-induced oxidative stress in ischemic rat brains.In conclusion, our findings suggest that 3-alkyl-2,3-dihydro-1H-isoindol-1-ones, a novel series of compounds, might be candidate drugs for the treatment of acute ischemic strokes, and 3d may be a promising therapeutic agent for the primary and secondary prevention of ischemic stroke.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, People's Republic of China.

ABSTRACT
To develop novel anti-ischemic stroke agents with better therapeutic efficacy and bioavailability, we designed and synthesized a series of 3-alkyl-2,3-dihydro-1H-isoindol-1-ones compounds (3a-i) derivatives, one of which (3d) exhibited the strongest inhibitory activity for the adenosine diphosphate-induced and arachidonic acid-induced platelet aggregation. This activity is superior to that of 3-n-butylphthalide and comparable with aspirin and edaravone. Meanwhile, 3d not only exhibited a potent activity in scavenging free radicals and improving the survival of HT22 cells against the reactive oxygen species-mediated cytotoxicity in vitro but also significantly attenuated the ischemia/reperfusion-induced oxidative stress in ischemic rat brains. Results from transient middle cerebral artery occlusion and permanent middle cerebral artery occlusion model, indicated that 3d could significantly reduce infarct size, improve neurobehavioral deficits, and prominently decrease attenuation of cerebral damage. Most importantly, 3d possessed a very high absolute bioavailability and was rapidly distributed in brain tissue to keep high plasma drug concentration for the treatment of ischemic strokes. In conclusion, our findings suggest that 3-alkyl-2,3-dihydro-1H-isoindol-1-ones, a novel series of compounds, might be candidate drugs for the treatment of acute ischemic strokes, and 3d may be a promising therapeutic agent for the primary and secondary prevention of ischemic stroke.

No MeSH data available.


Related in: MedlinePlus