Limits...
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

Structure of 3d (-n-Butyl-2, 3-dihydro-1H-isoindol-1-one).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4492651&req=5

f1-dddt-9-3377: Structure of 3d (-n-Butyl-2, 3-dihydro-1H-isoindol-1-one).

Mentions: Previous studies have suggested that a class of compounds, isoindoline derivatives, exhibit a good activity in treating the central nervous systemic disease.27–34 Because the structure of isoindoline derivatives is very similar to that of NBP and its amide bond is more stable than ester bond of NBP in the gastrointestinal tract, 3-alkyl-2,3-dihydro-1H-isoindol-1-ones may exhibit better anti-ischemic stroke activity than NBP. Therefore, we designed and synthesized a novel class of compounds 3-alkyl-2,3-dihydro-1H-isoindol-1-ones by replacing the oxygen atom at the 2-position of phthalide with nitrogen and introducing various lengths of straight/branch chain alkyl into 3-position of phthalide. The resulting compound 3d (Figure 1) displayed potent antiplatelet aggregation, antioxidation activity, and anti-ischemic stroke activity, which was comparable with NBP and edaravone (Eda). More importantly, 3d displayed higher bioavailability than NBP, which will be beneficial to the clinical treatment of acute ischemic strokes.


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)

Structure of 3d (-n-Butyl-2, 3-dihydro-1H-isoindol-1-one).
© Copyright Policy
Related In: Results  -  Collection

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

f1-dddt-9-3377: Structure of 3d (-n-Butyl-2, 3-dihydro-1H-isoindol-1-one).
Mentions: Previous studies have suggested that a class of compounds, isoindoline derivatives, exhibit a good activity in treating the central nervous systemic disease.27–34 Because the structure of isoindoline derivatives is very similar to that of NBP and its amide bond is more stable than ester bond of NBP in the gastrointestinal tract, 3-alkyl-2,3-dihydro-1H-isoindol-1-ones may exhibit better anti-ischemic stroke activity than NBP. Therefore, we designed and synthesized a novel class of compounds 3-alkyl-2,3-dihydro-1H-isoindol-1-ones by replacing the oxygen atom at the 2-position of phthalide with nitrogen and introducing various lengths of straight/branch chain alkyl into 3-position of phthalide. The resulting compound 3d (Figure 1) displayed potent antiplatelet aggregation, antioxidation activity, and anti-ischemic stroke activity, which was comparable with NBP and edaravone (Eda). More importantly, 3d displayed higher bioavailability than NBP, which will be beneficial to the clinical treatment of acute ischemic strokes.

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