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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

Synthesis of compounds 3a–i.Notes: Reagents and conditions: (A) CH2Cl2, under N2, stirred for 3 hours and (B) anhydrous CH2Cl2, with Et3SiH and F3B⋅OEt2, −15°C under N2 then to room temperature, overnight.Abbreviation: rt, room temperature.
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f2-dddt-9-3377: Synthesis of compounds 3a–i.Notes: Reagents and conditions: (A) CH2Cl2, under N2, stirred for 3 hours and (B) anhydrous CH2Cl2, with Et3SiH and F3B⋅OEt2, −15°C under N2 then to room temperature, overnight.Abbreviation: rt, room temperature.

Mentions: Our method for the synthesis of target compounds 3a–i, a flexible approach to 3-alkyl-2,3-dihydro-1H-isoindol-1-ones via the reductive-alkylation procedure,39 is displayed in Figure 2. An ice-bath chilled solution of phthalimide (10 mmol) in CH2Cl2 was subjected to a reaction with the Grignard reagents for 3 hours under ice-bath temperature to generate hydroxyl compounds 2a–i, which had a high yield of 97%. These compounds were converted to 3a–i which resulted in a 45%–69% yield via the reductive-alkylation procedure by reaction with triethylsilane and trifluoroboron etherate at −15°C under N2 atmosphere. The crude product was subjected to column chromatography purification on silica gel to get the pure target products, followed by MS, 1H NMR, 13C NMR, and HPLC to identify their structures. Compounds 3a–i in a purity of >95% were used for subsequent experiments.


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)

Synthesis of compounds 3a–i.Notes: Reagents and conditions: (A) CH2Cl2, under N2, stirred for 3 hours and (B) anhydrous CH2Cl2, with Et3SiH and F3B⋅OEt2, −15°C under N2 then to room temperature, overnight.Abbreviation: rt, room temperature.
© Copyright Policy
Related In: Results  -  Collection

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

f2-dddt-9-3377: Synthesis of compounds 3a–i.Notes: Reagents and conditions: (A) CH2Cl2, under N2, stirred for 3 hours and (B) anhydrous CH2Cl2, with Et3SiH and F3B⋅OEt2, −15°C under N2 then to room temperature, overnight.Abbreviation: rt, room temperature.
Mentions: Our method for the synthesis of target compounds 3a–i, a flexible approach to 3-alkyl-2,3-dihydro-1H-isoindol-1-ones via the reductive-alkylation procedure,39 is displayed in Figure 2. An ice-bath chilled solution of phthalimide (10 mmol) in CH2Cl2 was subjected to a reaction with the Grignard reagents for 3 hours under ice-bath temperature to generate hydroxyl compounds 2a–i, which had a high yield of 97%. These compounds were converted to 3a–i which resulted in a 45%–69% yield via the reductive-alkylation procedure by reaction with triethylsilane and trifluoroboron etherate at −15°C under N2 atmosphere. The crude product was subjected to column chromatography purification on silica gel to get the pure target products, followed by MS, 1H NMR, 13C NMR, and HPLC to identify their structures. Compounds 3a–i in a purity of >95% were used for subsequent experiments.

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