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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

Effect of 3d on the infarct volume in rat brain at 24 hours after tMCAO and pMCAO.Notes: (A) Effect of 3d on infarct volume in rat brain after tMCAO. Data shown are representative animals from each treatment group of rats. Infarct tissue is white, whereas live tissue is red stained by TTC (n=6). (B) Quantitative analysis of the infarcted brain regions. The ratios of infarct size to the whole brain size in individual rats were calculated. Data were expressed as the mean ± SD of individual groups of rats (n=6) and were analyzed by one-way analysis of variance (ANOVA) followed by Newman–Keuls test: ***P<0.001 vs the sham group; #P<0.05 vs the model group. ##P<0.01 and ###P<0.001 vs the model group. (C) Effect of 3d on infarct volume in rat brain after pMCAO. Data shown are representative animals from each treatment group of rats (n=9). (D) Quantitative analysis of the infarcted brain regions (n=9).Abbreviations: Eda, edaravone; NBP, 3-n-butylphthalide; pMCAO, permanent middle cerebral artery occlusion; SD, standard deviation; tMCAO, transient middle cerebral artery occlusion; TTC, 2,3,5-triphenyltetrazolium chloride; L-3d, low-dose(3d); M-3d, medium-dose(3d); H-3d, high-dose (3d).
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f6-dddt-9-3377: Effect of 3d on the infarct volume in rat brain at 24 hours after tMCAO and pMCAO.Notes: (A) Effect of 3d on infarct volume in rat brain after tMCAO. Data shown are representative animals from each treatment group of rats. Infarct tissue is white, whereas live tissue is red stained by TTC (n=6). (B) Quantitative analysis of the infarcted brain regions. The ratios of infarct size to the whole brain size in individual rats were calculated. Data were expressed as the mean ± SD of individual groups of rats (n=6) and were analyzed by one-way analysis of variance (ANOVA) followed by Newman–Keuls test: ***P<0.001 vs the sham group; #P<0.05 vs the model group. ##P<0.01 and ###P<0.001 vs the model group. (C) Effect of 3d on infarct volume in rat brain after pMCAO. Data shown are representative animals from each treatment group of rats (n=9). (D) Quantitative analysis of the infarcted brain regions (n=9).Abbreviations: Eda, edaravone; NBP, 3-n-butylphthalide; pMCAO, permanent middle cerebral artery occlusion; SD, standard deviation; tMCAO, transient middle cerebral artery occlusion; TTC, 2,3,5-triphenyltetrazolium chloride; L-3d, low-dose(3d); M-3d, medium-dose(3d); H-3d, high-dose (3d).

Mentions: The ischemic infarct volume of each group of rats was assessed by the 2,3,5-triphenyltetrazolium chloride assay. As shown in Figure 6A and C, no infarct volume was observed in the sham-operated group, whereas the model group exhibited a white infarct area. From Figure 6B and D, we could see that 3d significantly reduced the infarct size. With doses of 10, 20, and 50 mg/kg in tMCAO rats, the infarct size in the 3d-treated groups was reduced by 30.22% (10 mg/kg), 63.84% (20 mg/kg), and 76.13% (50 mg/kg), respectively. In addition, the effect of moderate- and high-dose 3d was comparable with that of Eda (69.65%) and more potent than that of NBP (26.19%). Interestingly, 3d significantly reduced the infarct size at doses of 50 mg/kg in pMCAO rats; the effect of 3d (50 mg/kg) was more potent than that of NBP (50 mg/kg) and Eda (3 mg/kg).


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)

Effect of 3d on the infarct volume in rat brain at 24 hours after tMCAO and pMCAO.Notes: (A) Effect of 3d on infarct volume in rat brain after tMCAO. Data shown are representative animals from each treatment group of rats. Infarct tissue is white, whereas live tissue is red stained by TTC (n=6). (B) Quantitative analysis of the infarcted brain regions. The ratios of infarct size to the whole brain size in individual rats were calculated. Data were expressed as the mean ± SD of individual groups of rats (n=6) and were analyzed by one-way analysis of variance (ANOVA) followed by Newman–Keuls test: ***P<0.001 vs the sham group; #P<0.05 vs the model group. ##P<0.01 and ###P<0.001 vs the model group. (C) Effect of 3d on infarct volume in rat brain after pMCAO. Data shown are representative animals from each treatment group of rats (n=9). (D) Quantitative analysis of the infarcted brain regions (n=9).Abbreviations: Eda, edaravone; NBP, 3-n-butylphthalide; pMCAO, permanent middle cerebral artery occlusion; SD, standard deviation; tMCAO, transient middle cerebral artery occlusion; TTC, 2,3,5-triphenyltetrazolium chloride; L-3d, low-dose(3d); M-3d, medium-dose(3d); H-3d, high-dose (3d).
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f6-dddt-9-3377: Effect of 3d on the infarct volume in rat brain at 24 hours after tMCAO and pMCAO.Notes: (A) Effect of 3d on infarct volume in rat brain after tMCAO. Data shown are representative animals from each treatment group of rats. Infarct tissue is white, whereas live tissue is red stained by TTC (n=6). (B) Quantitative analysis of the infarcted brain regions. The ratios of infarct size to the whole brain size in individual rats were calculated. Data were expressed as the mean ± SD of individual groups of rats (n=6) and were analyzed by one-way analysis of variance (ANOVA) followed by Newman–Keuls test: ***P<0.001 vs the sham group; #P<0.05 vs the model group. ##P<0.01 and ###P<0.001 vs the model group. (C) Effect of 3d on infarct volume in rat brain after pMCAO. Data shown are representative animals from each treatment group of rats (n=9). (D) Quantitative analysis of the infarcted brain regions (n=9).Abbreviations: Eda, edaravone; NBP, 3-n-butylphthalide; pMCAO, permanent middle cerebral artery occlusion; SD, standard deviation; tMCAO, transient middle cerebral artery occlusion; TTC, 2,3,5-triphenyltetrazolium chloride; L-3d, low-dose(3d); M-3d, medium-dose(3d); H-3d, high-dose (3d).
Mentions: The ischemic infarct volume of each group of rats was assessed by the 2,3,5-triphenyltetrazolium chloride assay. As shown in Figure 6A and C, no infarct volume was observed in the sham-operated group, whereas the model group exhibited a white infarct area. From Figure 6B and D, we could see that 3d significantly reduced the infarct size. With doses of 10, 20, and 50 mg/kg in tMCAO rats, the infarct size in the 3d-treated groups was reduced by 30.22% (10 mg/kg), 63.84% (20 mg/kg), and 76.13% (50 mg/kg), respectively. In addition, the effect of moderate- and high-dose 3d was comparable with that of Eda (69.65%) and more potent than that of NBP (26.19%). Interestingly, 3d significantly reduced the infarct size at doses of 50 mg/kg in pMCAO rats; the effect of 3d (50 mg/kg) was more potent than that of NBP (50 mg/kg) and Eda (3 mg/kg).

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