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

The maximum platelet aggregation inhibition rate of 3a–i, NBP, ASP, and Eda (1.28 mM each) on the ADP-induced and AA-induced platelet aggregation in vitro.Abbreviations: AA, arachidonic acid; ADP, adenosine diphosphate; ASP, aspirin; Eda, edaravone; NBP, 3-n-butylphthalide.
© Copyright Policy
Related In: Results  -  Collection

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

f3-dddt-9-3377: The maximum platelet aggregation inhibition rate of 3a–i, NBP, ASP, and Eda (1.28 mM each) on the ADP-induced and AA-induced platelet aggregation in vitro.Abbreviations: AA, arachidonic acid; ADP, adenosine diphosphate; ASP, aspirin; Eda, edaravone; NBP, 3-n-butylphthalide.

Mentions: As shown in Table 1, for the ADP-induced platelet aggregation, five compounds displayed significant inhibitory activities. The inhibitory effects of 3d, 3e, 3f, 3h, and 3i (IC50 of 1.38, 1.48, 1.43, 1.53, and 1.52 mM, respectively) were stronger than those of Eda (IC50=1.76 mM), ASP (IC50=1.58 mM), and NBP (IC50>1.79 mM). Compounds 3d and 3f (IC50 of 1.01 and 0.96 mM, respectively) inhibited AA-induced platelet aggregation more effectively than NBP (IC50= 1.10 mM) and less effectively than Eda (IC50=0.85 mM) and ASP (IC50=0.81 mM). In particular, as shown in Figure 3, the inhibitory effect of 1.28 mM 3d (71.69%) on the ADP-induced platelet aggregation was 1.71-, 2.22-, and 2.34-fold stronger than that of NBP (41.93%), ASP (32.25%), and Eda (30.64%), whereas its inhibition on the AA-induced platelet activation (83.33%) was 1.10- and 1.31-fold more potent than that of NBP (75.86%) and Eda (63.49%), comparable with that of ASP (95.43%). These data revealed that compounds with straight-chain alkyl had stronger inhibitory platelet aggregation activity than those with branch-chain alkyl. The results indicated that 3d had a potent antiplatelet aggregation activity in both the ADP- and AA-induced platelet aggregation. Thus, 3d was used for the following biological 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)

The maximum platelet aggregation inhibition rate of 3a–i, NBP, ASP, and Eda (1.28 mM each) on the ADP-induced and AA-induced platelet aggregation in vitro.Abbreviations: AA, arachidonic acid; ADP, adenosine diphosphate; ASP, aspirin; Eda, edaravone; NBP, 3-n-butylphthalide.
© Copyright Policy
Related In: Results  -  Collection

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

f3-dddt-9-3377: The maximum platelet aggregation inhibition rate of 3a–i, NBP, ASP, and Eda (1.28 mM each) on the ADP-induced and AA-induced platelet aggregation in vitro.Abbreviations: AA, arachidonic acid; ADP, adenosine diphosphate; ASP, aspirin; Eda, edaravone; NBP, 3-n-butylphthalide.
Mentions: As shown in Table 1, for the ADP-induced platelet aggregation, five compounds displayed significant inhibitory activities. The inhibitory effects of 3d, 3e, 3f, 3h, and 3i (IC50 of 1.38, 1.48, 1.43, 1.53, and 1.52 mM, respectively) were stronger than those of Eda (IC50=1.76 mM), ASP (IC50=1.58 mM), and NBP (IC50>1.79 mM). Compounds 3d and 3f (IC50 of 1.01 and 0.96 mM, respectively) inhibited AA-induced platelet aggregation more effectively than NBP (IC50= 1.10 mM) and less effectively than Eda (IC50=0.85 mM) and ASP (IC50=0.81 mM). In particular, as shown in Figure 3, the inhibitory effect of 1.28 mM 3d (71.69%) on the ADP-induced platelet aggregation was 1.71-, 2.22-, and 2.34-fold stronger than that of NBP (41.93%), ASP (32.25%), and Eda (30.64%), whereas its inhibition on the AA-induced platelet activation (83.33%) was 1.10- and 1.31-fold more potent than that of NBP (75.86%) and Eda (63.49%), comparable with that of ASP (95.43%). These data revealed that compounds with straight-chain alkyl had stronger inhibitory platelet aggregation activity than those with branch-chain alkyl. The results indicated that 3d had a potent antiplatelet aggregation activity in both the ADP- and AA-induced platelet aggregation. Thus, 3d was used for the following biological 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