Novel hybrids of 3-n-butylphthalide and edaravone: Design, synthesis and evaluations as potential anti-ischemic stroke agents

Sheng, Xiao; Hua, Kai; Yang, Chunyu; Wang, Xiaoli; Ji, Hui; Xu, Jinyi; Huang, Zhangjian; Zhang, Yihua

doi:10.1016/j.bmcl.2015.06.090

Cited by 43 publications

(22 citation statements)

References 27 publications

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“…The majority displayed promising, sometimes superior effects through several yet unknown mechanisms. Studies on 3-n-butyl-2,3-dihydro-1H-isoindol-1-one (Figure 1), a synthetic compound resulting from a coupling of NBP and edaravone, demonstrated a direct inhibitory effect on blood clots formation, and adenosine diphosphate (ADP) and arachidonic acid (AA) induced platelet aggregation [14, 15]. In two other studies, the first involved 2,5-Bis { 2-[(S)-(+)-1-(2-(4-methylpiperazin-1-yl)acetoxy)]-pentyl } benzoate-1,4 : 3,6-dianhydro-D-glucitol , an active ring-opened NBP derivative, and the second involved (±)-(E)-2-methoxy-4-(3-(2-(nitrooxy)ethoxy)-3-oxoprop-1-en-1-yl)phenyl2-(1-(2-(4-(5-(4-(3-thioxo-3H-1,2-dithiol-5-yl)phenoxy)pentyl)piperazin-1-yl)acetoxy)pentyl)benzoate , an NO/H 2 S-donating derivative, and both compounds exhibited additional benefits such as in vitro nitric oxide (NO) and hydrogen sulfate (H 2 S) production, protection against acute thrombosis, and inhibition of the ischemia/reperfusion-related injury.…”

Section: Nbp and Ischemic Strokementioning

confidence: 99%

A Review of Recent Advances in Neuroprotective Potential of 3-N-Butylphthalide and Its Derivatives

Abdoulaye

Guo

2016

BioMed Research International

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The research of alternative treatment for ischemic stroke and degenerative diseases has always been a priority in neurology. 3-N-Butylphthalide (NBP), a family of compounds initially isolated from the seeds of Apium graveolens Linn., has shown significant neuroprotective effects. Previous extensive studies have demonstrated that NBP promotes a better poststroke outcome and exerts a multitargeted action on several mechanisms, from oxidative stress to mitochondrial dysfunction to apoptosis to inflammation. Additionally, recent findings on several neurological disorders have shown that NBP's beneficial effects extend beyond the management of stroke. However, despite the increasing number of studies toward a better understanding and the rapid advances made in therapeutic options, to date, dl-3-N-butylphthalide, a synthetic variation of l-3-N-butylphthalide, remains the only clinically approved anti-ischemic agent in China, stressing the difficulties for a viable and effective transition from experimental to clinical practice. Events indicate that NBP, due to its multitargeted effect and the adaptability of its basic structure, can be an important game changer and a precursor to a whole new therapeutic approach to several neurological conditions. The present review discusses recent advances pertaining to the neuroprotective mechanisms of NBP-derived compounds and the possibility of their clinical implementation in the management of various neurological conditions.

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Section: Nbp and Ischemic Strokementioning

confidence: 99%

A Review of Recent Advances in Neuroprotective Potential of 3-N-Butylphthalide and Its Derivatives

Abdoulaye

Guo

2016

BioMed Research International

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“…A larger number of NBP derivatives have been explored and biological evaluated in order to improve the pharmacological activities of NBP (Wang et al, 2013 ; Sheng et al, 2015 ; Yin et al, 2016 ). Our previous study showed that 3-butyl-6-bromo-1(3 H )-isobenzofuranone (Br-NBP; Figure 1 ) could attenuate hydrogen peroxide-induced damage and platelet aggregation (Gao et al, 2010 ; Wang et al, 2010 ; Ma et al, 2012 ).…”

Section: Introductionmentioning

confidence: 99%

Preclinical Pharmacokinetics, Tissue Distribution, and Plasma Protein Binding of Sodium (±)-5-Bromo-2-(α-Hydroxypentyl) Benzoate (BZP), an Innovative Potent Anti-ischemic Stroke Agent

Tian

Wei

et al. 2016

Front. Pharmacol.

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Sodium (±)-5-bromo-2-(α-hydroxypentyl) benzoate (BZP) is a potential cardiovascular drug and exerts potent neuroprotective effect against transient and long-term ischemic stroke in rats. BZP could convert into 3-butyl-6-bromo-1(3H)-isobenzofuranone (Br-NBP) in vitro and in vivo. However, the pharmacokinetic profiles of BZP and Br-NBP still have not been evaluated. For the purpose of investigating the pharmacokinetic profiles, tissue distribution, and plasma protein binding of BZP and Br-NBP, a rapid, sensitive, and specific method based on liquid chromatography coupled to mass spectrometry (LC-MS/MS) has been developed for determination of BZP and Br-NBP in biological samples. The results indicated that BZP and Br-NBP showed a short elimination half-life, and pharmacokinetic profile in rats (3, 6, and 12 mg/kg; i.v.) and beagle dogs (1, 2, and 4 mg/kg; i.v.gtt) were obtained after single dosing of BZP. After multiple dosing of BZP, there was no significant accumulation of BZP and Br-NBP in the plasma of rats and beagle dogs. Following i.v. single dose (6 mg/kg) of BZP to rats, BZP and Br-NBP were distributed rapidly into all tissues examined, with the highest concentrations of BZP and Br-NBP in lung and kidney, respectively. The brain distribution of Br-NBP in middle cerebral artery occlusion (MCAO) rats was more than in normal rats (P < 0.05). The plasma protein binding degree of BZP at three concentrations (8000, 20,000, and 80,000 ng/mL) from rat, beagle dog, and human plasma were 98.1–98.7, 88.9–92.7, and 74.8–83.7% respectively. In conclusion, both BZP and Br-NBP showed short half-life, good dose-linear pharmacokinetic profile, wide tissue distribution, and different degree protein binding to various species plasma. This was the first preclinical pharmacokinetic investigation of BZP and Br-NBP in both rats and beagle dogs, which provided vital guidance for further preclinical research and the subsequent clinical trials.

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“…Since commercially available arylhydrazine hydrochlorides were intended to be applied for further transformations, the reactions of 4 with 5b ·HCl using an equivalent amount of NaOAc in AcOH, both under conventional heating and MW irradiation, were also carried out. Although similar reaction conditions have been described in the literature for the reactions of methyl acetoacetate with arylhydrazine hydrochlorides to afford the corresponding pyrazol-5-ones in 50–70% yields within 5–10 h [ 30 ], no full conversion of 4 could be achieved. Even after refluxing the mixture for 24 h the desired product 6b was obtained only in low yield (≈30%).…”

Section: Resultsmentioning

confidence: 99%

Microwave-assisted synthesis of biologically relevant steroidal 17-exo-pyrazol-5'-ones from a norpregnene precursor by a side-chain elongation/heterocyclization sequence

Mótyán¹,

Mérai²,

Kiss³

et al. 2018

Beilstein J. Org. Chem.

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Multistep syntheses of novel 17β-pyrazol-5'-ones in the Δ5-androstane series were efficiently carried out from pregnenolone acetate. A steroidal 17-carboxylic acid was first synthesized as a norpregnene precursor by the bromoform reaction and subsequent acetylation. Its CDI-activated acylimidazole derivative was then converted to a β-ketoester containing a two carbon atom-elongated side chain than that of the starting material. A Knorr cyclization of the bifunctional 1,3-dicarbonyl compound with hydrazine and its monosubstituted derivatives in AcOH under microwave heating conditions led to the regioselective formation of 17-exo-heterocycles in good to excellent yields. The suppression of an acid-catalyzed thermal decarboxylation of the β-ketoester and thus a significant improvement in the yield of the desired heterocyclic products could be achieved by the preliminary liberation of the arylhydrazines from their hydrochloride salts in EtOH in the presence of NaOAc. The reaction rates were found to depend on the electronic character of the substituent present in the phenylhydrazine applied. The antiproliferative activities of the structurally related steroidal pyrazol-5'-ones and their deacetylated analogs were screened on three human adherent breast cancer cell lines (MCF7, T47D and MDA-MB-231): the microculture tetrazolium assay revealed that some of the presented derivatives exerted cell growth inhibitory effects on some of these cell lines comparable to those of the reference compound, cisplatin.

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Novel hybrids of 3-n-butylphthalide and edaravone: Design, synthesis and evaluations as potential anti-ischemic stroke agents

Cited by 43 publications

References 27 publications

A Review of Recent Advances in Neuroprotective Potential of 3-N-Butylphthalide and Its Derivatives

A Review of Recent Advances in Neuroprotective Potential of 3-N-Butylphthalide and Its Derivatives

Preclinical Pharmacokinetics, Tissue Distribution, and Plasma Protein Binding of Sodium (±)-5-Bromo-2-(α-Hydroxypentyl) Benzoate (BZP), an Innovative Potent Anti-ischemic Stroke Agent

Microwave-assisted synthesis of biologically relevant steroidal 17-exo-pyrazol-5'-ones from a norpregnene precursor by a side-chain elongation/heterocyclization sequence

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