Research progress of 3-n-butylphthalide and its derivatives in combating cerebral ischemia

Abstract

Ischemic stroke (IS) presents a major threat to human life and health due to its high disability and mortality rates. 3-n-Butylphthalide (NBP), derived from celery seeds of the Apiaceae family native to the Mediterranean region, was first introduced in China for acute IS treatment in 2004. NBP demonstrates multiple therapeutic actions, including reconstruction of microcirculation in the cerebral ischemia area, inhibition of platelet aggregation, reduction of cerebral infarction volume, maintenance of blood-brain barrier (BBB) integrity, and enhancement of cerebral blood perfusion. However, its overall efficacy remains moderate, limited by poor water solubility and low bioavailability, which constrains its clinical application. To address these limitations, researchers have actively pursued the development of NBP derivatives and analogs, achieving notable progress. These efforts, including substituent introduction, ring opening derivatization, esterification, and atom substitution, have generated diverse NBP derivatives. Several of these derivatives have advanced to clinical studies. Specifically, potassium 2-(1-hydroxypentyl)-benzoate (PHPB), brozopentyl sodium (BZP), and XY-03-EA (ZONK1103) have reached phase II clinical trials, while (S)-2-(1-acetoxypentyl)benzoic acid L-arginine salt (AAPB) has received clinical trial approval for 2024. This review examines the structural modification and optimization of NBP over the past two decades from a medicinal chemistry perspective, aiming to facilitate the development of superior derivatives and advance cerebral ischemia treatment.

Keywords

Ischemic stroke / 3-n-Butylphthalide / Derivatives / Structural modification / Cerebral ischemia

References

[1] Sacco RL, Kasner SE, Broderick JP, et al. An updated definition of stroke for the 21^st century: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013; 44(7):2064-2089. https://doi.org/10.1161/STR.0b013e318296aeca.

[2] Singh M, Pandey PK, Bhasin A, et al. Application of stem cells in stroke: a multifactorial approach. Front Neurosci. 2020;14:473. https://doi.org/10.3389/fnins.2020.00473.

[3] Connelly JA, Zhang X, Chen Y, et al. Protein kinase D2 confers neuroprotection by promoting AKT and CREB activation in ischemic stroke. Neurobiol Dis. 2023;187:106305. https://doi.org/10.1016/j.nbd.2023.106305.

[4] Zhang Y, Shen L, Xie J, et al. Pushen Capsule treatment promotes functional recovery after ischemic stroke. Phytomedicine. 2023;111:154664. https://doi.org/10.1016/j.phymed.2023.154664.

[5] Shin TH, Lee DY, Basith S, et al.Metabolome changes in cerebral ischemia. Cells. 2020; 9(7):1630. https://doi.org/10.3390/cells9071630.

[6] Li J, Shen S, Shen H. Heat-shock protein A12A attenuates oxygen-glucose deprivation/reoxygenation-induced human brain microvascular endothelial cell dysfunction via PGC-1α/SIRT3 pathway. Drug Develop Res. 2024; 85(1):e22130. https://doi.org/10.1002/ddr.22130.

[7] Shah FA, Liu G, Al Kury LT, et al. Melatonin protects MCAO-induced neuronal loss via NR2A mediated prosurvival pathways. Front Pharmacol. 2019;10:297. https://doi.org/10.3389/fphar.2019.00297.

[8] Guo L, Pan J, Li F, et al. A novel brain targeted plasma exosomes enhance the neuroprotective efficacy of edaravone in ischemic stroke. IET Nanobiotechnol. 2021; 15(1):107-116. https://doi.org/10.1049/nbt2.12003.

[9] Lu Y, Jiang R, Cui B, et al. Quantification and visualization of hydrogen peroxide in an ischemic model and serum samples from stroke patients using a reaction-based fluorescence sensor. Sensor Actuat B-Chem. 2023;397:134662. https://doi.org/10.1016/j.snb.2023.134662.

[10] Parvez S, Kaushik M, Ali M, et al. Dodging blood brain barrier with “nano” warriors: novel strategy against ischemic stroke. Theranostics. 2022; 12(2):689-719. https://doi.org/10.7150/thno.64806.

[11] Zhou X, Chen H, Wang L, et al. Mitochondrial dynamics: a potential therapeutic target for ischemic stroke. Front Aging Neurosci. 2021;13:721428. https://doi.org/10.3389/fnagi.2021.721428.

[12] Xiong Y, Wakhloo AK, Fisher M. Advances in acute ischemic stroke therapy. Circ Res. 2022; 130(8):1230-1251. https://doi.org/10.1161/CIRCRESAHA.121.319948.

[13] Viticchi G, Falsetti L, Altamura C, et al. Impact of carotid stenosis on the outcome of stroke patients submitted to reperfusion treatments: a narrative review. Rev Neurosci. 2024; 35(5):575-583. https://doi.org/10.1515/revneuro-2024-0002.

[14] Hurd MD, Goel I, Sakai Y, et al. Current status of ischemic stroke treatment: from thrombolysis to potential regenerative medicine. Regen Ther. 2021; 18:408-417. https://doi.org/10.1016/j.reth.2021.09.009.

[15] Xie Q, Li H, Lu D, et al. Neuroprotective effect for cerebral ischemia by natural products: a review. Front Pharmacol. 2021;12:607412. https://doi.org/10.3389/fphar.2021.607412.

[16] Liu A, Hu J, Yeh TS, et al. Neuroprotective strategies for stroke by natural products: advances and perspectives. Curr Neuropharmacol. 2023; 21(11):2283-2309. https://doi.org/10.2174/1570159X21666230717144752.

[17] Newman DJ, Cragg GM. Natural products as sources of new drugs from 1981 to 2014. J Nat Prod. 2016; 79(3):629-661. https://doi.org/10.1021/acs.jnatprod.5b01055.

[18] Abourashed EA. Review of discovery and development of neuroprotective agents from natural products. J Nat Prod. 2018; 81(8):1917-1918. https://doi.org/10.1021/acs.jnatprod.8b00515.

[19] Li Y, Cheng S, Tian Y, et al. Recent ring distortion reactions for diversifying complex natural products. Nat Prod Rep. 2022; 39(10):1970-1992. https://doi.org/10.1039/d2np00027j.

[20] Marco-Contelles J, Zhang Y. From seeds of Apium graveolens Linn. to a cerebral ischemia medicine: the long journey of 3-n-butylphthalide. J Med Chem. 2020; 63(21):12485-12510. https://doi.org/10.1021/acs.jmedchem.0c00887.

[21] Mu Q, Yao K, Syeda MZ, et al. Ligustrazine nanoparticle hitchhiking on neutrophils for enhanced therapy of cerebral ischemia-reperfusion injury. Adv Sci. 2023; 10(19):e2301348. https://doi.org/10.1002/advs.202301348.

[22] Cheng CY, Su SY, Tang NY, et al. Ferulic acid inhibits nitric oxide-induced apoptosis by enhancing GABA(B1) receptor expression in transient focal cerebral ischemia in rats. Acta Pharmacol Sin. 2010; 31(8):889-899. https://doi.org/10.1038/aps.2010.66.

[23] Liu X, An C, Jin P, et al. Protective effects of cationic bovine serum albumin-conjugated PEGylated tanshinone IIA nanoparticles on cerebral ischemia. Biomaterials. 2013; 34(3):817-830. https://doi.org/10.1016/j.biomaterials.2012.10.017.

[24] Tan SW, Xie T, Malik TH, et al. Advances of neurovascular protective potential of 3-N-butylphthalide and its derivatives in diabetic related diseases. J Diabetes Complicat. 2022; 36(11):108335. https://doi.org/10.1016/j.jdiacomp.2022.108335.

[25] Wang BN, Wu CB, Chen ZM, et al. DL-3-n-butylphthalide ameliorates diabetes-associated cognitive decline by enhancing PI3K/Akt signaling and suppressing oxidative stress. Acta Pharmacol Sin. 2021; 42(3):347-360. https://doi.org/10.1038/s41401-020-00583-3.

[26] Huang L, Wang S, Ma F, et al. From stroke to neurodegenerative diseases: the multi-target neuroprotective effects of 3-n-butylphthalide and its derivatives. Pharmacol Res. 2018; 135:201-211. https://doi.org/10.1016/j.phrs.2018.08.007.

[27] Du Y, Li L, Li X, et al. Synergistic effects and molecular mechanisms of DL-3-n-butylphthalide combined with dual antiplatelet therapy in acute ischemic stroke. Int Immunopharmacol. 2024;129:111592. https://doi.org/10.1016/j.intimp.2024.111592.

[28] Jian Y, Ji J, Huang Z, et al. Enantiomers of 3-pentylbenzo[c]thiophen-1(3H)-one: preparation and evaluation of anti-ischemic stroke activities. RSC Adv. 2016; 6(43):36888-36897. https://doi.org/10.1039/c6ra04251a.

[29] Peng Y, Sun J, Hon S, et al. L-3-n-butylphthalide improves cognitive impairment and reduces amyloid-beta in a transgenic model of Alzheimer’s disease. J Neurosci. 2010; 30(24):8180-8189. https://doi.org/10.1523/JNEUROSCI.0340-10.2010.

[30] Peng Y, Zeng X, Feng Y, et al. Antiplatelet and antithrombotic activity of L-3-n-butylphthalide in rats. J Cardiovasc Pharmacol. 2004; 43(6):876-881. https://doi.org/10.1097/00005344-200406000-00018.

[31] Liu CL, Liao SJ, Zeng JS, et al. Dl-3n-butylphthalide prevents stroke via improvement of cerebral microvessels in RHRSP. J Neurol Sci. 2007; 260(1-2):106-113. https://doi.org/10.1016/j.jns.2007.04.025.

[32] Zhao F, Luo Y. Potential protective effect of dl-3-n-butylphthalide on chronic cerebral ischemia brain injury. CNS Neurol Disord Dr. 2022; 21(9):734-737. https://doi.org/10.2174/1871527321666211221160922.

[33] Wang Y, Qi W, Zhang L, et al. The novel targets of DL-3-n-butylphthalide predicted by similarity ensemble approach in combination with molecular docking study. Quant Imaging Med Surg. 2017; 7(5):532-536. https://doi.org/10.21037/qims.2017.10.08.

[34] Zhu T, Dong S, Qin N, et al. Dl-3-n-butylphthalide attenuates cerebral ischemia/reperfusion injury in mice through AMPK-mediated mitochondrial fusion. Front Pharmacol. 2024;15:1357953. https://doi.org/10.3389/fphar.2024.1357953.

[35] Diao X, Deng P, Xie C, et al. Metabolism and pharmacokinetics of 3-n-butylphthalide (NBP) in humans: the role of cytochrome P450s and alcohol dehydrogenase in biotransformation. Drug Metab Dispos. 2013; 41(2):430-444. https://doi.org/10.1124/dmd.112.049684.

[36] Xue Y, Ren X, Zhu Z, et al. Site-specific protein modification by 3-n-butylphthalide in primary hepatocytes: covalent protein adducts diminished by glutathione and N-acetylcysteine. Life Sci. 2021;287:120125. https://doi.org/10.1016/j.lfs.2021.120125.

[37] Diao XX, Zhong K, Li XL, et al. Isomer-selective distribution of 3-n-butylphthalide (NBP) hydroxylated metabolites, 3-hydroxy-NBP and 10-hydroxy-NBP, across the rat blood-brain barrier. Acta Pharmacol Sin. 2015; 36(12):1520-1527. https://doi.org/10.1038/aps.2015.64.

[38] Li L, Tan J, Du Y, et al. A pharmacokinetics interaction study of antiplatelet agents aspirin and clopidogrel combined with dl-3-n-butylphthalide in rats by liquid chromatography-tandem mass spectrometry. Biomed Chromatogr. 2023; 37(9):e5668. https://doi.org/10.1002/bmc.5668.

[39] Qian Y, Lyu Y, Jiang M, et al. Human urinary kallidinogenase or edaravone combined with butylphthalide in the treatment of acute ischemic stroke. Brain Behav. 2019; 9(12):e01438. https://doi.org/10.1002/brb3.1438.

[40] Zhang A, Li J, Wang S, et al. Rapid and improved oral absorption of N-butylphthalide by sodium cholate-appended liposomes for efficient ischemic stroke therapy. Drug Deliv. 2021; 28(1):2469-2479. https://doi.org/10.1080/10717544.2021.2000678.

[41] Wang W, Zhou Y, Liu Y.The preparation and application of 3‐n‐butylphthalide derivative. China: CN102503919A. 2012-06-20.

[42] Wang W, Cha XX, Reiner J, et al. Synthesis and biological activity of n-butylphthalide derivatives. Eur J Med Chem. 2010; 45(5):1941-1946. https://doi.org/10.1016/j.ejmech.2010.01.036.

[43] Gao Y, Zhang HW, Qiao HL, et al. Protective effect of 3-butyl-6-bromo-1(3H)-isobenzofuranone on hydrogen peroxide-induced damage in PC12 cells. Brain Res. 2010; 1358:239-247. https://doi.org/10.1016/j.brainres.2010.08.043.

[44] Xu L, Ji MX, Zhao N, et al. 3-Butyl-6-fluoro-1(3H)-isobenzofuranone, a derivative of dl-n-butylphthalide, attenuates hydrogen peroxide-induced damage in PC12 cells. Drug Develop Res. 2011; 72(3):259-264. https://doi.org/10.1002/ddr.20393.

[45] Megson IL, Webb DJ. Nitric oxide donor drugs: current status and future trends. Expert Opin Inv Drug. 2002; 11(5):587-601. https://doi.org/10.1517/13543784.11.5.587.

[46] Martelli A, Rapposelli S, Calderone V.NO-releasing hybrids of cardiovascular drugs. Curr Med Chem. 2006; 13(6):609-625. https://doi.org/10.2174/092986706776055634.

[47] Wang X, Wang L, Huang Z, et al. Synthesis and biological evaluation of nitric oxide releasing derivatives of 6-amino-3-n-butylphthalide as potential antiplatelet agents. Bioorg Med Chem Lett. 2013; 23(7):1985-1988. https://doi.org/10.1016/j.bmcl.2013.02.035.

[48] Richard MJ, Connell BJ, Khan BV, et al. Cellular mechanisms by which lipoic acid confers protection during the early stages of cerebral ischemia: a possible role for calcium. Neurosci Res. 2011; 69(4):299-307. https://doi.org/10.1016/j.neures.2010.12.011.

[49] Connell BJ, Saleh MC, Rajagopal D, et al. UPEI-400, a conjugate of lipoic acid and scopoletin, mediates neuroprotection in a rat model of ischemia/reperfusion. Food Chem Toxicol. 2017; 100:175-182. https://doi.org/10.1016/j.fct.2016.12.026.

[50] Deng H, Zuo X, Zhang J, et al. Alpha-lipoic acid protects against cerebral ischemia/reperfusion-induced injury in rats. Mol Med Rep. 2015; 11(5):3659-3665. https://doi.org/10.3892/mmr.2015.3170.

[51] Uppakara K, Jamornwan S, Duan LX, et al. Novel α-lipoic acid/3-n-butylphthalide conjugate enhances protective effects against oxidative stress and 6-OHDA induced neuronal damage. ACS Chem Neurosci. 2020; 11(11):1634-1642. https://doi.org/10.1021/acschemneuro.0c00105.

[52] Sahu NK, Balbhadra SS, Choudhary J, et al. Exploring pharmacological significance of chalcone scaffold: a review. Curr Med Chem. 2012; 19(2):209-225. https://doi.org/10.2174/092986712803414132.

[53] Yu Q, Luo B, Luo Z, et al. Synthesis of novel 3-butylphthalide derivatives containing isopentenylphenol moiety as potential antiplatelet agents for the treatment of ischemic stroke. Chem Biodivers. 2023; 20(1):e202201002. https://doi.org/10.1002/cbdv.202201002.

[54] Yu Q, Li Y, Luo Z, et al. Novel 1,3,4-oxadiazole hybrids of 3-n-butylphthalide derivatives as potential anti-ischemic stroke agents. Bioorg Chem. 2024;143:107034. https://doi.org/10.1016/j.bioorg.2023.107034.

[55] Yang W, Qin H, Zhao X, et al. The preparation and application of 2‐( α‐hydroxyamyl) benzoate. China: CN1523003. 2004-08-25.

[56] Zhang Y, Wang L, Zhang L, et al. Effects of 2-(1-hydroxypentyl)-benzoate on platelet aggregation and thrombus formation in rats. Drug Develop Res. 2004; 63(4):174-180. https://doi.org/10.1002/ddr.10401.

[57] Zhang Y, Wang L, Li J, et al. 2-(1-Hydroxypentyl)-benzoate increases cerebral blood flow and reduces infarct volume in rats model of transient focal cerebral ischemia. J Pharmacol Exp Ther. 2006; 317(3):973-979. https://doi.org/10.1124/jpet.105.098517.

[58] Tian X, Li HM, Wei JY, et al. Preclinical pharmacokinetics, tissue distribution, and plasma protein binding of sodium (+/-)-5-bromo-2-(α-hydroxypentyl) benzoate (BZP), an innovative potent anti-ischemic stroke agent. Front Pharmacol. 2016;7:255. https://doi.org/10.3389/fphar.2016.00255.

[59] Tian X, Liu B, Zhang Y, et al. LC-MS/MS analysis and pharmacokinetics of sodium (+/-)-5-bromo-2-(α-hydroxypentyl) benzoate (BZP), an innovative potent anti-ischemic stroke agent in rats. Molecules. 2016; 21(4):501. https://doi.org/10.3390/molecules21040501.

[60] Gao Y, Wang Y, Li M, et al. Preventive and therapeutic effect of brozopine on stroke in Dahl salt-sensitive hypertensive rats. Brain Res. 2017; 1672:137-147. https://doi.org/10.1016/j.brainres.2017.07.019.

[61] Xiao Y, Song C, Lin Q, et al. Cardioprotection of (+/-)-sodium 5-bromo-2-(α-hydroxypentyl) benzoate (BZP) on mouse myocardium I/R injury through inhibiting 12/15-LOX-2 activity. J Mol Cell Cardiol. 2019; 135:52-66. https://doi.org/10.1016/j.yjmcc.2019.07.014.

[62] Siervo M, Scialo F, Shannon OM, et al. Does dietary nitrate say NO to cardiovascular ageing? Current evidence and implications for research. Proc Nutr Soc. 2018; 77(2):112-123. https://doi.org/10.1017/S0029665118000058.

[63] Chen SF, Pan MX, Tang JC, et al. Arginine is neuroprotective through suppressing HIF-1α/LDHA-mediated inflammatory response after cerebral ischemia/reperfusion injury. Mol Brain. 2020; 13(1):63. https://doi.org/10.1186/s13041-020-00601-9.

[64] Zhang Y, Huang Z, Zhu J. Salts formed by 2-(1-acyloxypentyl) benzoic acid with basic amino acid or aminoguanidine, preparation method and application in cardiovascular and cerebrovascular drugs. China: CN109678715B. 2019-11-12.

[65] Xiang H, Zhang Q, Han Y, et al. Novel brain-targeting 3-n-butylphthalide prodrugs for ischemic stroke treatment. J Control Release. 2021; 335:498-514. https://doi.org/10.1016/j.jconrel.2021.05.045.

[66] Krishnan K, Nguyen TN, Appleton JP, et al. Antiplatelet resistance: a review of concepts, mechanisms, and implications for management in acute ischemic stroke and transient ischemic attack. Stroke Vasc Interv Neurol. 2023; 3(3):e000576. https://doi.org/10.1161/svin.122.000576.

[67] Nakamura T, Kuroda Y, Yamashita S, et al. Edaravone attenuates brain edema and neurologic deficits in a rat model of acute intracerebral hemorrhage. Stroke. 2008; 39(2):463-469. https://doi.org/10.1161/STROKEAHA.107.486654.

[68] Yoshida H, Yanai H, Namiki Y, et al. Neuroprotective effects of edaravone: a novel free radical scavenger in cerebrovascular injury. CNS Drug Rev. 2006; 12(1):9-20. https://doi.org/10.1111/j.1527-3458.2006.00009.x.

[69] Shichinohe H, Kuroda S, Yasuda H, et al. Neuroprotective effects of the free radical scavenger edaravone (MCI-186) in mice permanent focal brain ischemia. Brain Res. 2004; 1029(2):200-206. https://doi.org/10.1016/j.brainres.2004.09.055.

[70] Sheng X, Hua K, Yang C, et al. Novel hybrids of 3-n-butylphthalide and edaravone: design, synthesis and evaluations as potential anti-ischemic stroke agents. Bioorg Med Chem Lett. 2015; 25(17):3535-3540. https://doi.org/10.1016/j.bmcl.2015.06.090.

[71] Jia J, Wu J, Ji D, et al. Synthesis and biological evaluation of hybrids from optically active ring-opened 3-N-butylphthalide derivatives and 4-fluro-edaravone as potential anti-acute ischemic stroke agents. Bioorg Med Chem. 2022;69:116891. https://doi.org/10.1016/j.bmc.2022.116891.

[72] Li X, Wang X, Miao L, et al. Design, synthesis, and neuroprotective effects of novel hybrid compounds containing edaravone analogue and 3-n-butylphthalide ring-opened derivatives. Biochem Biophys Res Commun. 2021; 556:99-105. https://doi.org/10.1016/j.bbrc.2021.03.171.

[73] Gilmer JF, Lally MN, Gardiner P, et al. Novel isosorbide-based substrates for human butyrylcholinesterase. Chem Biol Interact. 2005;157-158:317-319. https://doi.org/10.1016/j.cbi.2005.10.095.

[74] Moriarty LM, Lally MN, Carolan CG, et al. Discovery of a “true” aspirin prodrug. J Med Chem. 2008; 51(24):7991-7999. https://doi.org/10.1021/jm801094c.

[75] Wang X, Wang L, Li T, et al. Novel hybrids of optically active ring-opened 3-n-butylphthalide derivative and isosorbide as potential anti-ischemic stroke agents. J Med Chem. 2013; 56(7):3078-3089. https://doi.org/10.1021/jm4001693.

[76] Shuai SY, Liu SS, Liu XJ, et al. Essential oil of Ligusticum chuanxiong Hort. regulated P-gp protein and tight junction protein to change pharmacokinetic parameters of temozolomide in blood, brain and tumor. J Ethnopharmacol. 2022;298:115646. https://doi.org/10.1016/j.jep.2022.115646.

[77] Chen X, Cao Y, Guo N, et al. Z-ligustilide reduces cisplatin-induced nephrotoxicity via activation of NRF2/HO-1 signaling pathways. Trop J Pharm Res. 2020; 19(7):1359-1364. https://doi.org/10.4314/tjpr.v19i7.3.

[78] Lin Y, Wan Y, Du X, et al. TAT-modified serum albumin nanoparticles for sustained-release of tetramethylpyrazine and improved targeting to spinal cord injury. J Nanobiotechnol. 2021; 19(1):28. https://doi.org/10.1186/s12951-020-00766-4.

[79] Jia Y, Xiao H, Wang X, et al. Design, synthesis, and evaluation of n-butylphthalide and ligustrazine hybrids as potent neuroprotective agents for the treatment of ischemic stroke in vitro and in vivo. Bioorg Chem. 2024;142:106961. https://doi.org/10.1016/j.bioorg.2023.106961.

[80] Wang X, Li Y, Zhao Q, et al. Design, synthesis and evaluation of nitric oxide releasing derivatives of 3-n-butylphthalide as antiplatelet and antithrombotic agents. Org Biomol Chem. 2011; 9(16):5670-5681. https://doi.org/10.1039/c1ob05478c.

[81] Wang X, Zhao Q, Wang X, et al. Studies on the enantiomers of ZJM-289: synthesis and biological evaluation of antiplatelet, antithrombotic and neuroprotective activities. Org Biomol Chem. 2012; 10(45):9030-9040. https://doi.org/10.1039/c2ob26511g.

[82] Li Y, Wang X, Fu R, et al. Synthesis and evaluation of nitric oxide-releasing derivatives of 3-n-butylphthalide as anti-platelet agents. Bioorg Med Chem Lett. 2011; 21(14):4210-4214. https://doi.org/10.1016/j.bmcl.2011.05.082.

[83] Szabo C. Hydrogen sulphide and its therapeutic potential. Nat Rev Drug Discov. 2007; 6(11):917-935. https://doi.org/10.1038/nrd2425.

[84] Calvert JW, Coetzee WA, Lefer DJ. Novel insights into hydrogen sulfide-mediated cytoprotection. Antioxid Redox Sign. 2010; 12(10):1203-1217. https://doi.org/10.1089/ars.2009.2882.

[85] Wallace JL.Hydrogen sulfide-releasing anti-inflammatory drugs. Trends Pharmacol Sci. 2007; 28(10):501-505. https://doi.org/10.1016/j.tips.2007.09.003.

[86] Wang X, Wang L, Sheng X, et al. Design, synthesis and biological evaluation of hydrogen sulfide releasing derivatives of 3-n-butylphthalide as potential antiplatelet and antithrombotic agents. Org Biomol Chem. 2014; 12(31):5995-6004. https://doi.org/10.1039/c4ob00830h.

[87] Wang L, Wang X, Li T, et al. 8e protects against acute cerebral ischemia by inhibition of PI3Kγ-mediated superoxide generation in microglia. Molecules. 2018; 23(11):2828. https://doi.org/10.3390/molecules23112828.

[88] Yin W, Lan L, Huang Z, et al. Discovery of a ring-opened derivative of 3-n-butylphthalide bearing NO/H₂S-donating moieties as a potential anti-ischemic stroke agent. Eur J Med Chem. 2016; 115:369-380. https://doi.org/10.1016/j.ejmech.2016.03.044.

[89] Wang XL, Wang ZY, Ling JJ, et al. Synthesis and biological evaluation of nitric oxide (NO)-hydrogen sulfide (H₂S) releasing derivatives of (S)-3-n-butylphthalide as potential antiplatelet agents. Chin J Nat Med. 2016; 14(12):946-953. https://doi.org/10.1016/S1875-5364(17)30021-3.

[90] Sun AL, Wang CC, Zhou H, et al. Design, synthesis, and evaluation of isoindoline derivatives as new antidepressant agents. Lett Drug Des Discov. 2022; 19(8):769-777. https://doi.org/10.2174/1570180819666220301141149.

[91] Lan Z, Xu X, Xu W, et al. Discovery of 3-n-butyl-2,3-dihydro-1H-isoindol-1-one as a potential anti-ischemic stroke agent. Drug Des Devel Ther. 2015; 9:3377-3391. https://doi.org/10.2147/DDDT.S84731.

[92] Zenkov NK, Menshchikova EB, Kandalintseva NV, et al. Antioxidant and antiinflammatory activity of new water-soluble sulfur-containing phenolic compounds. Biochem (Mosc). 2007; 72(6):644-651. https://doi.org/10.1134/s0006297907060077.

[93] Barce Ferro CT, Dos Santos BF, da Silva CDG, et al. Review of the syntheses and activities of some sulfur-containing drugs. Curr Org Synth. 2020; 17(3):192-210. https://doi.org/10.2174/1570179417666200212113412.

[94] Wu J, Ling J, Wang X, et al. Discovery of a potential anti-ischemic stroke agent: 3-pentylbenzo[c]thiophen-1(3H)-one. J Med Chem. 2012; 55(16):7173-7181. https://doi.org/10.1021/jm300681r.

[95] Zhou J, Zhang YH, Song HZ, et al. 5d, a novel analogue of 3-n-butylphthalide, decreases NADPH oxidase activity through the positive regulation of CK2 after ischemia/reperfusion injury. Oncotarget. 2016; 7(26):39444-39457. https://doi.org/10.18632/oncotarget.8548.

[96] Fang JG, Wang XL, Ling JJ, et al. Synthesis and antiplatelet aggregation/antioxidant activity of 3-alkyl-benzo[c]selenophen-1(3H)-ones. J Chin Pharm Univ. 2015; 46(5):552-555. https://doi.org/10.11665/j.issn.1000-5048.20150506.

[97] Chen L, Fan B, Wang F, et al. Research progress in pharmacological effects and mechanisms of Angelica sinensis against cardiovascular and cerebrovascular diseases. Molecules. 2024; 29(9):2100. https://doi.org/10.3390/molecules29092100.

[98] Kuang X, Yao Y, Du JR, et al. Neuroprotective role of Z-ligustilide against forebrain ischemic injury in ICR mice. Brain Res. 2006; 1102(1):145-153. https://doi.org/10.1016/j.brainres.2006.04.110.

[99] Peng HY, Du JR, Zhang GY, et al. Neuroprotective effect of Z-ligustilide against permanent focal ischemic damage in rats. Biol Pharm Bull. 2007; 30(2):309-312. https://doi.org/10.1248/bpb.30.309.

[100] Wu ML, Zou X, Chen XY, et al. Phthalide derivative CD21 regulates the platelet-neutrophil extracellular trap-thrombin axis and protects against ischemic brain injury in rodents. Int Immunopharmacol. 2023;114:109547. https://doi.org/10.1016/j.intimp.2022.109547.

[101] Yang Z, Luo G, Ying Y, et al. Novel 2,6-disubstituted benzofuran-3-one analogues improve cerebral ischemia/reperfusion injury via neuroprotective and antioxidative effects. Bioorg Chem. 2023;132:106346. https://doi.org/10.1016/j.bioorg.2023.106346.