3-芳基香豆素衍生物的合成及抑菌性能

Synthesis and Antibacterial Properties of 3-Arylcoumarin Derivatives

摘要

细菌对抗生素耐药性的增强迫切需要开发新型抗菌剂。以2-羟基-4,5-二甲氧基苯甲醛和卤素/羟基取代苯乙酸为原料,经Perkin反应制备3-芳基香豆素衍生物,并测试其对大肠杆菌、铜绿假单胞菌、枯草芽孢杆菌和金黄色葡萄球菌的抑制效果。结果表明,这些衍生物表现出明显的抑菌活性,且抑菌活性与取代基的种类密切相关。其中,含氟取代的衍生物3-(3-氟苯基)-6,7-二甲氧基-香豆素(4a)显示较强的抑菌活性,对前3种菌的最小抑菌质量浓度(minimum inhibitory concentration,MIC)为16 μg/mL,对金黄色葡萄球菌的MIC为32 μg/mL;衍生物4a对大肠杆菌的抑制主要是通过破坏其细胞膜结构实现的。通过结构修饰可以显著提高3-芳基香豆素衍生物的抗菌活性,为抗菌剂的开发和应用提供了先导化合物。

Abstract

The increasing resistance of bacteria to antibiotics urgently requires the development of novel antibacterial agents. In this study, a series of 3-arylcoumarin derivatives were prepared through Perkin reaction using 2-hydroxy-4,5-dimethoxybenzaldehyde and halogen/hydroxyl substituted phenylacetic acid as raw materials. Their antibacterial activities against E. coli, P. aeruginosa, B. Subtilis, and S. aureus were investigated. Results show that these derivatives exhibit remarkable antibacterial activities, and the antibacterial activities are closely related with the types of substituents. Among them, derivative with fluorine substitution 3-(3-fluorophenyl)-6,7-dimethoxy-coumarin (4a) displays potent antibacterial activity with minimum inhibitory concentration (MIC) of 16 μg/mL against the first three bacteria, and 32 μg/mL against S. aureus. The inhibition of E. coli by derivative 4a is mainly achieved through the destruction of its cell membrane structure. This study demonstrates that structural modification can significantly enhance the antibacterial activity of 3-arylcoumarins, offering lead compounds for the development and application of antibacterial agents.

关键词

3-芳基香豆素衍生物 / 卤素/羟基取代 / 抑菌活性 / 结构修饰 / 抑菌机制 / 化学合成

Key words

3-arylcoumarin derivatives / halogen/hydroxyl substitution / antibacterial activity / structural modification / antibacterial mechanism / chemical synthesis

参考文献

[1] Brown E D, Wright G D . Antibacterial drug discovery in the resistance era [J]. Nature, 2016, 529(7586): 336-343.

[2] Levin—reisman I, Ronin I, Gefen O, et al. Antibiotic tolerance facilitates the evolution of resistance [J]. Science, 2017, 355(6327): 826-830.

[3] Hu Y, Hu C, Pan G, et al. Novel chalcone—conjugated, multi—flexible end—group coumarin thiazole hybrids as potential antibacterial repressors against methicillin—resistant Staphylococcus aureus [J]. Eur J Med Chem, 2021, 222: 113628.

[4] Sahoo C R, Sahoo J, Mahapatra M, et al. Coumarin derivatives as promising antibacterial agent(s) [J]. Arab J Chem, 2021, 14(2): 102922.

[5] Laxminarayan R, Mills A J, Breman J G, et al. Advancement of global health: key messages from the Disease Control Priorities Project [J]. Lancet, 2006, 367(9517): 1193-1208.

[6] Liu H, Ren Z L, Wang W, et al. Novel coumarin—pyrazole carboxamide derivatives as potential topoisomerase Ⅱ inhibitors: design, synthesis and antibacterial activity [J]. Eur J Med Chem, 2018, 157: 81-87.

[7] Magarò G, Prati F, Garofalo B, et al. Virtual screening approach and investigation of structure—activity relationships to discover novel bacterial topoisomerase inhibitors targeting gram—positive and gram—negative pathogens [J]. J Med Chem, 2019, 62(16): 7445-7472.

[8] Zhang J, Feng M, Guan W . Naturally occurring aesculetin coumarin exerts antiproliferative effects in gastric cancer cells mediated via apoptotic cell death, cell cycle arrest and targeting PI3K/AKT/M—TOR signalling pathway [J]. Acta Biochim Pol, 2021, 68(1): 109-113.

[9] Carmona—gutierrez D, Zimmermann A, Kainz K, et al. The flavonoid 4,4'—dimethoxychalcone promotes autophagy—dependent longevity across species [J]. Nat Commun, 2019, 10(1): 651.

[10] Wright G D, Sutherland A D . New strategies for combating multidrug—resistant bacteria [J]. Trends Mol Med, 2007, 13(6): 260-267.

[11] Rathore D, Mccutchan T F, Sullivan M, et al. Antimalarial drugs: current status and new developments [J]. Expert Opin Investig Drugs, 2005, 14(7): 871-873.

[12] Yu H H, Kim K J, Cha J D, et al. Antimicrobial activity of berberine alone and in combination with ampicillin or oxacillin against methicillin—resistant Staphylococcus aureus [J]. J Med Food, 2005, 8(4): 454-461.

[13] Qin H L, Zhang Z W, Ravindar L, et al. Antibacterial activities with the structure—activity relationship of coumarin derivatives [J]. Eur J Med Chem, 2020, 207: 112832.

[14] Ugurel E, Danis O, Mutlu O, et al. Inhibitory effects of aryl—coumarin derivatives on bacteroides fragilis d—lactate dehydrogenase [J]. Int J Biol Macromol, 2019, 127: 197-203.

[15] Jayakumar T, Huang C J, Yen T L, et al. Activation of Nrf2 by esculetin mitigates inflammatory responses through suppression of NF—κB signaling cascade in RAW 264.7 cells [J]. Molecules, 2022, 27(16): 5143.

[16] Wang S K, Chen T X, Wang W, et al. Aesculetin exhibited anti—inflammatory activities through inhibiting NF—кB and MAPKs pathway in vitro and in vivo [J]. J Ethnopharmacol, 2022, 296: 115489.

[17] Matos M J, Vazquez S, Santana L, et al. Synthesis and structure—activity relationships of novel amino/nitro substituted 3—arylcoumarins as antibacterial agents [J]. Molecules, 2013, 18(2): 1394-1404.

[18] Pisano M B, Kumar A, Medda R, et al. Antibacterial activity and molecular docking studies of a selected series of hydroxy—3—arylcoumarins [J]. Molecules, 2019, 24(15): 2815.

[19] 成昭, 梁玲玲, 苗延青 . 3—芳基香豆素衍生物的合成及其生物活性研究 [J]. 合成化学, 2019, 27(7): 554-558.

[20] Cheng Z, Liang L L, Miao Y Q . Synthesis and biological activities of 3—aryl coumarin derivatives [J]. Chin J Syn Chem, 2019, 27(7): 554-558. (in Chinese)

[21] Wu C, Li T, Zhu B, et al. Scoparone protects neuronal cells from oxygen glucose deprivation/reoxygenation injury [J]. RSC Advances, 2019, 9(4): 2302-2308.

[22] Hui Y, Wang X, Yu Z, et al. Scoparone as a therapeutic drug in liver diseases: pharmacology, pharmacokinetics and molecular mechanisms of action [J]. Pharmacol Res, 2020, 160: 105170.

[23] Yang J Y, Han J, Li Y, et al. Esculetin inhibits the apoptosis in H9c2 cardiomyocytes via the MAPK signaling pathway following hypoxia/reoxygenation injury [J]. Biomed Pharmacother, 2017, 88: 1206-1210.

[24] Pan H, Wang B, Lv W, et al. Esculetin induces apoptosis in human gastric cancer cells through a cyclophilin D—mediated mitochondrial permeability transition pore associated with ROS [J]. Chem—biol Interact, 2015, 242: 51-60.

[25] Oh S Y, Kim Y H, Kang M K, et al. Aesculetin attenuates alveolar injury and fibrosis induced by close contact of alveolar epithelial cells with blood—derived macrophages via IL—8 signaling [J]. Int J Mol Sci, 2020, 21(15): 5518.

[26] Kumar C, Chibber P, Painuli R, et al. Scoparone chemical modiffication into semi—synthetic analogues featuring 3—substitution for their anti—inflammatory activity [J]. Mol Divers, 2024, 28: 2467-2478.

[27] Danis O, Demir S, Gunduz C, et al. Synthesis of selected 3—and 4—arylcoumarin derivatives and evaluation as potent antioxidants [J]. Res Chem Intermed, 2016, 42(6): 6061-6077.

[28] Katopodi A, Tsotsou E, Iliou T, et al. Synthesis, bioactivity, pharmacokinetic and biomimetic properties of multi—substituted coumarin derivatives [J]. Molecules, 2021, 26(19): 5999.

[29] Yang J, Liu G Y, Dai F, et al. Synthesis and biological evaluation of hydroxylated 3—phenylcoumarins as antioxidants and antiproliferative agents [J]. Bioorg Med Chem Lett, 2011, 21(21): 6420-6425.

[30] Xiao C F, Zou Y, Du J L, et al. Hydroxyl substitutional effect on selective synthesis of cis, trans stilbenes and 3—arylcoumarins through Perkin condensation [J]. Synthetic Commun, 2012, 42(9): 1243-1258.

[31] Han M J, Feng J M, Wang X Y, et al. Synthesis and biological evaluation of esculetin derivatives as antidiabetic agents [J]. J Mol Struct, 2025, 1324: 140942.

[32] Gao W W, Rasheed S, Tangadanchu V K R, et al. Design, synthesis and biological evaluation of amino organophosphorus imidazoles as a new type of potential antimicrobial agents [J]. Sci China Chem, 2017, 60(6): 769-785.

[33] Wang J, Zhang W, Tang C, et al. Synergistic effect of B—type oligomeric procyanidins from lotus seedpod in combination with water—soluble poria cocos polysaccharides against E. coli and mechanism [J]. J Funct Foods, 2018, 48: 134-143.

[34] Hurtov􀅡M, K􀅡ˇnov􀅡K, Dobiasov􀅡S, et al. Selectively halogenated flavonolignans—preparation and antibacterial activity [J]. Int J Mol Sci, 2022, 23(23): 15121.

[35] Zhou Y, Yao Q, Zhang T, et al. Antibacterial activity and mechanism of green tea polysaccharide conjugates against Escherichia coli [J]. Ind Crop Prod, 2020, 152: 112464.

[36] Zhang W, Huang Y, Chen Y, et al. Amphiphilic tetraphenylethene—based pyridinium salt for selective cell—membrane imaging and room—light—induced special reactive oxygen species generation [J]. ACS Appl Mater Interfaces, 2019, 11(11): 10567-10577.

[37] Chang Y, Chen J Y, Yang J, et al. Targeting the cell membrane by charge—reversal amphiphilic pillar[5]arene for the selective killing of cancer cells [J]. ACS Appl Mater Interfaces, 2019, 11(42): 38497-38502.

[38] Liu T, Shen H, Wang F, et al. Thinned—young apple polyphenols inhibit halitosis—related bacteria through damage to the cell membrane [J]. Front Microbiol, 2022, 12: 745100.

[39] Yang C, Lv T, Wang B, et al. The damaging effects of pedunsaponin A on pomacea canaliculata hemocytes [J]. Toxins, 2019, 11(7): 390.

[40] Lin L, Wang X, Li C, et al. Inactivation mechanism of E. coli O157∶H7 under ultrasonic sterilization [J]. Ultrason Sonochem, 2019, 59: 104751.

基金资助

福建省对外合作产业化项目(2024I1009)

河北大学医学学科培育项目(2021A07)