6-氟(氯)-4(3H)-喹唑啉酮类Schiff碱的设计合成及其抑菌活性研究
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摘要
以2-氨基-5-氟(氯)苯甲酸为起始原料,与乙酸酐经酰化、关环两步制得6-氟(氯)-2-甲基噁嗪-4-酮(2);化合物2在质量分数为85%水合肼中回流反应制得6-氟(氯)-2-甲基-3-氨基-4(3H)-喹唑啉酮(3);化合物3分别与吡啶甲醛反应合成了6种新型的6-氟(氯)-4(3H)-喹唑啉酮类Schiff碱(4a～4f),其结构经~1H NMR,~(13)C NMR,IR和元素分析表征。采用琼脂扩散法研究了化合物4a～4f对大肠杆菌、金黄色葡萄球菌和枯草杆菌的抑制活性。结果表明,用药质量浓度为500μg/mL时,6-氟-2-甲基-3-(4-吡啶苯亚甲胺基)-4(3H)-喹唑啉酮(4c)对大肠杆菌的抑菌圈直径为9.60 mm,6-氯-2-甲基-3-(4-吡啶苯亚甲胺基)-4(3H)-喹唑啉酮(4f)对枯草杆菌的抑菌圈直径为9.88 mm,表明吡啶杂环中N原子的位置对抑菌活性具有一定的影响。
3-Amino-6-fluoro(chloro)-2-methyl-4(3H)-quinazolinone(3) was prepared via 85% N_2H_4·H_2O and 6-fluoro(chloro)-2-methyl-3,1-benzoxazin-4-one(2), which was obtained by using 5-fluoro(chloro)anthranilic acid as the raw material through two steps of acetylation and cyclization with acetic anhydride. Six new 6-fluoro(chloro)-4(3H)-quinazolinone Schiff bases(4 a～4 f) were synthesized by the reaction of 3 with pyridylaldehyde. Their structures were characterized by ~1H NMR, ~(13)C NMR, IR and elementary analysis. The preliminary antibacterial activities of 4 a～4 f against Escherichia coli, Staphylococcus aureus and Bacillus subtilis were investigated by agar diffusion method with a concentration of 500 μg/mL. The results showed that 6-fluoride-2-methyl-3-[(4-pyridyl) methylene amimo]-4(3H)-quinazolinone(4 c) and 6-chloro-2-methyl-3-[(4-pyridyl)methylene amimo]-4(3H)-quinazolinone(4 f) produced 9.60 and 9.88 mm inbibition zone diameters against Escherichia coli and Bacillus subtilis, respectively.
3-Amino-6-fluoro(chloro)-2-methyl-4(3H)-quinazolinone(3) was prepared via 85% N_2H_4·H_2O and 6-fluoro(chloro)-2-methyl-3,1-benzoxazin-4-one(2), which was obtained by using 5-fluoro(chloro)anthranilic acid as the raw material through two steps of acetylation and cyclization with acetic anhydride. Six new 6-fluoro(chloro)-4(3H)-quinazolinone Schiff bases(4 a～4 f) were synthesized by the reaction of 3 with pyridylaldehyde. Their structures were characterized by ~1H NMR, ~(13)C NMR, IR and elementary analysis. The preliminary antibacterial activities of 4 a～4 f against Escherichia coli, Staphylococcus aureus and Bacillus subtilis were investigated by agar diffusion method with a concentration of 500 μg/mL. The results showed that 6-fluoride-2-methyl-3-[(4-pyridyl) methylene amimo]-4(3H)-quinazolinone(4 c) and 6-chloro-2-methyl-3-[(4-pyridyl)methylene amimo]-4(3H)-quinazolinone(4 f) produced 9.60 and 9.88 mm inbibition zone diameters against Escherichia coli and Bacillus subtilis, respectively.
引文
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[20] Li M,Zhang Y N,Tian Y S.Synthesis and Antitumor Activity Evaluation of the Derivatives of 1,2,4-Triazole-5-thione Bis-Schiff Base [J].J Pharm Res,2016,35(7):376-378 (in Chinese).(李敏,张玉娜,田玉顺.三唑硫酮双席夫碱类衍生物的合成及其抗肿瘤活性研究[J].药学研究,2016,35(7):376-378.)
[21] Zhang H J.Synthesis and Herbicidal Activities of Trifluoromethyl-substituted Triazoletriazole Schiff Base and Bis-amide Compounds [D].Wuhan:Central China Normal University,2012 (in Chinese).(张瀚匀.含三氟甲基的三唑席夫碱类化合物及双酰胺类化合物的合成与除草活性研究[D].武汉:华中师范大学,2012.)
[22] Liu J,Wang H F,Lu J,et al.Synthesis and Antibacterial Activities of Novel 6-Chloro-4(3H)-quinazolinone Schiff Bases [J].Chin J Synth Chem,2016,24(11):942-945 (in Chinese).(刘杰,王慧峰,陆娟,等.新型6-氯-4(3H)-喹唑啉酮类Schiff碱合成及其抑菌活性[J].合成化学,2016,24(11):942-945.)
[23] Liu J,Shen H,Zhu Z W,et al.Synthesis and Antibacterial Activities of Novel 6-Fluoro-4(3H)-quinazolinone Schiff Bases [J].Chin J Synth Chem,2019,27(1):25-30 (in Chinese).(刘杰,沈昊,朱泽文,等.新型6-氟-4(3H)-喹唑啉酮类Schiff碱的合成及其抑菌活性[J].合成化学,2019,27(1):25-30.)
[24] Sheldrick G M.SHELXTLV 5.1 Software Reference Manual [CP].Madison:Bruker AXS Inc,1997.
[2] Kshirsagar U A.Recent Developments in the Chemistry of Quinazolinone Alkaloids [J].Org Biomol Chem,2015,13:9 336-9 352.
[3] Mohamed M S,Kamel M M,Kassem E M M,et al.Novel 6,8-Dibromo-4(3H)-quinazolinone Derivatives of Atibacterial and Anti-fungal Activities [J].Eur J Med Chem,2010,45(8):3 311-3 319.
[4] Du H,Fan Z J,Yang L,et al.Synthesis and Antimicrobial Activities of Novel 1,2,4-Triazole-acylhydrazone Derivatives Containing the Quinazolin-4-one Moiety [J].Chin J Org Chem,2018,38(2):531-538 (in Chinese).(杜欢,范治江,杨岚,等.含喹唑啉-4-酮片段的新型1,2,4-三唑酰腙类衍生物的合成及抗菌活性[J].有机化学,2018,38(2):531-538.)
[5] Cui M T,Jiang L,Goto M,et al.In vivo and Mechanistic Studies on Antitumor Lead 7-Methoxy-4-(2-methylquinazolin-4-yl)-3,4-dihydroquinoxalin-2(1H)-one and Its Modification as a Novel Class of Tubulin-binding Tumor-vascular Disrupting Agents [J].J Med Chem,2017,60(13):5 586-5 598.
[6] Cheng Y,Shen J,Peng R Z,et al.Structure-based Optimization and Derivatization of 2-Substituted Quinolone-based Non-nucleoside HCV NS5B Inhibitors with Submicromolar Cellular Replicon Potency [J].Bioorg Med Chem Lett,2016,26:2 900-2 906.
[7] Dong D Q,Hao S H,Wang Z L,et al.Hypervalent Iodine:A Powerful Electrophile for Asymmetric α-Functionalization of Carbonylcompounds [J].Org Biomol Chem,2014,12:4 278-4 289.
[8] Yan C R,Yang L,Guo A R,et al.Synthesis and An-ticoccidial Activities of Novel N-(2-Aminophenyl)-2-quinazolinone-acetamide Hydrochloride [J].Asian J Chem,2013,25(9):4 970-4 974.
[9] Ahmed B,Samad A,Hasan M.Molecular Modelling Studies,Synthesis and Antimicrobial Screening of Some Novel Sulphonamide Quinazolin-4(3H)-one Fused Derivatives [J].Int J Pharm Pharm Sci,2014,6(4):312-317.
[10] Zhang J,Chen P,Ma Y M,et al.Ultrasonic Synthesis and Anti-phytopathogenic Fungi Activity Evaluation of 2-Sulfanylidene-2,3-dihydroquinazoline-4(1H)-one [J].Chin J Org Chem,2016,36(6):1 368-1 374 (in Chinese).(张金,程佩,马养民,等.超声辐射法合成2-硫亚基喹唑啉-4(1H)-酮类化合物及其抗植物病原菌活性研究 [J].有机化学,2016,36(6):1 368-1 374.)
[11] Yan B R,Lv X Y,Du H,et al.Synthesis and Biological Activities of Novel Quinazolinone Derivatives Containing a 1,2,4-Triazolylthioether Moiety [J].Chem Pap,2016,70(7):983-993.
[12] Xu L B,Li P,Xu J B,et al.Design,Synthesis and Acaricidal Activity of 3-(5-Trifluoroethylsulfanyl-phen-1-yl)-2,3-dihydroquinazolin-4(1H)-one Derivatives [J].Agrochemicals,2018,57(11):795-798 (in Chinese).(徐利保,李鹏,徐靖博,等.3-(5-三氟乙硫基)苯基-2,3-二氢喹唑啉-4(1H)-酮类衍生物的设计、合成及杀螨活性[J].农药,2018,57(11):795-798.)
[13] Li X H,Long Z X,Wang R,et al.Synthesis and Fluorescent Sensing Properties for Zinc(Ⅱ) of a Di-Schiff Base Fluorescent Probe [J].Chem Res Appl,2017,29(8):1 136-1 141 (in Chinese).(李晓红,龙昭现,王若,等.一种双席夫碱荧光探针的合成及其对Zn(Ⅱ)的传感性质研究[J].化学研究与应用,2017,29(8):1 136-1 141.)
[14] Liao Z Q,Dong C,Carlson K E,et al.Triaryl-substituted Schiff Bases are High-affinity Subtype-selective Ligands for the Estrogen Receptor [J].J Med Chem,2014,57(8):3 532-3 545.
[15] Chen L,Xie J,Song H,et al.Design,Synthesis,and Biological Activities of Spirooxindoles Containing Acylhydrazone Fragment Derivatives Based on the Biosynthesis of Alkaloids Derived from Tryptophan [J].J Agric Food Chem,2016,64(34):6 508-6 516.
[16] Wei Z Y,Chi K Q,Yu Z K,et al.Synthesis and Biological Evaluation of Chalcone Derivatives Containing Aminoguanidine or Acylhydrazonemoieties [J].Bioorg Med Chem Lett,2016,26(24):5 920-5 925.
[17] Zhang N,Fan Y H,Huang G M,et al.L-Tryptophan Schiff Base Cadmium(Ⅱ) Complexes as a New Class of Proteasome Inhibitors and Apoptosis Inducers in Human Breast Cancer Cells [J].Inorg Chim Acta,2017,466(1):478-485.
[18] Jin F,Wan F X,Zan N N,et al.Synthesis and Antifungal Activities of Novel Schiff Bases Bearing Benzimidazole and Isoxazole Moieties [J].Chin J Synth Chem,2017,25(1):9-13 (in Chinese.) (靳飞,万福贤,昝宁宁,等.含苯并咪唑和异噁唑结构席夫碱的合成及其抑菌活性[J].合成化学,2017,25(1):9-13.)
[19] Xu Y L,Lin H Y,Cao R J,et al.Pyrazolone-quinazolone Hybrids:A Novel Class of Human 4-Hydroxyphenylpyruvate Dioxygenase Inhibitors [J].Bioorg Med Chem,2014,22(19):5 194-5 211.
[20] Li M,Zhang Y N,Tian Y S.Synthesis and Antitumor Activity Evaluation of the Derivatives of 1,2,4-Triazole-5-thione Bis-Schiff Base [J].J Pharm Res,2016,35(7):376-378 (in Chinese).(李敏,张玉娜,田玉顺.三唑硫酮双席夫碱类衍生物的合成及其抗肿瘤活性研究[J].药学研究,2016,35(7):376-378.)
[21] Zhang H J.Synthesis and Herbicidal Activities of Trifluoromethyl-substituted Triazoletriazole Schiff Base and Bis-amide Compounds [D].Wuhan:Central China Normal University,2012 (in Chinese).(张瀚匀.含三氟甲基的三唑席夫碱类化合物及双酰胺类化合物的合成与除草活性研究[D].武汉:华中师范大学,2012.)
[22] Liu J,Wang H F,Lu J,et al.Synthesis and Antibacterial Activities of Novel 6-Chloro-4(3H)-quinazolinone Schiff Bases [J].Chin J Synth Chem,2016,24(11):942-945 (in Chinese).(刘杰,王慧峰,陆娟,等.新型6-氯-4(3H)-喹唑啉酮类Schiff碱合成及其抑菌活性[J].合成化学,2016,24(11):942-945.)
[23] Liu J,Shen H,Zhu Z W,et al.Synthesis and Antibacterial Activities of Novel 6-Fluoro-4(3H)-quinazolinone Schiff Bases [J].Chin J Synth Chem,2019,27(1):25-30 (in Chinese).(刘杰,沈昊,朱泽文,等.新型6-氟-4(3H)-喹唑啉酮类Schiff碱的合成及其抑菌活性[J].合成化学,2019,27(1):25-30.)
[24] Sheldrick G M.SHELXTLV 5.1 Software Reference Manual [CP].Madison:Bruker AXS Inc,1997.