吡啶联异噁唑啉类杂环衍生物的合成及生物活性
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摘要
以2-氯-5-氯甲基吡啶为原料,合成了12个吡啶联异噁唑啉类杂环衍生物(Ⅸa～l),其结构经~1HNMR、~(13)CNMR、MS及IR确证。体外抗菌活性测试结果表明,所得目标化合物对金黄色葡萄球菌(ATCC25923)、肺炎链球菌(ATCC49619)和粪肠球菌(ATCC29212)均有抑制作用。其中,化合物Ⅸf和Ⅸl对金黄色葡萄球菌的最小抑菌浓度(MIC)均为16 mg/L,对肺炎链球菌和粪肠球菌的MIC均为32 mg/L,抗菌效果最佳;体外驱虫活性测试结果表明:目标化合物均有驱虫效果,在质量浓度2 g/L下化合物Ⅸa～b和Ⅸg～h对蚯蚓的麻痹时间和死亡时间均明显少于阿苯达唑,驱虫效果明显强于阿苯达唑。
Twelve pyridinyl-4,5-2 H-isoxazole heterocyclic derivatives(Ⅸa～l) were synthesized from 2-chloro-5-chloromethylpyridine and their structures were characterized by ~1HNMR, ~(13)CNMR, MS and IR. Antibacterial activities results indicated all of compounds exhibited potent activities against Staphylococcus aureus(ATCC25923), Streptococcus pneumonia(ATCC49619) and Enterococcus faecalis(ATCC29212). Especially, compounds Ⅸf and Ⅸl showed the best activities, the minimal inhibitory concentration(MIC) values of Ⅸf and Ⅸl against Staphylococcus aureus were 16 mg/L, the MIC values of Ⅸf and Ⅸl against Streptococcus pneumonia and Enterococcus faecalis were 32 mg/L. All the target compounds displayed excellent anthelmintic activities, paralyzing time and death time of compounds Ⅸa, Ⅸb, Ⅸg and Ⅸh were significantly less than those of albendazole against Indian earthworm at 2 g/L concentration, indicating that these four compounds had much stronger anthelmintic effects than albendazole.
Twelve pyridinyl-4,5-2 H-isoxazole heterocyclic derivatives(Ⅸa～l) were synthesized from 2-chloro-5-chloromethylpyridine and their structures were characterized by ~1HNMR, ~(13)CNMR, MS and IR. Antibacterial activities results indicated all of compounds exhibited potent activities against Staphylococcus aureus(ATCC25923), Streptococcus pneumonia(ATCC49619) and Enterococcus faecalis(ATCC29212). Especially, compounds Ⅸf and Ⅸl showed the best activities, the minimal inhibitory concentration(MIC) values of Ⅸf and Ⅸl against Staphylococcus aureus were 16 mg/L, the MIC values of Ⅸf and Ⅸl against Streptococcus pneumonia and Enterococcus faecalis were 32 mg/L. All the target compounds displayed excellent anthelmintic activities, paralyzing time and death time of compounds Ⅸa, Ⅸb, Ⅸg and Ⅸh were significantly less than those of albendazole against Indian earthworm at 2 g/L concentration, indicating that these four compounds had much stronger anthelmintic effects than albendazole.
引文
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[9]Wang Dan(王丹),Xu Zhiqiang(许志强),Li Xinyi(李心怡),et al.Developments of linezolid and its derivatives[J].Journal of Liaoning University(Natural Sciences Edition)(辽宁大学学报自然科学版),2017,44(4):333-336.
[10]Yang Hongliang(杨洪亮),Xu Guoxing(徐国兴),Pei Yazhong(裴亚中).Synthesis,preliminary structure-activity relationships and biological evaluation of pyridinyl-4,5-2H-isoxazole derivatives as potent antitumor agents[J].Chemical Research in Chinese Universities(高等学校化学研究),2017,33(1):61-69.
[11]Yang Hongliang(杨洪亮),Xu Guoxing(徐国兴),Bao Meiying(宝梅英),et al.Design and synthesis of pyridinylisoxazoles and their anticancer activities[J].Chemical Journal of Chinese Universities(高等学校化学学报),2015,35(12):2584-2592.
[12]Hu Shengli(胡胜利),Zhang Hesheng(张合胜).A study on the synthesis of 6-chloro-3-pyridinecarboxaldehyde[J].Chemical Reagents(化学试剂),2005,27(6):373-374.
[13]Yapi A D,Desbois N,Chezal J M,et al.Design and preparation of aza-analogues of benzo[c]phenanthridine framework with cytotoxic and antiplasmodial activities[J].European Journal of Medicinal Chemistry,2010,45(7):2854-2859.
[14]Kamal A,Dastagiri D,Ramaiah M J,et al.Synthesis and apoptosis inducing ability of new anilino substituted pyrimidine sulfonamides as potential anticancer agents[J].European Journal of Medicinal Chemistry,2011,46(12):5817-5824.
[15]Hwang S H,Wagner K M,Morisseau C,et al.Synthesis and structure-activity relationship studies of urea-containing pyrazoles as dual inhibitors of cyclooxygenase-2 and soluble epoxide hydrolase[J].Journal of Medicinal Chemistry,2011,54(8):3037-3050.
[16]Espinel S S.Manual of clinical microbiology american society for microbiology[M].Washington,DC,USA:American Society for Microbiology,1980.
[17]Ayaz M,Junaid M,Subhan F,et al.Heavy metals analysis,phytochemical,phytotoxic and anthelmintic investigations of crude methanolic extract,subsequent fractions and crude saponins from Polygonum hydropiper L[J].BMC Complementary and Alternative Medicine,2014,14(1):465-473.
[18]Shruthi N,Poojary B,Kumar V,et al.Synthesis,molecular properties and evaluation of anthelmintic activity of new thiazolopyrimidine derivatives[J].Journal of Chemical and Pharmaceutical Research,2015,7(6):181-191.
[19]Deb P K,Ghosh R,Das S,et al.In-vitro anthelmintic activity of Acorus calamus leaves[J].Asian Journal of Pharmaceutical&Clinical Resdearch,2013,6(3):135-137.
[20]Mondal P,Jana S,Balaji A,et al.Synthesis of some new isoxazoline derivatives of chalconised indoline 2-one as a potential analgesic,antibacterial and anthelmintic agents[J].Journal of Young Pharmacists,2012,4(1):38-41.
[21]Das S S,Dey M,Ghosh A K.Determination of anthelmintic activity of the leaf and bark extract of Tamarindus indica Linn[J].Indian Journal of Pharmaceutical Sciences,2011,73(1):104-107.