1-对甲苯基-5-取代苯基亚胺基-1,2,3-三唑甲酸/甲酰胺的合成及生物活性研究
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摘要
以对甲基苯胺为原料,经过重氮化反应生成对甲基叠氮苯(1).在强碱性条件下,1分别与氰基乙酸乙酯、氰基乙酰胺反应,制得中间体1-对甲苯基-5-氨基-1,2,3-三唑甲酸乙酯(2)和1-对甲苯基-5-氨基-1,2,3-三唑甲酰胺(5);中间体2经水解生成1-对甲苯基-5-氨基-1,2,3-三唑甲酸(3),进而在弱酸性条件下与取代苯甲醛反应得到6个未见文献报道的目标化合物1-对甲苯基-5-取代苯基亚胺基-1,2,3-三唑甲酸(4a～4f),5与取代苯甲醛反应得到6个未见文献报道的目标化合物1-对甲苯基-5-取代苯基亚胺基-1,2,3-三唑甲酰胺(6a～6f),化合物的结构均经IR,1H NMR,13C NMR确证.初步生物测试表明,12个化合物均表现出良好的抑菌活性,其中化合物4d～4f和6d～6f对金黄色葡萄球菌、白色念球菌的最小抑菌浓度(MIC)值为2～8μg/mL,抗菌效果优于氟康唑和三氯生.
4-Methylphenylazide(1) was synthesized through diazotization reactions from 4-methylaniline,and then reacted with ethyl cyanoacetate or 2-cyano-acetamide to obtain 1-(4-methyl)phenyl-5-amino-1,2,3-triazole carboxylic ethyl ester(2) and 1-(4-methyl)phenyl-5-amino-1,2,3-triazole carboxylic acid amide(5) in strong alkaline condition.Compound 2 hydrolyzed into 1-(4-methyl)phenyl-5-amino-1,2,3-triazole carboxylic acid(3).Then,in weak acidic condition,1-(4-methyl) phenyl-5-substituted phenylimino-1,2,3-triazole carboxylic acids(4a～4f) were obtained from compound 3 and substituted benzaldehyde.Meanwhile,other 6 novel 1-(4-methyl)phenyl-5-substituted phenylimino-1,2,3-triazole carboxylic acid amides(6a～6f) were synthesized from compound 5 and substituted benzaldehyde.The structures of all compounds have been confirmed by 1H NMR,13C NMR and IR.The preliminary bioassay showed that,all target compounds possessed efficient antibacterial activities.Especially,the mic values of compounds 4d～4f and 6d～6f were 2～8 μg/mL,lower than fluconazole and triclosan.
4-Methylphenylazide(1) was synthesized through diazotization reactions from 4-methylaniline,and then reacted with ethyl cyanoacetate or 2-cyano-acetamide to obtain 1-(4-methyl)phenyl-5-amino-1,2,3-triazole carboxylic ethyl ester(2) and 1-(4-methyl)phenyl-5-amino-1,2,3-triazole carboxylic acid amide(5) in strong alkaline condition.Compound 2 hydrolyzed into 1-(4-methyl)phenyl-5-amino-1,2,3-triazole carboxylic acid(3).Then,in weak acidic condition,1-(4-methyl) phenyl-5-substituted phenylimino-1,2,3-triazole carboxylic acids(4a～4f) were obtained from compound 3 and substituted benzaldehyde.Meanwhile,other 6 novel 1-(4-methyl)phenyl-5-substituted phenylimino-1,2,3-triazole carboxylic acid amides(6a～6f) were synthesized from compound 5 and substituted benzaldehyde.The structures of all compounds have been confirmed by 1H NMR,13C NMR and IR.The preliminary bioassay showed that,all target compounds possessed efficient antibacterial activities.Especially,the mic values of compounds 4d～4f and 6d～6f were 2～8 μg/mL,lower than fluconazole and triclosan.
引文
[1](a)Alvarez,R.;Velazquez,S.;San-Felix,A.;Aquaro,S.;De-Clercq,E.;Perno,C.-F.;Karlsson,A.;Balzarini,J.;Carmarasa,M.J.J.Med.Chem.1994,37,4185.(b)Velaquez,S.;Alvarez,R.;Perez,C.;Gogo,F.;De,C.;Balzarini,J.;Carmarasa,M.J.Antiviral Chem.Chemother.1998,9,481.
[2]Dalip,K.;Buchi,R.V.;Anil,K.;Deendayal,M.;Rakesh,T.;Keykavous,P.Bioorg.Med.Chem.Lett.2011,21,449.
[3]Dabak,K.;Sezer,O.;Akar,A.;Anac,O.Eur.J.Med.Chem.2003,38,215.
[4]Zhang,S.-S.;Wan,J.;Li,X.-M.;Li,C.-L.;Xu,L.-Z.Chem.Res.Chin.Univ.2007,23,120.
[5]Kelley,J.L.;Koble,C.S.;Davis,R.G.;McLean,E.W.;Soroko,F.E.;Cooper,B.R.J.Med.Chem.1995,38,4131.
[6]Genin,M.J.;Allwine,D.A.;Anderson,D.J.;Barbachyn,M.R.;Emmert,D.E.;Garmon,S.A.;Graber,D.R.;Grega,K.C.;Hester,J.B.;Hutchinson,D.K.;Morris J.;Reischer,R.J.;Ford,C.W.;Zurenko,G.E.;Hamel,J.C.;Schaadt,R.D.;Stapert,D.;Yagi,B.H.J.Med.Chem.2000,43,953.
[7]Sun,X.-H.;Tao,Y.;Liu,Y.-F.;Jia,Y.-Q.;Chen,B.;Yang,J.-W.Chin.J.Org.Chem.2008,28,155(in Chinese).(孙晓红,陶燕,刘源发,贾婴琦,陈邦,杨建武,有机化学,2008,28,155.)
[8]Wang,B.-L.;Shi,Y.-X.;Ma,Y.;Liu,X.-H.;Li,Y.-H.;Song,H.-B.;Li,B.-J.;Li,Z.-M.J.Agric.Food Chem.2010,58,5515.
[9]Liliana,M.;Finkielsztein,E.F.;Castro,L.E.;Fabian,L.E.;Mol-trasio,G.Y.Eur.J.Med.Chem.2008,43,1767.
[10]Zhao,Q.;Lu,J.-R.;Xin,C.-W.;Bao,X.-R.;Gao,H.-Y.;Zhao,X.;Li,S.;Rui,T.-T.Chem.J.Chin.Univ.2011,32,2806(in Chinese).(赵芡,卢俊瑞,辛春伟,鲍秀荣,高海燕,赵旭,李莎,芮甜甜,高等学校化学学报,2011,32,2806.)
[11]Zhao,X.;Lu,J.-R.;Xin,C.-W.;Lu,B.-W.;Bao,X.-R.;Li,J.-F.;Liu,Y.;Yang,X.-Y.;Yuan,Y.Chem.Res.Chin.Univ.2012,28(3),1.
[12]Mu,M.-M.;Lu,B.-W.;Lu,J.-R.;Xin,C.-W.;Ji,D.;Li,J.-F.;Bao,X.-R.Chin.J.Org.Chem.2012,32,1101(in Chinese).(穆曼曼,卢博为,卢俊瑞,辛春伟,戢丹,李建发,鲍秀荣,有机化学,2012,32,1101.)
[13]Bucking,J.Dictionary of Organic Compunds,5 th ed,Chapmanand Hall,New York,1982,p.808.
[14]Elzbieta,C.;Zygmunt,E.;Romuald,K.Diss.Pharm.1964,15(5),369.
[15]Charansingh,G.;Ganesh,J.;Mohammad,S.;Rajesh,K.;Anant,G.;Deepak,N.;Mahendra,S.Bioorg.Med.Chem.Lett.2008,18,6244.
[2]Dalip,K.;Buchi,R.V.;Anil,K.;Deendayal,M.;Rakesh,T.;Keykavous,P.Bioorg.Med.Chem.Lett.2011,21,449.
[3]Dabak,K.;Sezer,O.;Akar,A.;Anac,O.Eur.J.Med.Chem.2003,38,215.
[4]Zhang,S.-S.;Wan,J.;Li,X.-M.;Li,C.-L.;Xu,L.-Z.Chem.Res.Chin.Univ.2007,23,120.
[5]Kelley,J.L.;Koble,C.S.;Davis,R.G.;McLean,E.W.;Soroko,F.E.;Cooper,B.R.J.Med.Chem.1995,38,4131.
[6]Genin,M.J.;Allwine,D.A.;Anderson,D.J.;Barbachyn,M.R.;Emmert,D.E.;Garmon,S.A.;Graber,D.R.;Grega,K.C.;Hester,J.B.;Hutchinson,D.K.;Morris J.;Reischer,R.J.;Ford,C.W.;Zurenko,G.E.;Hamel,J.C.;Schaadt,R.D.;Stapert,D.;Yagi,B.H.J.Med.Chem.2000,43,953.
[7]Sun,X.-H.;Tao,Y.;Liu,Y.-F.;Jia,Y.-Q.;Chen,B.;Yang,J.-W.Chin.J.Org.Chem.2008,28,155(in Chinese).(孙晓红,陶燕,刘源发,贾婴琦,陈邦,杨建武,有机化学,2008,28,155.)
[8]Wang,B.-L.;Shi,Y.-X.;Ma,Y.;Liu,X.-H.;Li,Y.-H.;Song,H.-B.;Li,B.-J.;Li,Z.-M.J.Agric.Food Chem.2010,58,5515.
[9]Liliana,M.;Finkielsztein,E.F.;Castro,L.E.;Fabian,L.E.;Mol-trasio,G.Y.Eur.J.Med.Chem.2008,43,1767.
[10]Zhao,Q.;Lu,J.-R.;Xin,C.-W.;Bao,X.-R.;Gao,H.-Y.;Zhao,X.;Li,S.;Rui,T.-T.Chem.J.Chin.Univ.2011,32,2806(in Chinese).(赵芡,卢俊瑞,辛春伟,鲍秀荣,高海燕,赵旭,李莎,芮甜甜,高等学校化学学报,2011,32,2806.)
[11]Zhao,X.;Lu,J.-R.;Xin,C.-W.;Lu,B.-W.;Bao,X.-R.;Li,J.-F.;Liu,Y.;Yang,X.-Y.;Yuan,Y.Chem.Res.Chin.Univ.2012,28(3),1.
[12]Mu,M.-M.;Lu,B.-W.;Lu,J.-R.;Xin,C.-W.;Ji,D.;Li,J.-F.;Bao,X.-R.Chin.J.Org.Chem.2012,32,1101(in Chinese).(穆曼曼,卢博为,卢俊瑞,辛春伟,戢丹,李建发,鲍秀荣,有机化学,2012,32,1101.)
[13]Bucking,J.Dictionary of Organic Compunds,5 th ed,Chapmanand Hall,New York,1982,p.808.
[14]Elzbieta,C.;Zygmunt,E.;Romuald,K.Diss.Pharm.1964,15(5),369.
[15]Charansingh,G.;Ganesh,J.;Mohammad,S.;Rajesh,K.;Anant,G.;Deepak,N.;Mahendra,S.Bioorg.Med.Chem.Lett.2008,18,6244.