含氨基酸结构的磺酰胺衍生物合成与生物活性

Synthesis and biological activities of sulfonamide derivatives containing amino acid moiety

采用分子杂交策略设计合成了15个氨基酸结构的磺酰胺衍生物,对其进行了抗菌活性评价。首先,苯磺酰氯与氨基酸反应制得了苯磺酰氨基酸(中间体Ⅰ);然后,以芳香醛、亚磷酸酯、乙酸铵和三氟甲磺酸铝为原料,一锅法制得了α-氨基膦酸酯(中间体Ⅱ);最后,中间体Ⅰ与Ⅱ缩合制得目标物。经^(1)HNMR、^(13)CNMR和MS确认结构。结果表明,该类化合物对大肠杆菌(E.coli)和耐氟喹诺酮大肠杆菌(FREC)活性最为显著。其中,化合物Ⅲb[{(2-氟苯基)[2-(苯基磺酰氨基)苯丙酰氨基]甲基}膦酸二乙酯]、Ⅲc[{(4-氟苯基)[2-(苯基磺酰氨基)苯丙酰氨基]甲基}膦酸二乙酯]、Ⅲh[{(2-氟苯基)[2-(苯基磺酰氨基)异戊酰氨基]甲基}膦酸二乙酯]和Ⅲm[{(苯基)[2-(苯基磺酰氨基)乙酰氨基]甲基}膦酸二乙酯]对E.coli的最小抑菌质量浓度(MIC)均为16μg/L,化合物Ⅲn[{(2-氟苯基)[2-(苯基磺酰氨基)乙酰氨基]甲基}膦酸二乙酯]对E.coli的MIC为8μg/L,抗菌活性不低于对照药苯唑西林;化合物Ⅲb、Ⅲh、Ⅲm和Ⅲn对FREC的MIC分别为32、32、32和16μg/L,优于对照药苯唑西林和诺氟沙星。

Fifteen sulfonamide derivatives containing amino acid moiety were designed and synthesized by molecular hybridization strategy,and evaluated for their antibacterial activity.Specifically,benzenesulfonyl amino acids(intermediateⅠ)was firstly prepared from reaction of benzenesulfonyl chloride and amino acids.α-Aminophosphonates(intermediateⅡ)were then synthesized from one pot reaction of aromatic aldehyde,phosphite,ammonium acetate and aluminum trifluoromethanesulfonate.Finally,the target products were obtained by condensation reaction of intermediateⅠandⅡ.The structures of the target products obtained were confirmed by ^(1)HNMR,^(13)CNMR and MS.The results showed that these compounds exhibited the most significant activities against Escherichia coli(E.coli)and fluoroquinolone-resistant Escherichia coli(FREC).Among them,the MIC ofⅢb(diethyl{(2-fluorophenyl)[2-(phenylsulfonylamino)phenylpropanylamino]methyl}phosphonate),Ⅲc(diethyl{(4-fluorophenyl)[2-(phenylsulfonylamino)phenylpropanylamino]methyl}phosphonate),Ⅲh(diethyl{(2-fluorophenyl)[2-(phenylsulfonylamino)isovalerylamino]methyl}phosphonate)andⅢm(diethyl{(phenyl)[2-(phenylsulfonyl amino)acetamido]methyl}phosphonate)displayed a MIC to E.coli of 16μg/L,whileⅢn(diethyl{(2-fluorophenyl)[2-(phenylsulfonylamino)acetamido]methyl}phosphonate)showed a MIC against E.coli of 8μg/L,which were no less effective when compared with control drug Oxacillin.The MIC ofⅢb,Ⅲh,Ⅲm andⅢn against FREC were 32,32,32 and 16μg/L,respectively,