7-AZETIDINYLQUINOLONES AS ANTIBACTERIAL AGENTS .2. SYNTHESIS AND BIOLOGICAL-ACTIVITY OF 7-(2,3-DISUBSTITUTED-1-AZETIDINYL)-4-OXOQUINOLINE-3-CARBOXYLIC AND 7-(2,3-DISUBSTITUTED-1-AZETIDINYL)-1,8-NAPHTHYRIDINE-3-CARBOXYLIC ACIDS - PROPERTIES AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF QUINOLONES WITH AN AZETIDINE MOIETY

被引：44

作者：

FRIGOLA, J ^{[1
]}

TORRENS, A ^{[1
]}

CASTRILLO, JA ^{[1
]}

MAS, J ^{[1
]}

VANO, D ^{[1
]}

BERROCAL, JM ^{[1
]}

CALVET, C ^{[1
]}

SALGADO, L ^{[1
]}

REDONDO, J ^{[1
]}

GARCIAGRANDA, S ^{[1
]}

VALENTI, E ^{[1
]}

QUINTANA, JR ^{[1
]}

机构：

[1] UNIV OVIEDO,DEPT PHYS CHEM,E-33006 OVIEDO,SPAIN

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1994年 / 37卷 / 24期

关键词：

D O I：

10.1021/jm00050a016

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of 7-(2,3-disubstituted-1-azetidinyl)-1,4-dihydro-6-fluoro-4-oxoquinoline- and -1,8-naphthyridine-3-carboxylic acids, with varied substituents at the 1-, 5-, and 8-positions, was prepared to study the effects on potency and physicochemical properties of the substituent at position 2 of the azetidine moiety. The activity of the title compounds was determined in vitro against Gram-positive and Gram-negative bacteria, and the in vivo efficacy of selected derivatives was determined using a mouse infection model. The X-ray crystal structures of 6b, 6c, and 6d were found to be in reasonable agreement with the corresponding AM1 calculated geometries. Correlations between antibacterial potency of all the synthesized 7-azetidinylquinolones and naphthyridines and their calculated electronic properties and experimental capacity factors were established. Antibacterial efficacy and pharmacokinetic and physicochemical properties of selected derivatives were compared to the relevant 7-(3-amino-1-azetidinyl) and 7-(3-amino-3-methyl-1-azetidinyl) analogues (for Part 1, see: J. Med. Chem. 1993, 36, 801-810). A combination of a cyclopropyl or a substituted phenyl group at N-1 and a trans-3-amino-2-methyl-1-azetidinyl group at C-7 conferred the best overall antibacterial, pharmacokinetic, and physicochemical properties to the azetidinylquinolones studied.

引用

页码：4195 / 4210

页数：16

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