7-Azetidinylquinolones as Antibacterial Agents. 2. Synthesis and Biological Activity of 7-(2,3-Disubstituted-1-azetidinyl)-4-oxoquinoline- and -1,8-naphthyridine-3-carboxylic Acids. Properties and Structure-Activity Relationships of Quinolones with an Azetidine Moiety

• Published in: Journal of medicinal chemistry 1994-11, Vol.37 (24), p.4195-4210
• Main Authors: Frigola, Jordi, Torrens, Antoni, Castrillo, Jose A, Mas, Josep, Vano, David, Berrocal, Juana M, Calvet, Carme, Salgado, Leonardo, Redondo, Jordi
• Format: Article
• Language: English
• Subjects: 4-Quinolones; Animals; Anti-Infective Agents - chemical synthesis; Anti-Infective Agents - pharmacokinetics; Anti-Infective Agents - pharmacology; Azetidines - chemical synthesis; Azetidines - pharmacokinetics; Azetidines - pharmacology; Bacteria - drug effects; Bacterial Infections - drug therapy; Crystallography, X-Ray; Mice; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00050a016

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.