Synthesis and structure--antibacterial activity relationships of 7-(3-amino-1-propynyl and 3-amino-1-propenyl)quinolones

Abstract

7-(3-Amino-1-propynyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4- oxoquinoline-3-carboxylic acid (7a) and some related compounds (7b-f, 8a, b, 9) were prepared via palladium(0)-catalyzed cross-coupling reaction of 7-iodoquinolone 12 with acetylenic compounds and their antibacterial activity was tested. The methylene homologue (7d) and the N-methyl derivative (7e) of 7a showed essentially the same activity as that of 7a. Addition of methyl group(s) to C'-3 of 7a (giving 7b, c) reduced the activity. The hydrogenation of 7a to (Z)-3-amino-1-propenyl (8a), (E)-3-amino-1-propenyl (8b) and 3-amino-1-propyl (9) compounds retained or enhanced the activity of 7a. Among the compounds prepared, 8a was the most active, but was less active than ciprofloxacin (1). In order to get insight into structure-activity relationships, the spatial distribution of the amino groups of 7a, 8a, b, and 9 was examined by means of computer-aided molecular modeling.