Synthesis And Antibacterial Activity Of 7-Substituted Aminomethyl-FIuoroquinoIone Derivatives

Synthesis and Antibacterial Activity of 7-Substituted Aminomethyl-FIuoroquinoIone DerivativesPh. D. Candidate: SCKenfaJZKanj Supervisors: Prof. eWicHenj and Prof. AbstractOver the past decades, more than ten fluoroquinolones have been launched into market as antibacterial agents. One of the most notable characteristics of their structures is the presence of the cycloamine group linked at position 7 of the fluoroquinolone framework by C-N bond. In order to investigate the extensive structure-activity relationship of fluoroquinlones, 113 fluoroquinolone carboxylic acids bearing 7-substituted-aminomethyl were designed and synthesized and their preliminary antibacterial activities were evaluated.In the synthesis of these compounds, three routes have been studied according to their specific structural characteristics. In the first route, the unprecendented aromatic nucleophilic substitution (SuAr) of some 6,7-difluoro-quinolone intermediates with nitromethane has been studied in detail. The 7-nitromethyl fluoroquinolones IV, served as the important intermediates in this paper, have been prepared in high yield by the SNAr. Reduction of the nitrocompounds followed by cyclization and hydrolysis successively gave A22 and A23.In order to prepare more compounds with structural diversity, the second route was explored. IV was converted to the aldehydes VII by the modified Nef reaction. The conditions of this reaction have been optimized, resulting in raising the yield from poor to moderate. Reduction of the aldehydes VII gave the carbinols VIII. The bromides IX were prepared by the bromination of VIII. Displacement of the bromides with various amines provided the intermediates VI, which gave the proper target compounds after hydrolysis.By the reductive amination of VII, the introduction of the aromatic amines to the fluoroquinolone nucleus was achieved and after hydrolysis some targets were obtained by the third route, which was the alternative way of route 2. All the targets were the unknown compounds and were confirmed by 'HNMR and elemental analyses or HREIMS.All the compounds were tested in vitro against five Gram-positive and eleven Gram-negative bacteria using the serial two-fold dilution method. Some of them exhibited potent antibacterial activity. The activities of Al, A2, A5, Cl, C4, Dl and D2 against Gram-negative organisms were equivalent to or slightly more potent than those of lomefloxacin and pazufloxacin. More than ten agents including A10, All, Cll and C12 exhibited good activities against Gram-positive organism, which were equivalent to or slightly more potent than those of lomefloxacin, pazufloxacin and vancomycin.The structure-activity relationship showed that the derivatives bearing a cyclopropylaminomethyl at position 7 of fluoroquinolones, such as C4 and D2 provided good activity against G" bacteria. On the other hand, those with a dialkylated aminomethyl (e.g., the piperazinyl methyl group) side chain showed weak activities in this series. Potent inhibitions against Gram-positive organisms were found in the compounds with the W-halophenyl group in the 7-aminomethyl substitutes.