.7 - Different Amine Substituted Quinolones Synthesis And Antibacterial Activity

Quinolone antibacterial agents have emerged as one of the dominant classes of chemotherapeutic drugs for the treatment of various bacterial infections because of their broad-spectrum potency and low toxicity.However,most of the quinolones currently on the market or under development have only moderate activity against many Gram-positive pathogens,Anaerobion,Mycoplasma and Chlamydia,and some of them damage cartilague of immature animals.Hence,it is imminent to find novel quinolones with high antibacterial activities and low toxicities.In 1998,Fujita et al.reported that 2-aminomethylazetidine quinolones showed more active antibacterial activities than sparfloxacin in vitro and compared the antibacterial activities of 2-aminomethylazetidine,2-aminomethylpyrrolidine, 2-aminomethylpiperidine quinolones and found the order of their antibacterial activity: 2-amino-methylazetidine quinolones＞2-aminomethylpyrrolidine quinolones＞2-amino methylpiperidine quinolones.Hence,we designed and synthesized a series of novel fluoroquinolones containing 2-aminomethylaziridine as the C-7 side chain.In 2001,Lawrence et al.reported BMS-284756(garenoxacin) was 4-8 times more active than its C-8 methoxy analogue compound BMS-433366 against Gram-negative and Gram-positive isolates.In 2006,Liu et al.reported replacement of the C-8 methyl ether linkage of moxifloxacin with a difluoromethoxy group increased or maintained antibacterial activity in vitro and in vivo.And 7-pyrrolidine-substituted quinolone gemifloxacin possessed potent antibacterial activity against both Gram-positive and Gram-negative organisms including methicillin resistant Staphylococcus aureus(MRSA).Hence,we designed and synthesized a series of the C-8 difluoromethoxylated counterparts to gemifloxacin and its analogues.In 1997,Hong et al.reported 4-aminomethyl-3-methoxyiminopyrrolidine quinolone gemifloxacin possessed potent antibacterial activity against both Gram-positive and Gram-negative organisms.In 1995,Nakane et al.reported 3-methylamino-1-piperidine quinolone balofloxacin had excellent antibacterial activities against Gram-positive organisms.Hence we introduced methylaminomethyl and methoxyimino groups into C-3 and C-4 position of the piperidine ring,designed and synthesized a series of fluoroquinolones containing 3-methyaminomethyl-4-methoxyiminopiperidine as the C-7 side chain.Their antibacterial activities in vitro were tested.We also developed a cost-effective process for the practical and scalable synthesis of(R,S)-2-amino-1-propanol,the key intermediate for the synthesis of Ofloxacin.The synthetic pathway comprises an effective three-step synthesis including alkylation,hydrolysis and amination.This process was accomplished efficiently to produce(R,S)-2-amino-1-propanol in 43.9%overall yield.In the doctoral dissertation,totally three series of novel quinolone analogues and 97 compounds bad been synthesized,62 of them were novel(including 17 objective compounds).Their structures were established by MS(ESI-MS and HRMS) and ~1H NMR spectra.All objective compounds were evaluated for their in vitro antibacterial activities against a variety of Gram-positive and Gram-negative bacteria.The results showed that a series of quinolone analogues which contained 2-aminomethylaziridine on the C-7 position displayed less antibacterial activity against 30 strains of bacteria(including 19 Gram-positive strains and 11 Gram-negative strains) using ciprofloxacin,levofloxacin and pazufloxacin as control.We analysized the possible reasons for their low activities and discussed their structure-activity relationships.Six compounds of 7-[4-(aminomethyl)-3-(methoxyimino)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-difluoromethoxy-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid and its analogues were less active than gemifloxacin and levofloxacin against 24 strains of bacteria(including 12 Gram-positive strains and 12 Gram-negative strains).And a series of quinolone analogues which contained 3-methyaminomethyl -4-rnethoxyiminopiperidine on the C-7 position displayed comparable activity against 19 strains Gram-positive organisms using ciprofloxacin and levofloxacin as control, but their antibacterial activity against Gram-negative organisms was far less than ciprofloxacin or levofloxacin.We used Hypo Gen software to predict their activities against S.aureus ATCC29213.The activities predicted by Hypo Gen corresponded to real activities of these series of target compounds.Although these three series of target compounds had only moderate or low activities against both Gram-positive and Gram-negative organisms and were not intended for more research,our research for them helped establish some new structure-activity relationships about the quinolones.The process for the synthesis of (R,S)-2-amino-1-propanol was practical,cost-effective,scalable and helped to decrease the cost for the production of ofloxacin,an important active pharmaceutical ingredient.