Synthesis And Antibacterial Activity Of Fluoroquinolone Derivatives .7 - Containing Replaced By Pyrrolidine / Piperidine Structure Fragments

Since the discovery of nalidixic acid by Lesher et al. in 1962, the quinolones have evolved into an important class of antibacterial agents used mainly for the treatment of various bacterial infections because of their broad-spectrum, high potency and low toxicity. After the cephalosporins, the quinolones represent the next most potent class of antimicrobial drugs in clinical and the fastest growing market share as a class of chemotherapeutic drugs. However, the spread and increase of quinolone resistance seem to be inevitable due to wide use and even abuse. Furthermore, these drugs have relatively low antibacterial activity against Gram-positive bacteria, especially MRSA. What's worse, they even have the potential to cause joint cartilage damage in juvenile animals. Therefore, finding novel quinolones that can provide improved Gram-positive antibacterial activity and low toxicity while retaining the good Gram-negative activity of early fluoroquinolones is still a hotspot at present and in the future. Newly marketed trovafloxacin, gatifloxacin, moxifloxacin and gemifloxacin all have greatly enhanced potency against Gram-positive bacteria, while retaining the excellent activity against Gram-negative bacteria. But some side effects of them are unacceptable. For example, gatifloxacin was withdrawn from US market in 2006, due to increased cases of dysglycemia in clinical findings. Similarly, trovafloxacin therapy should be limitedly used concerning its severe hepatotoxicity. In addition, both moxifloxacin and gemifloxacin, which were applied patents of compounds and granted in China, can not be imitated till 2017. So it is imminent for us to develop novel fluorquinolones by changing and modifying their structures as soon as possible.Structure-activity relationship (SAR) studies of quinolone antibacterial agents showed that the basic group at the 7-position is the most adaptable site for chemical change and an area that greatly influences their potency, spectrum and safety. And the most intensive structural variation has been carried out on cycloamines at the 7-position. In general,5-and 6-membered nitrogen heterocycles including piperazinyl, pyrrolidinyl and piperidinyl type side chains have been proven to be the optimal substituents. It is interesting that gemifloxacin, originated from the introduction of a methoxyimino group (the most common structural moiety in the substituents at the 7-position of the third and fourth generation cephalosporins) to 3-methylaminopyrrolidine, is currently used widely in clinical to deal with systemic bacterial infections (especially respiratory) due to its broad-spectrum activity and excellent pharmacokinetic properties. Compared with gemifloxacin, its methyl derivative DW286 (Phase I clinical trial completed) and spirocyclic analogue DW224a (Phaseâ…¡clinical trial undergoing) were found to have better in vitro and in vivo activity against resistant Gram-positive bacteria.Based on "combination principles" used widely in design strategy of new drugs, the 3-aminopyrazole function group at the 3-position of some fourth generation cephalosporins, such as cefoselis, was fused with a pyrrolidine or piperidine to offer fused heterocyclic compounds including 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine,2,4,5,6-tetrahydro-2-methylpyiTolo[3,4-c]pyrazol-3-amine,2-(3-amino-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)ethanol,5,6-dihydro-4H-pyrrolo[3,4-c]isoxazol-3-amine,4,5,6,7-tetrahydro-2-methyl-2H-pyrazolo[4,3-c]pyridin-3-amine,2-(3-amino-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-2-yl)ethanol and 4,5,6,7-tetrahydroisoxazolo [4,3-c]pyridin-3-amine. Novel fluoroquinolone derivatives containing these fused heterocyclic moieties and 3-amino-3-methyl-4-alkyloxyiminopyrrolidinyl group at 7-postion were designed and synthesized. Our primary objective was to optimize the potency of these compounds against Gram-positive and Gram-negative organisms.The research of this dissertation could be divided into three chapters as follows:First, five series of fluoroquinolone derivatives containing fused heterocyclic moieties at the 7-position were designed, synthesized and evaluated for in vitro antibacterial activity against representative Gram-positive and Gram-negative strains. Results revealed that the target compound 1-4 exhibits good potency in inhibiting the growth of Staphylococcus aureus including MRSA, Staphylococcus epidermidis including MRSE and Streptococcus pneumoniae.Second, a series of 7-(3-amino-2-hydroxyethylpyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl) fluoroquinolone derivatives and another series of 7-(3-amino-6,7-dihydro-2-hydroxyethyl-2H-pyrazolo[4,3-c]pyridin-5(4H)-yl)fluoroquinolone derivatives were designed, synthesized and evaluated for in vitro antibacterial activity against representative G+ and G- strains. Results revealed that some of the target compounds exhibit good potency in inhibiting the growth of MRSA and MRSE.Third, a series of 7-(3-amino-4-methoxyimino-3-methylpyrrolidin-l-yl) fluoroquinolones were designed and synthesized. The evaluation for their in vitro antibacterial activity against representative G+ and G- strains is now being carried on.In this dissertation,102 compounds were synthesized,76 (including 62 target compounds) of which have been not reported in the literatures yet. Their structures were established by MS,1HNMR and HRMS spectra. In addition, the structures of two side chain compounds were confirmed based on the single crystal X-ray diffraction experiments. It is worth noting that some of the target compounds exhibit considerable potency in inhibiting the growth of some Gram-positive bacteria including resistant strains, but they are generally less active than reference drugs against Gram-negative strains.