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7 - bit fluoroquinolone derivatives containing a substituted pyrrolidine / piperidine structure fragments Synthesis and antibacterial activity of

Author: GuoXin
Tutor: WangYuCheng；GuoHuiYuan
School: Beijing Union Medical College
Course: Microbial and Biochemical Pharmacy
Keywords: Fluoroquinolone Synthesis Antibacterial
CLC: R96
Type: PhD thesis
Year: 2011
Downloads: 123
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Abstract

Quinolones after nearly 50 years of development, has become a large class of widely used in clinical broad-spectrum, high efficiency, low toxicity of anti-infective chemotherapy drugs. Statistics show that the, quinolones market share of the fastest growing and has become the second largest category after cephalosporin anti-infective chemotherapy drugs. There are more than 20 varieties of clinical application, more than 10 varieties in clinical development. However, with their widespread use, and even abuse, a rapid increase in its drug-resistant, combined with their own there are some drawbacks to transform and modified its structure in order to obtain the more excellent new quinolone antibacterial drugs is still present one of the hot research field. How to maintain the excellent activity against gram-negative bacteria on the basis of activity against gram-positive bacteria (in particular staphylococcus and pneumococcus) is one of nearly ten years of the quinolone field research direction. The gatifloxacin Sand Star trovafloxacin, moxifloxacin, and gemifloxacin approved for marketing in recent years, they have maintained the third-generation quinolone (eg, ofloxacin, ciprofloxacin) against gram-negative The excellent activity of the bacteria, but also significantly improved activity against gram-positive bacteria. However, gatifloxacin withdrawal from the U.S. market due to blood sugar metabolism disorder appears trovafloxacin serious liver toxicity and strict restrictions on the use, moxifloxacin, and gemifloxacin due to patent protection in China for more than 2017 years ago. Can not imitation. Therefore, for our country, the development of effective against gram-positive bacteria, especially to deal with the structure of multi-drug resistant Gram-positive bacteria novel quinolone compounds is imperative. The structure-activity relationship studies have shown that substituents quinolone 7 - bit its antibacterial spectrum antibacterial activity and pharmacokinetics significantly impact only be allowed a larger structural changes position, so the 7 - bit substituents chemical transformation is one of the better new fluoroquinolone antimicrobial drugs. In fact, more than 30 years, the structural modification of such compounds are mainly concentrated in the 7 - bit in recent years, the new listing of outstanding quinolone antibacterial agents) are the substituent chemical transformation (except good enoxacin results. 7 - position of the substituent on the from the initial piperazinyl evolution (mainly against Gram-negative bacteria) to the current aminopyrrolidin-alkyl and amino-piperidinyl (on the basis to maintain the excellent anti-Gram-negative bacteria activity, anti- Gram-positive bacteria activity improved significantly). Particularly worth mentioning is that the third and fourth generation cephalosporin 7 - position substituted group of the most common methoximino fragment primer to the 3 - methylamino-pyrrolidine and the successful development gemifloxacin has a good spectrum of activity and good pharmacokinetic properties, has been widely used for the treatment of systemic infections caused by bacteria (especially respiratory) diseases. In addition, the methyl derivative of gemifloxacin the DW286 its corresponding spiro analogues DW224a, the more resistant Gram positive bacteria, the former has completed Phase I clinical trials, which have reached the Ⅱ clinical The pilot phase. Learn from the successful experience of the three kinds of fluoroquinolone developed, we are trying to take advantage of drug design, \pyrrolidine / piperidine fused to build two new structure and ring systems, i.e. the aminopyrazole with pyrrolidine / piperidine ring system. Wherein the pyrazole ring on the nitrogen atom of the 1 - on this basis, to the introduction of a methyl group or a hydroxyethyl group, or an oxygen atom with its isostere alternative to obtain a number of ring compounds. Be connected to these side chain compounds with common quinolone nucleus, forming a series of 7 - bits contain amino pyrazole / iso ah azole pyrrolidine / piperidine ring fragment fluoroquinolone compounds. In addition, we designed and synthesized a series of 7 - (3 - methyl-3 - amino-4 - methoxyimino pyrrolidine-1 - yl) fluoroquinolone compounds. Hope to screen get more characteristics candidate compounds, and to lay the foundation for further study on the basis of the preliminary evaluation of these new fluoroquinolone antibacterial activity in vitro. This thesis is divided into the following three parts: First, the design and synthesis of the 5 Series 7 - bits containing the aminopyrazole / isoxazole pyrrolidine / piperidine ring fragment fluoroquinolone compounds, and preliminary evaluation of their In vitro antibacterial activity. Found that the target I-4 Table Portugal bacteria Staphylococcus aureus, including MRSA and MRSE including good activity, and the activity of Streptococcus pneumoniae is equivalent to or significantly better than moxifloxacin, gemifloxacin gatifloxacin and levofloxacin, worthy of further evaluation. Second, the design and synthesis of two series of 7 - position containing 1 - hydroxyethyl -5 - aminopyrazole pyrrolidin / piperidine ring fragment fluoroquinolone compound and preliminary evaluation of their in vitro antimicrobial activity. Found that some of the targets of MRSA or MRSE show better activity. Third, the design and synthesis of a series of 7 - (3 - methyl-3 - amino-4 - methoxyimino pyrrolidine-1 - yl) quinolone compounds in vitro antibacterial activity being evaluated. Work by more than three-part study, the paper synthesized 102 compounds, including 76 new compounds have not been reported (62 target compounds). The structure of the new compounds were confirmed by MS, 1H NMR, target compounds is further confirmed by the HRMS. Meanwhile, wherein two 7 - position side chain compound also by single crystal X-ray diffraction analysis to determine their structure. Overall, some of the targets of some Gram-positive bacteria (including resistant strains) shows good in vitro antibacterial activity, but they generally Gram-negative bacteria is less active or even inactive. Nevertheless, the successful completion of these studies and the conclusions drawn therefrom undoubtedly further enrich the quinolone structure - activity relationship, but also of our future in the a new quinolone pharmacy design has important reference value.

7 - bit fluoroquinolone derivatives containing a substituted pyrrolidine / piperidine structure fragments Synthesis and antibacterial activity of

Abstract

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