7 - (Substituted Pyrrolidinyl) Synthesis And Antibacterial Activity Of Quinolone Compounds

The quinolone antibiotics have emerged as a significant class of chemothereapeutic agents. Especially, with fluorin atom at the C-6 position, with piperazine and its derivatives at the C-7 position on quinolone nucleus showed potent and broad-spectrum antibacterial activities. But these compounds have disadvantages of lower antibacterial activity against some strains (such as Streptococcus pneumonias, Pseudomonas aeruginosa, Mycoplasma and Chlamydia ), and some of them damage cartilague of immature animals. To find novel quinolones with high antibacterial activities and low toxicities is still one of hotspots at present.According to QSAR, the substituted groups at C-7 influence antibacterial spectrum , antibacterial activities and pharmacokinetic properties of quinolones. Comparing with piperazinyl analogs, introducing pyrrolidine derivatives to flouroquinolones resulted in a great improvement of Gram-positive bacteria, we have designed and synthesized a series of novel fluoroquinolones containing 7-(methyl) aminomethyl-5-azaspiro [2,4] heptane as side chains at the C-7 position. Their antibacterial activities in vitro were teseted.In order to consummate the QSAR, we have designed and synthesized another series of novel fluoroquinolones containing 4,4-dimethyl-3-(methyl) aminomethylpyrrolidine as side chains at the C-7 position and tested their antibacterial activities in vitro.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 two series of quinolone analogues possess potent antimicrobial activities against both Gram-negative and Gram-postive organism.Among these quinolone analogues with 7-(methyl) aminomethyl -5-azaspiro[2, 4] heptane side chains, the MIC values of compounds A-29,A-32,A-33 for 10 strains of Gram-positive bacteria were 0.01μg·mL^-1～0.12μg·mL^-1, which exhibited more potential activities than reference agents gatifloxacin (0.12μg·mL^-1～1μg·mL^-1) and ciprofloxacin (0.25μg·mL^-1～4μg·mL^-1). The MIC values of them for 10 strains Gram-negative bacteria were 0.01μg·mL^-1～2μg·mL^-1, which exhibited equal activities to reference agents.Among these quinolone analogues with 4, 4-dimethyl-3-(methyl) aminomethylpyrrolidine side chains, the MIC values of compound B-29,B-31 for 4 strains of Gram-positive quinolone-resistant bacteria (two strains of MRSA and two of MRSE) were 0.015μg·mL^-1～2μg·mL^-1, which exhibited more potential activities than reference agents gatifloxacin and ciprofloxacin (0.06μg·mL^-1～16μg·mL^-1).In this doctoral dissertation, totally two series of novel quinolone analgues and 80 compounds had been synthesized, 65 of them were novel compounds (including 21 objective compounds). Their structures were established by MS and ¹H NMR spectra.