Design, Synthesis And Biological Activities Of Novel Quinolone Derivatives

Quinolones are among the most common drugs in the anti-infective chemotherapy field.In spite of great advances have been achieved for the development of quinolones in the last 5 decades,the resistance of bacteria to quinolones develops rapidly and spreads widely throughout the world,creating urgent needs to develop new antibacterial agents.Structure-activity relationship studies of quinolones reveal that substituent at the C-7 position of quinolone motif have great influence on their potency,antibacterial spectrum and pharmacokinetic properties,and the C-7 position of quinolones is deemed as the most adaptable site for chemical modification.Further investigations indicated that incensement of molecular mass and bulkiness of substituent at C-7position of quinolone moiety is not a barrier to penetration,and the C-7 basic amines are favored to be connected with various biological pharmacophores.Some early fluoroquinolone agents are presently recommended to be used to treat primarily in cases involving resistance or intolerance to first-line anti-tuberculosis therapy by WHO.It was demonstrated that the lipophilicity of the fluoroquinolones play a pivotal role in the penetration of these compounds into bacterial cells,and simply increasing the lipophilicity character at C-7 position could also boost up the anti-tubercular activity.Moreover,C-8 methoxy fluoroquinolone derivatives with a N1-cyclopropyl substitution have been found to be much more potent than the corresponding 8-hydrogen analogues against drug-resistant mycobacterium tuberculosis.Moreover,introduction of fluorine atom into the N1-cyclopropyl could increase the antibacterial activity,improve the lipophilicity,change the electrostatic interaction,and consequently reduce the toxicity on central nervous system and human cells.Inspired by the above research results and as a continuous program to seek for new fluoroquinolone anti-tubercular and antibacterial candidates,three series of8-OMe fluoroquinolone?including 8-OMe ciprofloxacin,gatifloxacin and moxiflox-acin?hybrids conjugated with isatin,hydrazone and 1,2,4-triazole as well as a series of 1-[?1R,2S?-2-fluorocyclopropyl]ciprofloxacin-1,2,4-triazole-5?4H?-thione hybrids were designed,synthesized and screened for their in vitro anti-mycobacterial and antibacterial activities as well as cytotoxicity in this study.The research of this dissertation could be divided into the following four chapters:Firstly,a series of ethylene-1H-1,2,3-triazole-4-methylene tethered gatifloxacin hybrids were designed,synthesized and evaluated in vitro anti-mycobacterial activity against MTB H37Rv and MDR-TB strains as well as cytotoxicity.The results indicated that the hybrids I-11 and I-16 were 8 and 4 folds more active than gatifloxacin against MTB H37Rv and MDR-TB strains,the synthesized hybrids were much more toxic than the parent gatifloxacin,so further investigation should focus on reducing the cytotoxicity,worth to be further investigated.Secondly,a set of moxifloxacin-isatin hybrids tethered with ethylene or more flexible propylene-1H-1,2,3-triazole-4-methylene linker was screened for their in vitro anti-mycobacterial activity against MTB H37Rv and MDR-TB strains as well as cytotoxicity based on the above results.All hybrids displayed considerable activity,and the SAR demonstrated that the ethylene tethered hybrids were more potent than the corresponding propylene linked analogs.Among them,the most active moxifloxacin hybrid II-3 was 2->2,048 times more potent than moxifloxacin,isoniazid and rifampicin against the tested two strains,could act as a lead for further optimization.Thirdly,a new class of 8-OMe ciprofloxacin-hydrazone/azole hybrids was designed,synthesized and evaluated in vitro anti-tubercular and antibacterial activities.All conjugates displayed potential activity,and the anti-tubercular activity of hybrids III-3,III-11 and III-12¹6 was higher than moxifloxacin and isoniazid.The majority of the hybrids were comparable to ciprofloxacin and levofloxacin against the tested Gram-positive and Gram-negative pathogens,and the most active conjugate III-11was 8 and 2 folds more potent than the two references against Stenotrophomonas maltophilia,warrant further investigation.Finally,a series of 1-[?1R,2S?-2-Fluorocyclopropyl]ciprofloxacin-1,2,4-triazole-5?4H?-thione hybrids bearing various substituent at C-3 and N-4 positions of 1,2,4-triazole-5?4H?-thione motif were designed,synthesized and assessed for their in vitro antibacterial activities.The preliminary results indicated that all hybrids endowed with excellent activity against the tested Gram-positive and Gram-negative bacteria.Hereinto,the hybrid IV-16 was found to be most active against the majority of the tested strains with MIC in a range of?0.05⁶.47?M,which was comparable to levofloxacin and ciprofloxacin,more potent than 1-[?1R,2S?-2-fluorocyclopropyl]ciprofloxacin,8-methoxy-ciprofloxacin and vancomycin,suggesting its potential for development of novel anti-bacterial agents.In this doctoral dissertation,249 compounds were synthesized,126?including 88target compounds?of which have been not reported in the literature yet.Their structures were characterized by MS and ¹H NMR spectra,and some targets were further confirmed by ¹³C NMR spectra.