Design,synthesis And Antibacterial Activity Of The Novel Ketolide Antibiotic Based On Clarithromycin

Macrolide antibiotics are broad spectrum amtimicrobial agents, they have been widely used in clinic for their less side effects and low prices. Due to the abuse of antibiotics, bacterial resistance and super resistant bacteria have become particularly severe in recent years. Ketolides were developed as the third generation of macrolides for the problem of bacterial resistance, and telithromycin is the only one of ketolides used in clinic until now. However, the hepatotoxicity of telithromycin has be found in the IV clincial study that limits its clinical use, and the development of ketolides has now focused on the improvement of toxicity with significant antibacterial effects. Based on the SAR of macrolides, a series of novel ketolides were designed and synthesized in the thesis. The main researches are included as follows:(1) Based on telithromycin, homologues and bioisostere were used to modifying the 11, 12 side chain, foucused on the substituent group of N atoms. 15 compounds SJ1-15 were designed in order to investigate the preliminary SAR on the modification of the side chain by the antibacterial activity test. The modification included the change of the length and the terminal group(fat heterocyclic, aromatic ring, aromatic heterocyclic, etc.) of the side chain, besides the introduction of O or N in to the side chain;(2) By two 6-steps routes, the key intermediate 3-O-descladinosyl-3-oxo-10, 11-didehrdro-11-deoxy-12-(1H-1-imidazoylcarbonyl)-2’-benzoyl-clarithromycin(2) was obtained from clarithromycin by protection, acid hydrolysis, oxidation, etc. In route one, C-11 and C-12 hydroxyl groups of clarithromycin were protected with cyclic carbonate after the hydrolysis of C-3 cladinose, then the C-3 hydroxyl groups was oxidized by NCS and Me2 S. In route two, C-3 hydroxyl group was oxidized directly without the protection of C-11 and C-12 hydroxyl group. In comparison, the oxidation reaction in route one behaved high yield with little by-products, and route one has been proved to be much suitable in reaction time, reaction treatment and yield;(3) After the nucleophilic addition of 2 with various amines, the target compounds SJ1-15 were obtained by the deprotection of C-2’-hydroxyl. The structures of compounds SJ1-15 were identified by 1H-NMR, HR-ESI-MS, and IR;(4) Clarithromycin and erythromycin A as reference drugs, some intermediates and the target compounds were tested for antibacterial activities against B. subtilis 168, S. aureus USA300, E. coli DH5α, P. aeruginosa PAO1 and A. baumannii ATCC19606 in vitro by the double dilution method. The results showed that compounds SJ4, SJ5, SJ6 had better antibacterial activities than others;(5) A clarithromycin monohydrate crystal was observed. The crystal was determined by X- ray single crystal diffraction, and the structure was characterized by 1H-NMR, HR-ESI-MS, and IR.