Design And Synthesis Of Fluorinated Modification Based On Erythromycin And The Activity

Erythromycin is the first macrolide antibiotic which is found by human, mainly used for the treatment of a variety of infections of Gram-positive bacteria. However, it is easy for erythromycin to take place intramolecular dehydration reaction and degrade into inactive byproducts under acidic conditions, the direct result is the decreasing of bioavailability and produce gastrointestinal irritation. Compared to erythromycin, flurithromycin improved pharmacokinetic properties, prolonged biological half-life, acid stability, but flurithromycin antibacterial activity does not improve.Based on the characteristic of the high bioavailability, a long half-life period, the good stability of flurithromycin, we take two methods to modify the structure of flurithromycin in order to enhance the antibacterial ability and reduce resistance. The two strategies are as follows:1) To esterify the C-3 hydroxyl group of flurithromycin replacing the cladinosy;2) To modify the hydroxyl groups of C-11,12 in flurithromycin into cyclic carbonate.The work divided into the following four parts:(1) In order to improve the antibacterial activity, reducing its resistance, we designed 11 target compounds G1-11 on the basis of flurithromycin.(2) Flurithromycin starting from erythromycin was prepared in one-step reaction and the structure was confirmed by 1H-NMR,13C-NMR,HR-ESI-MS and IR spectra. The purity was determined by HPLC method.(3) Removing C-3 cladinosy, plusing C-2’ protective group, C-11、12 becoming a cyclic carbonate, esterifying the hydroxyl group of C-3, deleting the C-2’ protective group on the basis of flurithromycin we successfully got the target products G1-11. Part of the intermediates and target products were identified by 1H-NMR,HR-ESI-MS and IR. The purity was determined by HPLC method.(4) The antibactera activities for three intermediates 3,6 and 11 target products against B. subtilis 168, S. aureus USA300, E. coli DH5 a, P. aerμginosa PAO1, A. baumannii ATCC19606 were detected, and the results showed that compounds G1-11 had a antibacterial activity, especially for B subtilis 168. The compound G1 and G2 had a higher activity.