Synthesis And Antibacterial Activity Of Novel C-12 Pyrazolinyl Spiro Ketolides

Erythromycin is used for the treatment of upper and lower respiratory tract infections caused by gram-positive bacteria for more than five decades. However, with the extensive use of antibiotics, the increasing emergence of macro lide-resistant bacteria is becoming a big threat to the health of human being. To develop novel chemical entities which possess excellent activities against drug-resistant bacteria is becoming an important goal for researchers.The discovery of ketolide, in which C-3 cladinosyl is replaced by a keto group, was considered to be the breakthrough for the resistant bacteria problem. Telithromycin, which is the representative of ketolides, has come into market in 2001. It shows very good activity against some macrolide-resistant bacteria. Another ketolide, Cethromycin (ABT-773) also reached Phase III clinical trials in the US.Based on literatures study and biological isostere principle, novel ketolides were designed by replacing C-11,12 carbamate rings of telithromycin and cethromycin with C-12 pyrazolinyl rings. Then different side chains were introduced to ketolides. Compounds with good antibacterial activities were expected to obtain via those chemical modifications.In this thesis, clarithromycin was chosen as starting material. The first step was to protect 2',4"-dihydroxyl groups, and then C-9 ketone was reduced to hydroxyl group by sodium borohydride.2,2-dimethoxy-propane was applied to protect 9,11-dihydroxyl groups as acetonide. A C-12,21 double bond was resulted from dehydration of C-12 hydroxyl group with thionyl chloride in the fourth step. In the next 2 steps, C-3 cladinose was hydrolyzed and C-9, C-11 hydroxyl groups were converted to dimethylketal group again. Under reaction conditions, Oxidation of C-3 hydroxyl formed a C-12,21 exocyclic alkenyl ketolide derivative 7. In route one, C-12,21 exocyclic double bonds were attacked by different diazo compounds via [2+3] cycloaddition to form pyrazolinyl spiros with different substituent groups. After removing C-9 and C-11 protecting groups, C-9 hydroxy groups were selectively oxidized, and the final compounds were obtained after removing the C-2'protecting groups; In route two, C-9 hydroxy group of compound 8a from route one was selectively formylated, and then different aldehydes were introduced to the C-9 amide group to form another series of final compounds.Eight target compounds and total 24 new compounds were synthesized, and all the structures of these new target compounds were confirmed by MS,1H NMR, 13C NMR and HRMS. In vitro antibacterial activity of the target compounds was determined by using the tube dilution method. Among those compounds, the final products of route 1, which possessing different substituens on pyrazolinyl spiros, had better antibacterial activity against both macrolide-suscepible and macro lide-resistant bacteria than enthromycin A and clarithromycin. The antibacterial activities of compounds in series 2 were equal to or lower than those of enthromycin A and clarithromycin.