Synthesis and antibacterial activity of ketolides (6-O-methyl-3-oxoerythromycin derivatives):: A new class of antibacterials highly potent against macrolide-resistant and -susceptible respiratory pathogens

被引:186
作者
Agouridas, C
Denis, A
Auger, JM
Benedetti, Y
Bonnefoy, A
Bretin, F
Chantot, JF
Dussarat, A
Fromentin, C
D'Ambrières, SG
Lachaud, S
Laurin, P
Le Martret, O
Loyau, V
Tessot, N
机构
[1] Core Res Funct, Med Chem, F-93235 Romainville, France
[2] Hoechst Marion Roussel, Antiinfect Dis Grp, F-93235 Romainville, France
关键词
D O I
10.1021/jm980240d
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
In the search for new antibiotics active against macrolide-resistant pneumococci and Haemophilus influenzae, we synthesized a new class of 3-oxo-6-O-methylerythromycin derivatives, so-called "ketolides". A keto function was introduced in position 3 after removal of L-cladinose, a sugar which has long been thought essential. Further modifications of the macrolactone backbone allowed us to obtain three different series of 9-oxime, 11,12-carbamate, and 11,12-hydrazonocarbamate ketolides. These compounds were found to be very active against penicillin/erythromycin-resistant pneumococci and noninducers of MLS(B) resistance. The 11,12-substituted ketolide 61 (HMR 3004) demonstrated a potent activity against multiresistant pneumococci associated with a well-balanced activity against all bacteria involved in respiratory infections including H. influenzae, Mycoplasma catarrhalis, group A streptococci, and atypical bacteria. In addition HMR 3004 displayed high therapeutic activity in animals infected by all major strains, irrespective of their resistance phenotype.
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收藏
页码:4080 / 4100
页数:21
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