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
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
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DOI：
10.1021/jm980240d
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发表时间：
1998-10-08
影响因子：
7.3
通讯作者：
Tessot, N
中科院分区：
文献类型：
--
作者：
Agouridas, C;Denis, A;Tessot, N
在寻找对大环内酯耐药肺炎球菌和流感嗜血杆菌有活性的新抗生素的过程中，我们合成了一类新的3-氧代-6-O-甲基红霉素衍生物，即所谓的“酮内酯”。在去除L-克拉定糖（一种长期以来被认为是必需的糖）后，在3位引入酮基官能团。大环内酯骨架的进一步修饰使我们能够获得三个不同系列的9-肟，11，12-氨基甲酸酯和11，12-肼基氨基甲酸酯酮内酯。发现这些化合物对青霉素/红霉素耐药肺炎球菌和MLS（B）耐药的非诱导物非常有效。11，12-取代酮内酯61（HMR 3004）对多重耐药肺炎球菌表现出强效活性，对呼吸道感染中涉及的所有细菌（包括H.流感、卡他支原体、A组链球菌和非典型细菌。此外，HMR 3004在所有主要菌株感染的动物中显示出高治疗活性，无论其耐药表型如何。
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.