Renslo Adam R, Jaishankar Priyadarshini, Venkatachalam Revathy, Hackbarth Corinne, Lopez Sara, Patel Dinesh V, Gordeev Mikhail F
Discovery Research, Vicuron Pharmaceuticals, 34790 Ardentech Ct, Fremont, California 94555, USA.
J Med Chem. 2005 Jul 28;48(15):5009-24. doi: 10.1021/jm058204j.
The oxazolidinones are a new class of synthetic antibacterials effective against a broad range of pathogenic Gram-positive bacteria, including multi-drug-resistant strains. Linezolid is the first drug from this class to reach the market and has become an important new option for the treatment of serious infections, particularly those caused by methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enteroccocus faecium (VRE). In the search for novel oxazolidinones with improved potency and spectrum, we have prepared and evaluated the antibacterial properties of conformationally constrained analogues in which the morpholine ring of linezolid is replaced with various substituted azabicyclo[3.1.0]hexyl ring systems. Several classes of azabicyclic analogues were identified with activity comparable or superior to that of linezolid. These include analogues bearing hydroxyl, amino, amido, or carboxyl groups on the azabicyclic ring. The azabicyclic acid analogue 50 was 4 times more potent than linezolid against key Gram-positive and fastidious Gram-negative pathogens (S. aureus, Streptococcus pneumoniae, and E. faecalis MICs < or = 1 microg/mL; Haemophilus influenzae MIC = 4 microg/mL).
恶唑烷酮类是一类新型合成抗菌药物，对多种致病性革兰氏阳性菌有效，包括多重耐药菌株。利奈唑胺是该类药物中首个上市的药物，已成为治疗严重感染的重要新选择，尤其是由耐甲氧西林金黄色葡萄球菌（MRSA）和耐万古霉素粪肠球菌（VRE）引起的感染。为了寻找效力和抗菌谱更佳的新型恶唑烷酮类药物，我们制备并评估了构象受限类似物的抗菌性能，其中利奈唑胺的吗啉环被各种取代的氮杂双环[3.1.0]己基环系统所取代。已鉴定出几类氮杂双环类似物，其活性与利奈唑胺相当或优于利奈唑胺。这些包括在氮杂双环上带有羟基、氨基、酰胺基或羧基的类似物。氮杂双环酸类似物50对关键革兰氏阳性菌和苛求革兰氏阴性菌病原体（金黄色葡萄球菌、肺炎链球菌和粪肠球菌的MIC≤1μg/mL；流感嗜血杆菌的MIC = 4μg/mL）的效力比利奈唑胺高4倍。
