Chiral pool synthesis and biological evaluation of C-furanosidic and acyclic LpxC inhibitors.
Chiral pool synthesis and biological evaluation of C-furanosidic and acyclic LpxC inhibitors.
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DOI：
10.1016/j.ejmech.2016.01.032
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发表时间：
2016-03
影响因子：
6.7
通讯作者：
H. Müller;V. Gabrielli;Oriana Agoglitta;Ralph Holl
中科院分区：
文献类型：
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作者：
H. Müller;V. Gabrielli;Oriana Agoglitta;Ralph Holl
细菌脱乙酰酶LpxC的抑制剂已成为一类有前途的新型革兰氏阴性选择性抗菌剂。为了寻找新的LpxC抑制剂，在手性池合成中，从d-甘露糖开始，以立体化学纯的形式制备在四氢呋喃环的2和/或5位具有改变的构型的C-呋喃糖苷。此外，四氢呋喃环的3位和4位的取代模式以及2位的亲脂性侧链的结构也不同。最后，通过适当保护的C-糖苷的乙二醇裂解得到相应开链二醇的所有立体异构体。合成的异羟肟酸的生物评价显示，在C-糖苷的情况下，2，5-反式构型通常导致上级的抑制和抗菌活性。导致相应的开链衍生物的构象应变的救济通常引起苄氧基乙酰异羟肟酸的抑制和抗菌活性的增加。其中（S，S）构型的开链衍生物8和8 c的Ki值分别为0.35 μ m和0.23 μm，是这一系列化合物中最有效的LpxC抑制剂。
Inhibitors of the bacterial deacetylase LpxC have emerged as a promising new class of Gram-negative selective antibacterials. In order to find novel LpxC inhibitors, in chiral-pool syntheses starting fromd-mannose,C-furanosides with altered configuration in positions 2 and/or 5 of the tetrahydrofuran ring were prepared in stereochemically pure form. Additionally, the substitution pattern in positions 3 and 4 of the tetrahydrofuran ring as well as the structure of the lipophilic side chain in position 2 were varied. Finally, all stereoisomers of the respective open chain diols were obtained via glycol cleavages of properly protectedC-glycosides.The biological evaluation of the synthesized hydroxamic acids revealed that in case of theC-glycosides, 2,5-trans-configuration generally leads to superior inhibitory and antibacterial activities. The relief of the conformational strain leading to the respective open chain derivatives generally caused an increase in the inhibitory and antibacterial activities of the benzyloxyacetohydroxamic acids. With Ki-values of 0.35 μmand 0.23 μm, the (S,S)-configured open-chain derivatives8band8cwere found to be the most potent LpxC inhibitors of these series of compounds.