Synthesis and biological evaluation of enantiomerically pure glyceric acid derivatives as LpxC inhibitors.
Synthesis and biological evaluation of enantiomerically pure glyceric acid derivatives as LpxC inhibitors.
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DOI：
10.1016/j.bmc.2016.01.029
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发表时间：
2016-03
影响因子：
3.5
通讯作者：
Giovanni Tangherlini;T. Torregrossa;Oriana Agoglitta;Jens Köhler;Jelena Melesina;W. Sippl;Ralph Holl
中科院分区：
文献类型：
--
作者：
Giovanni Tangherlini;T. Torregrossa;Oriana Agoglitta;Jens Köhler;Jelena Melesina;W. Sippl;Ralph Holl
UDP-3-O-[（R）-3-羟基肉豆蔻酰基]-N-乙酰葡糖胺脱乙酰基酶（LpxC）的抑制剂代表一类有前途的新型抗生素，选择性地对抗革兰氏阴性菌。为了阐明二醇（S，S）-4的羟甲基对LpxC抑制活性的影响，合成了在苄基位置缺少羟甲基的甘油酸醚（R）-7a、（S）-7a、（R）-7b和（S）-7b。通过手性池合成和脂肪酶催化的对映体选择性去对称化反应，分别得到了对映体纯的化合物。对映体异羟肟酸（R）-7b（Ki= 230 nM）和（S）-7b（Ki= 390 nM）显示出有希望的酶抑制作用。然而，它们的抑制活性彼此之间没有实质性差异，导致低优生比。一般来说，合成的甘油酸衍生物7显示对两种大肠杆菌菌株的抗菌活性超过其各自的区域异构体6。
Inhibitors of the UDP-3-O-[(R)-3-hydroxymyristoyl]-N-acetylglucosamine deacetylase (LpxC) represent a promising class of novel antibiotics, selectively combating Gram-negative bacteria. In order to elucidate the impact of the hydroxymethyl groups of diol (S,S)-4on the inhibitory activity against LpxC, glyceric acid ethers (R)-7a, (S)-7a, (R)-7b, and (S)-7b, lacking the hydroxymethyl group in benzylic position, were synthesized. The compounds were obtained in enantiomerically pure form by a chiral pool synthesis and a lipase-catalyzed enantioselective desymmetrization, respectively. The enantiomeric hydroxamic acids (R)-7b(Ki= 230 nM) and (S)-7b(Ki= 390 nM) show promising enzyme inhibition. However, their inhibitory activities do not substantially differ from each other leading to a low eudismic ratio. Generally, the synthesized glyceric acid derivatives7show antibacterial activities against twoEscherichia colistrains exceeding the ones of their respective regioisomes6.