East Tokyo Laboratory, Genesis Research Institute, Inc., 717-86 Futamata, Ichikawa, Chiba, 272-0001, Japan.
Antimicrobial Resistance Research Center, National Institute of Infectious Diseases, 4-2-1 Aobamachi, Higashimurayama, Tokyo, 189-0002, Japan.
Sci Rep. 2022 May 6;12(1):7471. doi: 10.1038/s41598-022-11608-8.
This paper describes the synthesis and evaluation of lead compounds with a new chemical skeleton that is not found in conventional antimicrobial agents. The biologically attractive cyclopentenoid (+)-hygrophorone B, isolated from the fruiting bodies of Hygrophorus abieticola, and its analogues were synthesized in a longer linear sequence of twelve steps, starting from a cyclopentenone derivative. This synthesis involved the following crucial steps: (i) oximation of a ketone to stabilize the requisite aldehyde to install a side chain and (ii) coupling of an aldehyde with a side chain to assemble the desired hygrophorone. Then, the antimicrobial activity of these hygrophorones towards clinically relevant bacterial pathogens was evaluated. The results showed that hygrophorone B and its analogues are especially effective in preventing the proliferation of gram-positive bacteria. In addition, it was found that some structural features such as the presence of the enone moiety as well as the carbon-carbon triple bond on the hydrocarbon chain were pivotal to increase the antimicrobial activity of hygrophorone B. This study is expected to support the development of novel antimicrobial agents by flexibly synthesizing hygrophorone B analogues with a carbon five-membered ring skeleton from the common intermediate.
本文描述了具有新化学骨架的铅化合物的合成与评价，该骨架在传统抗菌剂中未被发现。从 Hygrophorus abieticola 的子实体中分离出的生物活性环戊烯酮 (+)-hygrophorone B 及其类似物，通过十二步的线性序列合成，从环戊烯酮衍生物开始。该合成涉及以下关键步骤：（i）酮的肟化以稳定所需的醛以安装侧链，以及（ii）醛与侧链的偶联以组装所需的 hygrophorone。然后，评估了这些 hygrophorones 对临床相关细菌病原体的抗菌活性。结果表明，hygrophorone B 及其类似物在预防革兰氏阳性菌增殖方面特别有效。此外，还发现一些结构特征，如烯酮部分的存在以及烃链上的碳-碳三键，对增加 hygrophorone B 的抗菌活性至关重要。这项研究有望通过从常见中间体灵活合成具有五元环骨架的 hygrophorone B 类似物，为新型抗菌剂的开发提供支持。
