Department of Chemistry, Illinois State University, Normal, IL, USA.
Chem Biol Drug Des. 2021 Aug;98(2):295-304. doi: 10.1111/cbdd.13903. Epub 2021 Jun 21.
The natural products, anaephenes A (1) and B (2), were found to have antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA). In this report, we expanded on our previous synthetic efforts by preparing a library of eighteen analogues in order to understand the structure-activity relationships (SAR) of this interesting class of natural products. These analogues were selected to explore the biological impact of structural variations in the alkyl chain and on the phenol moiety. Last, we further assessed the biological activity of anaephene B (2) and two additional analogues against other clinically relevant bacterial strains and the hemolytic activity of each and determined that these compounds act via a bactericidal mechanism. These studies led to the identification of compound 7, which was 4-fold more potent than the natural product (2) against MRSA (2 vs. 8 μg/ml) and a 2-hydroxypyridine analogue (18) which demonstrated equal potency compared with the natural product (2), albeit with a significant reduction in hemolytic activity (<1% vs. 80% at 100 μM).
天然产物 anaephenes A（1）和 B（2）被发现对耐甲氧西林金黄色葡萄球菌（MRSA）具有抗菌活性。在本报告中，我们扩展了之前的合成工作，制备了十八个类似物文库，以了解这一类有趣的天然产物的结构-活性关系（SAR）。这些类似物的选择是为了探索烷基链和酚部分结构变化对生物的影响。最后，我们进一步评估了 anaephene B（2）和另外两个类似物对其他临床相关细菌株的生物活性和每种化合物的溶血活性，并确定这些化合物通过杀菌机制起作用。这些研究确定了化合物 7，其对 MRSA 的活性（2 对 8μg/ml）比天然产物（2）高 4 倍，并且 2-羟基吡啶类似物（18）与天然产物（2）具有同等的效力，尽管溶血活性显著降低（<1%对 100μM 时为 80%）。
