Kirchhoffer Olivier Auguste, Nitschke Jahn, Luscher Alexandre, Nothias Louis-Félix, Marcourt Laurence, Hanna Nabil, Grondin Antonio, Köhler Thilo, Ferreira Queiroz Emerson, Soldati Thierry, Wolfender Jean-Luc
Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, CMU, Geneva 1211, Switzerland.
School of Pharmaceutical Sciences, University of Geneva, CMU, Geneva 1211, Switzerland.
ACS Bio Med Chem Au. 2025 Jun 9;5(4):650-664. doi: 10.1021/acsbiomedchemau.5c00052. eCollection 2025 Aug 20.
The present study investigates the potential anti-infective and antibacterial properties of phenylalkyl acetophenones and anacardic acids isolated from the ethyl acetate extract of the leaves of Knema oblongifolia, along with synthetic derivatives that were generated. As antibiotic resistance grows, the discovery of new anti-infective agents becomes crucial. The study utilizes a phenotypic screening approach, employing a 3R infection model with (Mm) and (Dd) as proxies for and human macrophages. This model helps to distinguish between general antibiotics and specific anti-infectives that inhibit bacterial growth inside host cells. A previous screening carried out on a collection of 1600 plant natural extracts revealed as a significant source of anti-infective compounds. The ethyl acetate extract of this plant exhibited a strong inhibition of Mm intracellular growth in the infection model while minimally affecting bacterial growth in broth. HPLC bioactivity profiling of this extract based on a high-resolution microfractionation strategy uncovered that the activity was associated with different LC-peaks spread over the chromatogram. LC-MS-based metabolite profiling of the extract revealed that they shared common substructural elements. Based on such information, fractionation of the extract at a larger scale led to the isolation of 12 bioactive natural products (NPs): four newly described acetophenone NPs and eight salicylic acid derivatives (three of which were new). These NPs were further tested for their activities against Mm (antibacterial and anti-infective), , and . Additionally, the study involved de novo synthesis of derivatives based on the backbones of the isolated acetophenones to enhance their bioactivity. Hemisynthesis on one of the isolated natural acetophenone was also carried out and resulted in an increase in potency but no increase in selectivity toward the inhibition of Mm intracellular growth. Overall, biological activity assessments revealed that some of the synthetic analogues generated were better candidates in terms of both selectivity and potency, with an improved activity profile compared to natural analogues. The best synthetic candidate reached an IC of 0.59 μM for the inhibition of intracellular bacterial growth during infection (anti-infective activity).
本研究调查了从长圆叶红光树叶片的乙酸乙酯提取物中分离出的苯烷基苯乙酮和漆树酸以及合成衍生物的潜在抗感染和抗菌特性。随着抗生素耐药性的增加，发现新的抗感染药物变得至关重要。该研究采用表型筛选方法，使用以（Mm）和（Dd）作为人类巨噬细胞替代物的3R感染模型。该模型有助于区分抑制宿主细胞内细菌生长的普通抗生素和特定抗感染药物。先前对1600种植物天然提取物进行的筛选显示，该植物是抗感染化合物的重要来源。该植物的乙酸乙酯提取物在感染模型中对Mm细胞内生长有强烈抑制作用，而对肉汤中细菌生长的影响最小。基于高分辨率微量分级策略对该提取物进行的HPLC生物活性分析发现，活性与色谱图上不同的液相色谱峰相关。基于液相色谱-质谱联用的提取物代谢物分析表明，它们具有共同的亚结构元素。基于这些信息，对提取物进行更大规模的分级分离，得到了12种生物活性天然产物（NPs）：四种新描述的苯乙酮NPs和八种水杨酸衍生物（其中三种是新的）。进一步测试了这些NPs对Mm（抗菌和抗感染）、和的活性。此外，该研究还基于分离出的苯乙酮骨架进行了衍生物的从头合成，以增强其生物活性。还对其中一种分离出的天然苯乙酮进行了半合成，结果提高了效力，但对抑制Mm细胞内生长的选择性没有增加。总体而言，生物活性评估表明，所生成的一些合成类似物在选择性和效力方面都是更好的候选物，与天然类似物相比，活性谱有所改善。最佳合成候选物在感染期间抑制细胞内细菌生长（抗感染活性）的IC为0.59μM。
