Frlan Rok, Hrast Martina, Gobec Stanislav
The Department of Pharmaceutical Chemistry, University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, 1000 Ljubljana, Slovenia.
ACS Omega. 2023 Aug 25;8(36):33006-33016. doi: 10.1021/acsomega.3c04813. eCollection 2023 Sep 12.
MurA catalyzes the first step of peptidoglycan (PG) biosynthesis and is a validated target for the development of new antimicrobial agents. In this study, a library of 49 plant flavonoids and their synthetic derivatives were evaluated for their inhibitory properties against MurA from. The compounds were tested with and without preincubation and with the addition of DTT to understand the mechanism of inhibition. Thirteen compounds were identified as reversible, time-dependent inhibitors, with inhibition levels ranging from 480 nM to 57 μM, and ampelopsin as the most potent compound. To investigate the major pharmacophore elements responsible for the activity, 2D-QSAR and docking analyzes were performed. The results showed that the catechol moiety and an additional aromatic system were the most important features contributing to the activity of the compounds. However, most of the compounds did not show antibacterial activity against andstrains, suggesting that their inhibitory activity against MurA may not be strong enough to induce antibacterial effects. Nevertheless, our results suggest that flavonoids are a promising starting point to develop new inhibitors of MurA and show great potential for further steps in drug development.
MurA催化肽聚糖（PG）生物合成的第一步，是开发新型抗菌剂的一个经过验证的靶点。在本研究中，评估了49种植物黄酮类化合物及其合成衍生物对MurA的抑制特性。在有和没有预孵育以及添加二硫苏糖醇（DTT）的情况下对这些化合物进行测试，以了解抑制机制。13种化合物被鉴定为可逆的、时间依赖性抑制剂，抑制水平在480 nM至57 μM之间，其中蛇葡萄素是最有效的化合物。为了研究负责活性的主要药效团元素，进行了二维定量构效关系（2D-QSAR）和对接分析。结果表明，儿茶酚部分和另一个芳香体系是对化合物活性起最重要作用的特征。然而，大多数化合物对[具体菌株]没有显示出抗菌活性，这表明它们对MurA的抑制活性可能不足以诱导抗菌效果。尽管如此，我们的结果表明黄酮类化合物是开发MurA新抑制剂的一个有前景的起点，并在药物开发的进一步步骤中显示出巨大潜力。
