School of Pharmacy, Linyi University, Linyi 276000, China.
Curr Med Chem. 2024;31(19):2788-2808. doi: 10.2174/0929867330666230512161856.
A series of novel emodin alcohols were designed and prepared in an effort to overcome the increasing microorganism resistance.
Novel emodin alcohols were prepared from commercial emodin and different nitrogen-containing heterocycles different synthetic strategies, such as O-alkylation and N-alkylation. The antimicrobial activity of synthesized emodin compounds was evaluated by a two-fold serial dilution technique. The interaction of emodin compound 3d with biomolecule was researched using UV-vis spectroscopic method and fluorescence spectroscopy.
Emodin compound 3d containing 2-methyl-5-nitro imidazole ring showed relatively good antimicrobial activity. Notably, it exhibited equivalent activity against in comparison to the reference drug norfloxacin (MIC = 4 μg/mL). The combination of strong active compound 3d with reference drugs showed better antimicrobial activity with less dosage and a broader antimicrobial spectrum than their separate use. Further research displayed that emodin compound 3d could intercalate into DNA to form the 3d-DNA complex, which might correlate with the inhibitory activity. The hydrogen bonds were found between DNA gyrase and strong active compound 3d during the docking research, which were in accordance with the spectral experiment results. The interaction with yeast RNA of compound 3d could also form a complex hydrogen bonds. The hydrogen bonds were found to play a major role in the transportation of emodin compound 3d by human serum albumin (HSA), as confirmed by molecular simulation.
This work provides a promising starting point to optimize the structures of emodin derivatives as potent antimicrobial agents.
为克服日益严重的微生物耐药性，设计并制备了一系列新型大黄素醇类化合物。
采用不同的合成策略，如 O-烷基化和 N-烷基化，从大黄素和不同的含氮杂环化合物制备新型大黄素醇类化合物。采用两倍连续稀释法评价合成大黄素化合物的抗菌活性。采用紫外可见光谱法和荧光光谱法研究大黄素化合物 3d 与生物分子的相互作用。
含 2-甲基-5-硝基咪唑环的大黄素化合物 3d 表现出相对较好的抗菌活性。值得注意的是，它对大肠杆菌的活性与参考药物诺氟沙星相当（MIC=4μg/mL）。与单独使用相比，将活性较强的化合物 3d 与参考药物联合使用，不仅用量较少，而且抗菌谱更广，表现出更好的抗菌活性。进一步研究表明，大黄素化合物 3d 可以嵌入 DNA 形成 3d-DNA 复合物，这可能与抑制活性有关。对接研究发现，DNA 拓扑异构酶和强活性化合物 3d 之间存在氢键，这与光谱实验结果一致。化合物 3d 与酵母 RNA 的相互作用也可以形成氢键复合物。分子模拟证实，氢键在大黄素化合物 3d 通过人血清白蛋白（HSA）的转运中起主要作用。
这项工作为优化大黄素衍生物作为潜在抗菌剂的结构提供了有希望的起点。
