获得具有潜在抗菌活性的取代苯酚衍生物

V. A. Sokhraneva, D. A. Yusupova, V. S. Boriskin, N. V. Groza
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引用次数: 1

摘要

目标。随着病原微生物对抗生素的耐药性日益增强,开发具有特定作用机制的新型抗菌药物成为一项紧迫的任务。只有少数抗菌剂对革兰氏阳性和革兰氏阴性细菌、霉菌和酵母具有广泛的活性。在这方面,本工作的目的是建立烷基取代酚的生物活性衍生物的合成方法(在羟基上的反应),以研究其生物效应。以取代酚为原料,分两步合成咪唑乙酸酯。在第一阶段,得到所选化合物的氯乙酰衍生物,然后加入咪唑。合成第一阶段的o -酰化反应在不同条件下进行。第一个版本的合成是使用氯乙酰氯作为酰化剂与高沸点溶剂一起进行的。在第二种变体中,使用氯乙酸酐,并尝试用低沸点的溶剂代替溶剂。以碘化甲酯为原料,改变反应参数,用已知方法合成了百里香酚甲氧基衍生物。通过合理选择溶剂和试剂配比,优化了芳香醇氯乙酰化和甲氧基化反应的工艺参数。合成了含有咪唑的百里酚(2-异丙基-5-甲基酚)和异丙酚(2,6-异丙基酚)衍生物,作为附加药效团,对微生物细胞膜蛋白具有亲和力。还得到了包含芳香醚的百里酚甲氧基衍生物,其疏水性增强。合成的化合物经核磁共振波谱表征。通过使用过量的酰化剂冷却反应混合物并增加反应时间(与文献数据相比),可以有效地合成芳香醇氯乙酰基衍生物。百里酚氯乙酸得率为75%,异丙酚氯乙酸得率为30%。这可以解释为异丙醇基团的空间阻碍反应,它在苯环的第2和第6位有异丙基取代基。
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Obtaining substituted phenol derivatives with potential antimicrobial activity
Objectives. With the growing resistance of pathogenic microorganisms to antibiotics, the development of new antimicrobial drugs offering specific mechanisms of action becomes an urgent task. Only few antimicrobials offer a broad spectrum of activity against gram-positive and gram-negative bacteria, molds, and yeasts. In this regard, the purpose of the work was to develop methods for synthesizing biologically active derivatives of alkyl-substituted phenols (reactions at the hydroxy group) to study their biological effect.Methods. The synthesis of imidazole acetates of substituted phenols was carried out in two stages. At the first stage, the chloroacetyl derivative of the selected compounds was obtained, to which imidazole was then added. O-acylation reactions at the first stage of the synthesis were carried out under varying conditions. The first version of the synthesis was carried out using chloroacetyl chloride as an acylating agent together with a high-boiling solvent. In the second variant, chloroacetic anhydride was used, along with an attempt to replace the solvent with a low-boiling one. A thymol methoxy derivative was additionally synthesized by a known method using methyl iodide and varying the reaction parameters.Results. The parameters of chloroacetylation and methoxylation of aromatic alcohols were optimized with rational selection of solvents and the ratio of reagents in the reactions. Synthesized thymol (2-isopropyl-5-methylphenol) and propofol (2,6-isopropylphenol) derivatives contained imidazole as an additional pharmacophore with affinity for microorganism cell membrane proteins. A thymol methoxy derivative comprising an aromatic ether exhibiting increased hydrophobicity was also obtained. The synthesized compounds were characterized by NMR spectroscopy.Conclusions. Chloroacetyl derivatives of aromatic alcohols can be effectively synthesized by cooling the reaction mixture using an excess quantity of an acylating agent and increasing the reaction time (compared to literature data). The yield of thymol chloroacetate was 75%, while that of propofol chloroacetate was 30%. This can be explained by the sterically hindered reaction of the propofol alcohol group, which has isopropyl substituents at the second and sixth positions of the benzene ring.
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