Obtaining substituted phenol derivatives with potential antimicrobial activity

• Published in: Tonkie himičeskie tehnologii (Online) Vol. 17; no. 3; pp. 210 - 230
• Main Authors: Sokhraneva, V. A., Yusupova, D. A., Boriskin, V. S., Groza, N. V.
• Format: Journal Article
• Language: English; Russian
• Published: MIREA - Russian Technological University 31.07.2022
• Subjects: alkyl-substituted phenols; chloroacetate; imidazole; propofol; thymol
• ISSN: 2410-6593; 2686-7575
• DOI: 10.32362/2410-6593-2022-17-3-210-230

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.