Design, synthesis and biological evaluation of potential antibacterial butyrolactones

• Published in: Bioorganic & medicinal chemistry Vol. 24; no. 22; pp. 5823 - 5833
• Main Authors: Sweidan, Alaa, Chollet-Krugler, Marylene, van de Weghe, Pierre, Chokr, Ali, Tomasi, Sophie, Bonnaure-Mallet, Martine, Bousarghin, Latifa
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier 15.11.2016
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Biochemistry & Molecular Biology; Cell Line; Cell Survival - drug effects; Chemical Sciences; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Dose-Response Relationship, Drug; Drug Design; Humans; Lactones - chemical synthesis; Lactones - chemistry; Lactones - pharmacology; Life Sciences & Biomedicine; Macrophages - drug effects; Microbial Sensitivity Tests; Molecular Structure; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; Streptococcus gordonii - drug effects; Structure-Activity Relationship; SURVIVAL; Butyrolactones; STREPTOCOCCUS-GORDONII; ACID; Streptococcus gordonii; Cytotoxicity; Antibacterial; IDENTIFICATION; Lichen; LICHENS; GROWTH; INHIBITOR; EXTRACTS; BIOFILM FORMATION
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2016.09.040

Novel butyrolactone analogues were designed and synthesized based on the known lichen antibacterial compounds, lichesterinic acids (B-10 and B-11), by substituting different functional groups on the butyrolactone ring trying to enhance its activity. All synthesized butyrolactone analogues were evaluated for their in vitro antibacterial activity against Streptococcus gordonii. Among the derivatives, B-12 and B-13 had the lowest MIC of 9.38 mu g/mL where they have shown to be stronger bactericidals, by 2-3 times, than the reference antibiotic, doxycycline. These two compounds were then checked for their cytotoxicity against human gingival epithelial cell lines, Ca9-22, and macrophages, THP-1, by MTT and LDH assays which confirmed their safety against the tested cell lines. A preliminary study of the structure-activity relationships unveiled that the functional groups at the C-4 position had an important influence on the antibacterial activity. An optimum length of the alkyl chain at the C-5 position registered the best antibacterial inhibitory activity however as its length increased the bactericidal effect increased as well. This efficiency was attained by a carboxyl group substitution at the C-4 position indicating the important dual role contributed by these two substituents which might be involved in their mechanism of action. (C) 2016 Elsevier Ltd. All rights reserved.