Antimicrobial 1,3,4-trisubstituted-1,2,3-triazolium salts

• Published in: Bioorganic & medicinal chemistry letters 2018-11, Vol.28 (20), p.3320-3323
• Main Authors: Fletcher, James T., Sobczyk, Jill M., Gwazdacz, Sarah C., Blanck, Aaron J.
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibacterial; Antifungal; Antifungal Agents - chemical synthesis; Antifungal Agents - chemistry; Antifungal Agents - pharmacology; Bacillus subtilis - drug effects; Benzylation; Candida albicans - drug effects; Cycloaddition; Enterobacter aerogenes - drug effects; Escherichia coli - drug effects; Hydrophobic and Hydrophilic Interactions; Microbial Sensitivity Tests; Molecular Structure; Organic salt; Saccharomyces cerevisiae - drug effects; Staphylococcus epidermidis - drug effects; Structure-Activity Relationship; Triazoles - chemical synthesis; Triazoles - chemistry; Triazoles - pharmacology
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2018.09.011

[Display omitted] •Aliphatic 1,3,4-trisubstituted-1,2,3-triazolium salts show antimicrobial properties.•Analogs representing selective and broad-spectrum antimicrobial activity identified.•Potency strongly influenced by hydrophobicity; regiochemistry less impactful.•Triazolium salts prepared efficiently using click and benzylation reaction steps. A series of 1,3,4-trisubstituted-1,2,3-triazolium bromide salts were prepared by efficient two-step sequences of azide-alkyne cycloaddition and benzylic substitution. The antimicrobial activity of each triazolium salt and correlating triazole precursor was evaluated using a minimum inhibitory concentration (MIC) assay. MIC activities as low as 1 µM against Gram-positive bacteria, 8 µM against Gram-negative bacteria and 4 µM against fungi were observed for salt analogs, while neutral triazoles were inactive. Analogs representing selective and broad-spectrum antimicrobial activity were each identified. MIC structure-activity relationships observed within this motif indicate that the presence of cationic charge and balance of overall hydrophobicity are strongly impactful, while benzyl vs. aryl substituent identity and variation of substituent regiochemistry are not.