Preparation and biological activity of isoperrottetin A and its phosphonium salts derivatives

Bacterial resistance to antibiotics in use represents a critical threat to public health. The treatment of nosocomial, often life-threatening infections is often challenging and requires the search for new antibacterial compounds. In this study a series of phosphonium salts derived from bis(bibenzyl) isoperrottetin A were studied. Bis(bibenzyls) are compounds unique for liverworts. Phosphonium salts were prepared by an eight-step synthesis. The key steps in its preparation were the Ullmann reaction and the Wittig reaction. Ten phosphonium salts were prepared. Isoperrottetin A and its phosphonium salts were tested for antibacterial activity. Some of the compounds exhibit significant biological activity. Most of the prepared derivatives are more potent than the original isoperrottetin A. Compounds were evaluated for the antibacterial activity against selected Gram-positive bacteria such as Staphylococcus aureus, methicillin sensitive and resistant, Enterococcus faecalis and vancomycin sensitive and resistant and Gram-negative bacteria such as Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae. Mycobacterium smegmatis and Mycobacterium marinum belonging to the genus Mycobacterium were also tested. Besides antibacterial activity, the compounds inhibit cell breathing and show cytotoxic activity against melanoma cells, retinal and epithelial cells. The results of antibacterial tests showed that the most effective compound is 5,5',5'',5'''-[1,7(1),4,5(1,3)-tetrabenzenaoctaphane-1³,4⁴,5⁶,8³-tetrayltetrakis(oxy)]tetrakis(5-oxo-P,P,P-triphenylpentane-1-phosphonium) tetrabromide (4P). The values of minimum bactericidal concentration (MBC) against S. aureus methicillin sensitive and resistant and E. faecalis vancomycin sensitive and resistant were < 1 µM. At the same time, the compound does not involve damaging the cell wall, as is known for cationic amphiphilic compounds, and showed favorable safety profiles at MBC values. These findings highlight the potential of compounds found in liverworts as active agents against sensitive and resistant bacterial strains. Chemical modification of bis(bibenzyls) with a phosphonium cation is promising in preparation of potent microbicidal compounds.