Abstract

A series of acylated phloroglucinols and triketones was synthesized and tested for activity against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecalis (VRE) and multi-drug-resistant Mycobacterium tuberculosis (MDR-TB). A tetra-methylated triketone with a C₁₂ side chain was the most active compound (MIC of around 1.0 μg/ml against MRSA) and was shown to stimulate oxygen consumption by resting cell suspensions, suggesting that the primary target was the cytoplasmic membrane.

Graphical abstract

Antibacterial triketones prepared from acylated phloroglucinols showed a range of activities in vitro against MRSA and other drug-resistant bacteria.

Full-size image (19K)

Keywords: Triketone; Phloroglucinol; Stucture–activity relations; Antibacterial; Drug-resistant; Membrane; Lipophilic

Article Outline

1. Introduction

2. Results and discussion

2.1. Syntheses

3. Bioactivity and mode of action

4. Conclusions

5. Experimental

5.1. General experimental procedures

5.2. Acylations

5.2.1. 1-(2,4,6-Trihydroxyphenyl)-1-decanone (13)

5.2.2. 1-(2,4,6-Trihydroxyphenyl)-1-dodecanone (15)

5.2.3. 1-(2,4,6-Trihydroxyphenyl)-1-hexadecanone (17)

5.2.4. 1-(2,4,6-Trihydroxyphenyl)-cyclohexylmethanone (19)

5.2.5. 1-(2,4,6-Trihydroxyphenyl)-3-cyclohexyl-1-propanone (21)

5.2.6. 1-(2,4,6-Trihydroxyphenyl)-2-phenylethanone (23)

5.3. Alkylations

5.3.1. 5-Hydroxy-4-(1-oxodecyl)-2,2,6,6-tetramethyl-4-cyclohexene-1,3-dione (14)

5.3.2. 5-Hydroxy-4-(1-oxododecyl)-2,2,6,6-tetramethyl-4-cyclohexene-1,3-dione (16)

5.3.3. 5-Hydroxy-4-(1-oxohexadecyl)-2,2,6,6-tetramethyl-4-cyclohexene-1,3-dione (18)

5.3.4. 5-Hydroxy-4-(1-oxocyclohexyl)-2,2,6,6-tetramethyl-4-cyclohexene-1,3- dione (20)

5.3.5. 5-Hydroxy-4-(1-oxo-ethylcyclohexyl)-2,2,6,6-tetramethyl-4-cyclohexene-1, 3-dione (22)

5.3.6. 5-Hydroxy-4-(1-oxophenylacetyl)-2,2,6,6-tetramethyl-4-cyclohexene-1,3- dione (24)

5.3.7. 5-Hydroxy-4-(1-oxododecyl)-2,2,6,6-tetraethyl-4-cyclohexene-1,3-dione (25)

5.3.8. 5-Hydroxy-4-(1-oxododecyl)-2,2,6,6-tetrakis(3-methyl-2-butenyl)-4-cyclohexene-1,3-dione (26) and 1-(2,4,6-trihydroxyphenyl)-3-(3-methyl-2-butenyl)-1-dodecanone (28)

5.3.9. 5-Hydroxy-4-(2-methyl-1-oxopropyl)-2,2,6,6-tetrakis(3-methyl-2-butenyl)-4-cyclohexene-1,3-dione (27)

5.3.10. 5-Hydroxy-4-(1-oxododecyl)-2,2,6-trimethyl-6-(3-methyl-2-butenyl)-4- cyclohexene-1,3-dione (29)

5.4. Biological assays

5.4.1. Effect of triketone 16 on oxygen consumption

5.4.2. Effect of triketone 16 on the membrane potential (Δψ)

5.4.3. Effect of triketone 16 on intracellular ATP levels and K⁺

Acknowledgements

References