Phenothiazinium photosensitisers VII: novel substituted asymmetric N-benzylphenothiaziniums as photoantimicrobial agents.
The synthesis of asymmetrical analogues of methylene blue, in which one of the dimethylamino groups is replaced by a diethylamino or di-n-propylamino group, and the other by benzylamino or 4-substituted benzylamino, is reported, the substituents being alkyl, alkoxyl or halogen. As expected, because of their longer alkyl chains these diethylamino- and di-n-propylamino derivatives proved to be considerably more lipophilic than the parent compound methylene blue, while maintaining suitable maximum absorption wavelengths and singlet oxygen efficiencies for photoantimicrobial use. Also as expected, in screening tests against Gram-positive and Gram-negative bacteria, the substituted benzylamino derivatives were highly active on illumination, presumably via singlet oxygen damage, and exhibited considerably increased activity against both classes relative to that of the standard, methylene blue. In addition, the more lipophilic derivatives exhibited greater activity against Escherichia coli. This may be due to increased interaction with the lipid-rich outer membrane of this Gram-negative bacterium. DNA binding of the derivatives was also increased, relative to methylene blue, showing large bathochromic shifts (>10nm) on binding typical of strong intercalators.
Wainwright
Mark
M
School of Pharmacy & Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool L3 3AF, United Kingdom. mark_wainwright@hotmail.com
Brandt
Simon D
SD
Smith
Andrew
A
Styles
Andrew
A
Meegan
Katie
K
Loughran
Ciara
C
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004249:DNA Damage; D006090:Gram-Negative Bacteria / Q000187:drug effects / Q000528:radiation effects; D006094:Gram-Positive Bacteria / Q000187:drug effects / Q000528:radiation effects; D008751:Methylene Blue / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D017319:Photosensitizing Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D026082:Singlet Oxygen / Q000378:metabolism
D000900:Anti-Bacterial Agents; D017319:Photosensitizing Agents; D026082:Singlet Oxygen; D008751:Methylene Blue