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 (>10 nm) on binding typical of strong intercalators. (C) 2010 Elsevier B.V. All rights reserved.