title: Phenothiazinium photoantimicrobials with basic side chains.
abstract: Derivatives of the standard cationic photosensitiser, methylene blue, were synthesised, having extra amino (basic) functionality in the auxochromic side-chain. The resulting analogues were profiled for photodynamic activity in vitro, and screened against standard Gram-positive and Gram-negative bacteria for photobactericidal activity. The substitution pattern of the derivatives was such that ionisation of the amino groups in situ, via protonation, provided a range of charge distribution and degree of charge across the molecular framework. While most examples exhibited greater activity than the lead compound, in addition to similar activity to the known, but more powerful, phenothiazinium photoantimicrobial, dimethyl methylene blue, this was also associated with relatively high dark toxicity, inferring that these compounds were targeting crucial structures before illumination. One derivative having an asymmetrical structure, with separation between a lipophilic and a hydrophilic region exhibited a combination of very high phototoxicity coupled with very low dark effects, against both the standard screen and an additional one containing further, relevant pathogen species, including Candida albicans. It is suggested that the great activity of this analogue is due to efficient membrane targeting.
authors.affiliation: School of Pharmacy & Biomolecular Sciences, Liverpool John Moores University, Liverpool L3 3AF, United Kingdom. Electronic address: mark_wainwright@hotmail.com.
authors.forename: Mark
authors.initials: M
authors.lastname: Wainwright
authors.affiliation: School of Pharmacy & Biomolecular Sciences, Liverpool John Moores University, Liverpool L3 3AF, United Kingdom.
authors.forename: Joanna
authors.initials: J
authors.lastname: Antczak
authors.affiliation: School of Pharmacy & Biomolecular Sciences, Liverpool John Moores University, Liverpool L3 3AF, United Kingdom.
authors.forename: Martyna
authors.initials: M
authors.lastname: Baca
authors.affiliation: School of Pharmacy & Biomolecular Sciences, Liverpool John Moores University, Liverpool L3 3AF, United Kingdom.
authors.forename: Ciara
authors.initials: C
authors.lastname: Loughran
authors.affiliation: School of Pharmacy & Biomolecular Sciences, Liverpool John Moores University, Liverpool L3 3AF, United Kingdom.
authors.forename: Katie
authors.initials: K
authors.lastname: Meegan
mesh_terms: D000890:Anti-Infective Agents / Q000737:chemistry / Q000494:pharmacology; D002176:Candida albicans / Q000187:drug effects / Q000254:growth & development; D006090:Gram-Negative Bacteria / Q000187:drug effects / Q000254:growth & development; D006094:Gram-Positive Bacteria / Q000187:drug effects / Q000254:growth & development; D008027:Light; D008751:Methylene Blue / Q000737:chemistry / Q000494:pharmacology; D010640:Phenothiazines / Q000737:chemistry / Q000494:pharmacology; D017319:Photosensitizing Agents / Q000737:chemistry / Q000494:pharmacology; D026082:Singlet Oxygen / Q000737:chemistry
chemical_list: D000890:Anti-Infective Agents; D010640:Phenothiazines; D017319:Photosensitizing Agents; D026082:Singlet Oxygen; D008751:Methylene Blue