title: Structure-function relationships of Nile blue (EtNBS) derivatives as antimicrobial photosensitizers.
abstract: The benzophenothiazinium dye EtNBS has previously been tested as a photosensitizer to mediate photodynamic therapy (PDT). It has been employed to kill cancer cells and microbial cells in vitro and to treat tumors and infections in vivo. We synthesized a panel of derivatives substituted at the 1-position of the benzene ring with electron donating or electron withdrawing groups (amino, acetamido and nitro) and tested their production of reactive oxygen species (ROS) and light-mediated killing of two species of Gram-positive and two species of Gram-negative bacteria. All three compounds showed lower fluorescence, lower yield of ROS and less microbial killing than parent EtNBS, while the order of activity (nitro > amino > acetamido) showed that an electron withdrawing substituent was better than electron donating. To test the hypothesis that 1-substitution distorts the planar structure of the conjugated rings we compared two compounds substituted with N-ethylpropylsulfonamido either at the 1-position or at the 4-position. The 4-isomer was significantly more photoactive than the 1-isomer. We also prepared an EtNBS derivative with a guanidinium group attached to the 5-amino group. This compound had high activity against Gram-negative bacteria due to the extra positive charge. Cellular uptake of the compounds by the four bacterial species was also measured and broadly correlated with activity. These results provided three separate pieces of structure-activity relationship data for antimicrobial photosensitizers based on the EtNBS backbone.
authors.affiliation: Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA 02114, USA.|Department of Dermatology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Daniela
authors.initials: D
authors.lastname: Vecchio
authors.affiliation: Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Brijesh
authors.initials: B
authors.lastname: Bhayana
authors.affiliation: Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA 02114, USA.|Department of Dermatology, Harvard Medical School, Boston, MA 02115, USA.|Department of Infectious Diseases, First Affiliated College & Hospital, Guangxi Medical University, Nanning, China 530021.
authors.forename: Liyi
authors.initials: L
authors.lastname: Huang
authors.affiliation: Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA 02114, USA.|Departamento de Biología, Facultad de Ciencias, Universidad Autónoma de Madrid, Madrid, Spain.|Instituto de Investigaciones Biomédicas "Alberto Sols", CSIC-Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Elisa
authors.initials: E
authors.lastname: Carrasco
authors.affiliation: Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA 02114, USA.|Department of Dermatology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Conor L
authors.initials: CL
authors.lastname: Evans
authors.affiliation: Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA 02114, USA.|Department of Dermatology, Harvard Medical School, Boston, MA 02115, USA.|Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA 02139, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hamblin
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D006090:Gram-Negative Bacteria / Q000187:drug effects* / Q000528:radiation effects; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy; D006094:Gram-Positive Bacteria / Q000187:drug effects* / Q000528:radiation effects; D016908:Gram-Positive Bacterial Infections / Q000188:drug therapy; D006801:Humans; D008027:Light; D008826:Microbial Sensitivity Tests; D010078:Oxazines / Q000737:chemistry / Q000494:pharmacology*; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013843:Thiazines / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D010078:Oxazines; D017319:Photosensitizing Agents; D013843:Thiazines; C081287:5-ethylamino-9-diethylaminobenzo(a)phenothiazinium; C008619:Nile Blue
keywords: Benzophenothiazinium dye; Electron withdrawing/donating substituents; Gram-negative bacteria; Gram-positive bacteria; Nile blue derivatives, antimicrobial photodynamic inactivation; Structure–activity relationships