Antimicrobial photodynamic inactivation (aPDI) employing the BODIPY-based photosensitizer 2,6-diiodo-1,3,5,7-tetramethyl-8-(N-methyl-4-pyridyl)-4,4′-difluoroboradiazaindacene (DIMPy-BODIPY) was explored in an in vitro assay against six species of bacteria (eight total strains), three species of yeast, and three viruses as a complementary approach to their current drug-based or non-existent treatments. Our best results achieved a noteworthy 5-6 log unit reduction in CFU at 0.1 μM for Staphylococcus aureus (ATCC-2913), methicillin-resistant S. aureus (ATCC-44), and vancomycin-resistant Enterococcus faecium (ATCC-2320), a 4-5 log unit reduction for Acinetobacter baumannii ATCC-19606 (0.25 μM), multidrug resistant A. baumannii ATCC-1605 (0.1 μM), Pseudomonas aeruginosa ATCC-97 (0.5 μM), and Klebsiella pneumoniae ATCC-2146 (1 μM), and a 3 log unit reduction for Mycobacterium smegmatis mc 2 155 (ATCC-700084). A 5 log unit reduction in CFU was observed for Candida albicans ATCC-90028 (1 μM) and Cryptococcus neoformans ATCC-64538 (0.5 μM), and a 3 log unit reduction was noted for Candida glabrata ATCC-15545 (1 μM). Infectivity was reduced by 6 log units in dengue 1 (0.1 μM), by 5 log units (0.5 μM) in vesicular stomatitis virus, and by 2 log units (5 μM) in human adenovirus-5. Overall, the results demonstrate that DIMPy-BODIPY exhibits antiviral, OPEN ACCESSMolecules 2015, 20 10605 antibacterial and antifungal photodynamic inactivation at nanomolar concentrations and short illumination times.
Toward the objective of developing platform technologies for anti-infective materials based upon photodynamic inactivation, we employed electrospinning to prepare a non-woven textile comprised of polyacrylonitrile nanofibers embedded with a porphyrin-based cationic photosensitizer; termed PAN-Por(+). Photosensitizer loading was determined to be 34.8 nmol/mg material; with thermostability to 300 °C. Antibacterial efficacy was evaluated against four bacteria belonging to the ESKAPE family of pathogens (Staphylococcus aureus; vancomycin-resistant Enterococcus faecium; Acinetobacter baumannii; and Klebsiella pneumonia), as well as Escherichia coli. Our results demonstrated broad photodynamic inactivation of all bacterial strains studied upon illumination (30 min; 65 ± 5 mW/cm2; 400–700 nm) by a minimum of 99.9996+% (5.8 log units) regardless of taxonomic classification. PAN-Por(+) also inactivated human adenovirus-5 (~99.8% reduction in PFU/mL) and vesicular stomatitis virus (>7 log units reduction in PFU/mL). When compared to cellulose-based materials employing this same photosensitizer; the higher levels of photodynamic inactivation achieved here with PAN-Por(+) are likely due to the combined effects of higher photosensitizer loading and a greater surface area imparted by the use of nanofibers. These results demonstrate the potential of photosensitizer-embedded polyacrylonitrile nanofibers to serve as scalable scaffolds for anti-infective or self-sterilizing materials against both bacteria and viruses when employing a photodynamic inactivation mode of action.
Compounds based on the pyrroloquinoxaline system can interact with serotonin 5-HT3 , cannabinoid CB1 , and μ-opioid receptors. Herein, a chiral pool synthesis of diastereomerically and enantiomerically pure bromolactam (S,R,R,R)-14A is presented. Introduction of the cyclohexenyl ring at the N-atom of (S)-proline derivatives 8 or methyl (S)-pyroglutamate (12) led to the N-cyclohexenyl substituted pyrrolidine derivatives 4 and 13, respectively. All attempts to cyclize the (S)-proline derivatives 4 with a basic pyrrolidine N-atom via [3 + 2] cycloaddition, aziridination, or bromolactamization failed. Fast aromatization occurred during treatment of cyclohexenamines under halolactamization conditions. In contrast, reaction of a 1:1 mixture of diastereomeric pyroglutamates (S,R)-13bA and (S,S)-13bB with LiO(t) Bu and NBS provided the tricyclic bromolactam (S,R,R,R)-14A with high diastereoselectivity from (S,R)-13bA, but did not transform the diastereomer (S,S)-13bB. The different behavior of the diastereomeric pyroglutamates (S,R)-13bA and (S,S)-13bB is explained by different energetically favored conformations.
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