title: Evaluation of pseudopteroxazole and pseudopterosin derivatives against Mycobacterium tuberculosis and other pathogens.
abstract: Pseudopterosins and pseudopteroxazole are intriguing marine natural products that possess notable antimicrobial activity with a commensurate lack of cytotoxicity. New semi-synthetic pseudopteroxazoles, pseudopteroquinoxalines and pseudopterosin congeners along with simple synthetic mimics of the terpene skeleton were synthesized. In order to build structure-activity relationships, a set of 29 new and previously reported compounds was assessed for in vitro antimicrobial and cytotoxic activities. A number of congeners exhibited antimicrobial activity against a range of Gram-positive bacteria including Mycobacterium tuberculosis H₃₇Rv, with four displaying notable antitubercular activity against both replicating and non-replicating persistent forms of M. tuberculosis. One new semi-synthetic compound, 21-((1H-imidazol-5-yl)methyl)-pseudopteroxazole (7a), was more potent than the natural products pseudopterosin and pseudopteroxazole and exhibited equipotent activity against both replicating and non-replicating persistent forms of M.tuberculosis with a near absence of in vitro cytotoxicity. Pseudopteroxazole also exhibited activity against strains of M. tuberculosis H₃₇Rv resistant to six clinically used antibiotics.
authors.affiliation: Department of Chemistry and Department of Biomedical Sciences, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, PEI C1A 4P3, Canada.
authors.forename: Malcolm W B
authors.initials: MWB
authors.lastname: McCulloch
authors.affiliation: Department of Chemistry and Department of Biomedical Sciences, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, PEI C1A 4P3, Canada.|Nautilus Biosciences Canada, Inc., Charlottetown, PEI C1A 4P3, Canada.
authors.forename: Brad
authors.initials: B
authors.lastname: Haltli
authors.affiliation: Department of Chemistry and Department of Biomedical Sciences, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, PEI C1A 4P3, Canada.
authors.forename: Douglas H
authors.initials: DH
authors.lastname: Marchbank
authors.affiliation: Department of Chemistry and Department of Biomedical Sciences, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, PEI C1A 4P3, Canada.|Nautilus Biosciences Canada, Inc., Charlottetown, PEI C1A 4P3, Canada.
authors.forename: Russell G
authors.initials: RG
authors.lastname: Kerr
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D000995:Antitubercular Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D002522:Chlorocebus aethiops; D004224:Diterpenes / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D024901:Drug Resistance, Multiple, Bacterial; D006027:Glycosides / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D006094:Gram-Positive Bacteria / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D010080:Oxazoles / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D013329:Structure-Activity Relationship; D018675:Toxicity Tests; D014709:Vero Cells
chemical_list: D000900:Anti-Bacterial Agents; D000995:Antitubercular Agents; D004224:Diterpenes; D006027:Glycosides; D010080:Oxazoles; C049922:pseudopterosins; C433836:pseudopteroxazole