title: Optimization and Evaluation of 5-Styryl-Oxathiazol-2-one Mycobacterium tuberculosis Proteasome Inhibitors as Potential Antitubercular Agents.
abstract: This is the first report of 5-styryl-oxathiazol-2-ones as inhibitors of the Mycobacterium tuberculosis (Mtb) proteasome. As part of the study, the structure-activity relationship of oxathiazolones as Mtb proteasome inhibitors has been investigated. Furthermore, the prepared compounds displayed a good selectivity profile for Mtb compared to the human proteasome. The 5-styryl-oxathiazol-2-one inhibitors identified showed little activity against replicating Mtb, but were rapidly bactericidal against nonreplicating bacteria. (E)-5-(4-Chlorostyryl)-1,3,4-oxathiazol-2-one) was most effective, reducing the colony-forming units (CFU)/mL below the detection limit in only seven days at all concentrations tested. The results suggest that this new class of Mtb proteasome inhibitors has the potential to be further developed into novel antitubercular agents for synergistic combination therapies with existing drugs.
authors.affiliation: Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, BMC, Uppsala University Box 574, 751 23, Uppsala, Sweden.
authors.forename: Francesco
authors.initials: F
authors.lastname: Russo
authors.affiliation: Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, BMC, Uppsala University Box 574, 751 23, Uppsala, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Gising
authors.affiliation: Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, BMC, Uppsala University Box 574, 751 23, Uppsala, Sweden.
authors.forename: Linda
authors.initials: L
authors.lastname: Åkerbladh
authors.affiliation: Department of Cell and Molecular Biology, Science for Life Laboratory, BMC, Uppsala University Box 596, 751 24, Uppsala, Sweden.
authors.forename: Annette K
authors.initials: AK
authors.lastname: Roos
authors.affiliation: Department of Cell and Molecular Biology, BMC, Uppsala University Box 596, 751 24, Uppsala, Sweden.
authors.forename: Agata
authors.initials: A
authors.lastname: Naworyta
authors.affiliation: Department of Cell and Molecular Biology, Science for Life Laboratory, BMC, Uppsala University Box 596, 751 24, Uppsala, Sweden.
authors.forename: Sherry L
authors.initials: SL
authors.lastname: Mowbray
authors.affiliation: Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, BMC, Uppsala University Box 574, 751 23, Uppsala, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Sokolowski
authors.affiliation: Medivir AB PO Box 1086, 141 22, Huddinge, Sweden.
authors.forename: Ian
authors.initials: I
authors.lastname: Henderson
authors.affiliation: TB Discovery Research, Infectious Disease Research Institute Seattle, WA, 98102, USA.
authors.forename: Torey
authors.initials: T
authors.lastname: Alling
authors.affiliation: TB Discovery Research, Infectious Disease Research Institute Seattle, WA, 98102, USA.
authors.forename: Mai A
authors.initials: MA
authors.lastname: Bailey
authors.affiliation: TB Discovery Research, Infectious Disease Research Institute Seattle, WA, 98102, USA.
authors.forename: Megan
authors.initials: M
authors.lastname: Files
authors.affiliation: TB Discovery Research, Infectious Disease Research Institute Seattle, WA, 98102, USA.
authors.forename: Tanya
authors.initials: T
authors.lastname: Parish
authors.affiliation: Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, BMC, Uppsala University Box 574, 751 23, Uppsala, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Karlén
authors.affiliation: Department of Medicinal Chemistry, Science for Life Laboratory, BMC, Uppsala University Box 574, 751 23, Uppsala, Sweden.
authors.forename: Mats
authors.initials: M
authors.lastname: Larhed
keywords: 5-styryl-oxathiazolones; Mtb proteasome inhibitor; Mycobacterium tuberculosis; antitubercular agents; nonreplicating Mtb; rapid bactericidal activity