Open AccessOptimization and Evaluation of 5‐Styryl‐Oxathiazol‐2‐one Mycobacterium tuberculosis Proteasome Inhibitors as Potential Antitubercular Agents
Author(s) -
Russo Francesco,
Gising Johan,
Åkerbladh Linda,
Roos Annette K.,
Naworyta Agata,
Mowbray Sherry L.,
Sokolowski Anders,
Henderson Ian,
Alling Torey,
Bailey Mai A.,
Files Megan,
Parish Tanya,
Karlén Anders,
Larhed Mats
Publication year - 2015
Publication title -
chemistryopen
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.644
H-Index - 29
ISSN - 2191-1363
DOI - 10.1002/open.201500001
Subject(s) - proteasome , mycobacterium tuberculosis , tuberculosis , chemistry , microbiology and biotechnology , bacteria , pharmacology , biology , biochemistry , medicine , genetics , pathology
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.