title: Synthesis and anti-tubercular activity of 3-substituted benzo[b]thiophene-1,1-dioxides.
abstract: We demonstrated that the 3-substituted benzothiophene-1,1-dioxide class of compounds are effective inhibitors of Mycobacterium tuberculosis growth under aerobic conditions. We examined substitution at the C-3 position of the benzothiophene-1,1-dioxide series systematically to delineate structure-activity relationships influencing potency and cytotoxicity. Compounds were tested for inhibitory activity against virulent M. tuberculosis and eukaryotic cells. The tetrazole substituent was most potent, with a minimum inhibitory concentration (MIC) of 2.6 µM. However, cytotoxicity was noted with even more potency (Vero cell TC50 = 0.1 µM). Oxadiazoles had good anti-tubercular activity (MICs of 3-8 µM), but imidazoles, thiadiazoles and thiazoles had little activity. Cytotoxicity did not track with anti-tubercular activity, suggesting different targets or mode of action between bacterial and eukaryotic cells. However, we were unable to derive analogs without cytotoxicity; all compounds synthesized were cytotoxic (TC50 of 0.1-5 µM). We conclude that cytotoxicity is a liability in this series precluding it from further development. However, the series has potent anti-tubercular activity and future efforts towards identifying the mode of action could result in the identification of novel drug targets.
authors.affiliation: TB Discovery Research, Infectious Disease Research Institute , Seattle, WA , USA.
authors.forename: N Susantha
authors.initials: NS
authors.lastname: Chandrasekera
authors.affiliation: TB Discovery Research, Infectious Disease Research Institute , Seattle, WA , USA.
authors.forename: Mai A
authors.initials: MA
authors.lastname: Bailey
authors.affiliation: TB Discovery Research, Infectious Disease Research Institute , Seattle, WA , USA.
authors.forename: Megan
authors.initials: M
authors.lastname: Files
authors.affiliation: TB Discovery Research, Infectious Disease Research Institute , Seattle, WA , USA.
authors.forename: Torey
authors.initials: T
authors.lastname: Alling
authors.affiliation: TB Discovery Research, Infectious Disease Research Institute , Seattle, WA , USA.
authors.forename: Stephanie K
authors.initials: SK
authors.lastname: Florio
authors.affiliation: TB Discovery Research, Infectious Disease Research Institute , Seattle, WA , USA.
authors.forename: Juliane
authors.initials: J
authors.lastname: Ollinger
authors.affiliation: TB Discovery Research, Infectious Disease Research Institute , Seattle, WA , USA.
authors.forename: Joshua O
authors.initials: JO
authors.lastname: Odingo
authors.affiliation: TB Discovery Research, Infectious Disease Research Institute , Seattle, WA , USA.
authors.forename: Tanya
authors.initials: T
authors.lastname: Parish
keywords: Antibacterial; Antimicrobial; Benzothiophene dioxide; Drug discovery; High throughput screening; Mycobacterium tuberculosis; Tuberculosis