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.

A high-throughput whole cell screen to identify inhibitors of Mycobacterium tuberculosis

“…tuberculosis . We were able to derive compounds that had good anti-tubercular activity (with MICs of 3–8 μM) but were unable to identify potent compounds analogs that were not cytotoxic to eukaryotic cells [44].…”

A high-throughput whole cell screen to identify inhibitors of Mycobacterium tuberculosis

“…Using this as a starting point we explored the BTD series and evaluated their activity against M. tuberculosis . We were able to derive compounds that had good anti-tubercular activity (with MICs of 3–8 μM) but were unable to identify potent compounds analogs that were not cytotoxic to eukaryotic cells (44).…”

Recent Developments on Pharmacological Potential of 1,3,4-Oxadiazole Scaffold

“…Chandrasekera et al tested the potential of newly synthesized 3-substituted benzothiophene-1,1-dioxide derivatives as inhibitors of virulent Mycobacterium tuberculosis. 23 The results revealed that the substitution at the C-3 position of the benzothiophene-1,1dioxide series influenced the anti-tubercular activity. Oxadiazoles 24(a-d) ( Figure 21) showed good anti-tubercular were found equipotent to standard in inhibiting the rat paw edema.…”