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ACS Med Chem Lett. 2014 Mar 3;5(5):587-91. doi: 10.1021/ml500039g. eCollection 2014 May 8.

Design and Syntheses of Anti-Tuberculosis Agents Inspired by BTZ043 Using a Scaffold Simplification Strategy.

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Department of Chemistry and Biochemistry, University of Notre Dame , Notre Dame, Indiana 46556, United States.
Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute , Beutenbergstrasse 11a, 07745 Jena, Germany.
Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago , 833 South Wood Street, Chicago, Illinois 60612, United States.


Tuberculosis (TB), a disease caused by Mycobacterium tuberculosis (Mtb), is a global public health concern because of the emergence of various resistant strains. Benzothiazin-4-ones (BTZs), represented by BTZ043, are a promising new class of agents for the treatment of tuberculosis and have been shown to kill Mtb in vitro, ex vivo, and in mouse models of TB. Herein we report the design and syntheses of nitroaromatic sulfonamide, reverse-amide, and ester classes of anti-TB agents using a scaffold simplification strategy based on BTZ043. The presented work explores the effect of functional groups such as sulfonamides, reverse-amides, and esters that are attached to the nitroaromatic rings on their anti-TB activity. The in vitro activity of the compounds evaluated against the H37Rv strain of Mtb show that nitroaromatic sulfonamides and nitrobenzoic acid esters with two nitro substituents were most active and highlights the importance of the electronic character (electron deficient aromatic ring) of the nitroaromatic ring as a central theme in these types of nitroaromatic anti-TB agents.


BTZ043; DprE1; Mycobacterium tuberculosis; nitroaromatics; scaffold simplification strategy

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