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  BTZ-Derived Benzisothiazolinones with In Vitro Activity against Mycobacterium tuberculosis

Richter, A., Seidel, R. W., Goddard, R., Eckhardt, T., Lehmann, C., Dörner, J., et al. (2022). BTZ-Derived Benzisothiazolinones with In Vitro Activity against Mycobacterium tuberculosis. ACS Medicinal Chemistry Letters, 13(8), 1302-1310. doi:10.1021/acsmedchemlett.2c00215.

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 Creators:
Richter, Adrian1, Author
Seidel, Rüdiger W.1, Author
Goddard, Richard2, Author           
Eckhardt, Tamira1, Author
Lehmann, Christoph1, Author
Dörner, Julia1, Author
Siersleben, Fabienne1, Author
Sondermann, Theresia1, Author
Mann, Lea1, Author
Patzer, Michael2, Author           
Jäger, Christian3, Author
Reiling, Norbert4, 5, Author
Imming, Peter1, Author
Affiliations:
1Martin-Luther-Universität Halle-Wittenberg, Wolfgang-Langenbeck-Strasse 4, 06120 Halle (Saale), Germany, ou_persistent22              
2Service Department Lehmann (EMR), Max-Planck-Institut für Kohlenforschung, Max Planck Society, ou_1445625              
3Fraunhofer-Institut für Zelltherapie und Immunologie, Außenstelle Molekulare Wirkstoffbiochemie und Therapieentwicklung, Weinbergweg 22, 06120 Halle (Saale), Germany, ou_persistent22              
4Microbial Interface Biology, Research Center Borstel, Leibniz Lung Center, , 23845 Borstel, Germany, ou_persistent22              
5German Center for Infection Research (DZIF), Site Hamburg-Lübeck-Borstel-Riems, 23845 Borstel, Germany, ou_persistent22              

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Free keywords: benzisothiazolinone; BTZ043; crystal structure; antimycobacterial activity; DprE1; tuberculosis
 Abstract: 8-Nitro-1,3-benzothiazin-4-ones (BTZs) are known as potent antitubercular agents. BTZ043 as one of the most advanced
compounds has reached clinical trials. The putative oxidation products of BTZ043, namely, the corresponding BTZ sulfoxide and
sulfone, were reported in this journal (Tiwari et al. ACS Med. Chem Lett. 2015, 6, 128−133). The molecular structures were later revised to the constitutionally isomeric benzisothiazolone and its 1-oxide, respectively. Here, we report two BTZ043-derived benzisothiazolinones (BITs) with in vitro activity against mycobacteria. The
constitutionally isomeric O-acyl benzisothiazol-3-ols, in contrast, show little or no antimycobacterial activity in vitro. The structures of the four compounds were investigated by X-ray crystallography and
NMR spectroscopy. Molecular covalent docking of the new compounds to Mycobacerium tuberculosis decaprenylphosphoryl-β-d-ribose 2′-epimerase (DprE1) suggests that the active BITs exert antimycobacterial activity through inhibition of DprE1 like BTZs.

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Language(s): eng - English
 Dates: 2022-05-102022-07-152022-07-252022-08-11
 Publication Status: Published in print
 Pages: 9
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1021/acsmedchemlett.2c00215
 Degree: -

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Title: ACS Medicinal Chemistry Letters
Source Genre: Journal
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Publ. Info: Washington, DC : ACS
Pages: - Volume / Issue: 13 (8) Sequence Number: - Start / End Page: 1302 - 1310 Identifier: ISSN: 1948-5875
CoNE: https://pure.mpg.de/cone/journals/resource/1948-5875