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Structural and Activity Relationships of 6-Sulfonyl-8-Nitrobenzothiazinones as Antitubercular Agents.

Structural and Activity Relationships of 6-Sulfonyl-8-Nitrobenzothiazinones as Antitubercular Agents.

Authors :
Fan D
Wang B
Stelitano G
Savková K
Shi R
Huszár S
Han Q
Mikušová K
Chiarelli LR
Lu Y
Qiao C
Source :
Journal of medicinal chemistry [J Med Chem] 2021 Oct 14; Vol. 64 (19), pp. 14526-14539. Date of Electronic Publication: 2021 Oct 05.
Publication Year :
2021

Abstract

The benzothiazinone (BTZ) scaffold compound PBTZ169 kills Mycobacterium tuberculosis by inhibiting the essential flavoenzyme DprE1, consequently blocking the synthesis of the cell wall component arabinans. While extraordinarily potent against M. tuberculosis with a minimum inhibitory concentration (MIC) less than 0.2 ng/mL, its low aqueous solubility and bioavailability issues need to be addressed. Here, we designed and synthesized a series of 6-methanesulfonyl substituted BTZ analogues; further exploration introduced five-member aromatic heterocycles as linkers to attach an aryl group as the side chain. Our work led to the discovery of a number of BTZ derived compounds with potent antitubercular activity. The optimized compounds 6 and 38 exhibited MIC 47 and 30 nM, respectively. Compared to PBTZ169, both compounds displayed increased aqueous solubility and higher stability in human liver microsomes. This study suggested that an alternative side-chain modification strategy could be implemented to improve the druglike properties of the BTZ-based compounds.

Details

Language :
English
ISSN :
1520-4804
Volume :
64
Issue :
19
Database :
MEDLINE
Journal :
Journal of medicinal chemistry
Publication Type :
Academic Journal
Accession number :
34609861
Full Text :
https://doi.org/10.1021/acs.jmedchem.1c01049