2. Academic Validation
  3. Structural and Activity Relationships of 6-Sulfonyl-8-Nitrobenzothiazinones as Antitubercular Agents

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

  • J Med Chem. 2021 Oct 14;64(19):14526-14539. doi: 10.1021/acs.jmedchem.1c01049.
Dongguang Fan 1,  Bin Wang 2,  Giovanni Stelitano 3,  Karin Savková 4,  Rui Shi 1,  Stanislav Huszár 4,  Quanquan Han 1,  Katarína Mikušová 4,  Laurent R Chiarelli 3,  Yu Lu 2,  Chunhua Qiao 1
Affiliations

Affiliations

  • 1 College of Pharmaceutical Sciences, Soochow University, 199 Renai Road, Suzhou 215123, P. R. China.
  • 2 Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Department of Pharmacology, Beijing Tuberculosis and Thoracic Tumor Research, Beijing Chest Hospital, 97 Ma Chang Street, Beijing 101149, P. R. China.
  • 3 Department of Biology and Biotechnology, University of Pavia, Via Ferrata 9, 27100 Pavia, Italy.
  • 4 Department of Biochemistry, Faculty of Natural Sciences, Comenius University in Bratislava, Mlynská dolina, Ilkovičova 6, 842 15 Bratislava, Slovakia.
PMID: 34609861 DOI: 10.1021/acs.jmedchem.1c01049
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.

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