2. Academic Validation
  3. Side Chain-Modified Benzothiazinone Derivatives with Anti-Mycobacterial Activity

Side Chain-Modified Benzothiazinone Derivatives with Anti-Mycobacterial Activity

  • Biomedicines. 2023 Jul 12;11(7):1975. doi: 10.3390/biomedicines11071975.
Dongguang Fan 1,  Bin Wang 2,  Giovanni Stelitano 3,  Karin Savková 4,  Olga Riabova 5,  Rui Shi 1,  Xiaomei Wu 1,  Laurent R Chiarelli 3,  Katarína Mikušová 4,  Vadim Makarov 5,  Yu Lu 2,  Yuzhi Hong 6 7,  Chunhua Qiao 1 7
Affiliations

Affiliations

  • 1 College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China.
  • 2 Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Department of Pharmacology, Beijing Tuberculosis and Thoracic Tumor Research, Beijing Chest Hospital, Beijing 101149, China.
  • 3 Department of Biology and Biotechnology, University of Pavia, 27100 Pavia, Italy.
  • 4 Department of Biochemistry, Faculty of Natural Sciences, Comenius University in Bratislava, 84215 Bratislava, Slovakia.
  • 5 Research Center of Biotechnology of the Russian Academy of Sciences, Moscow 119071, Russia.
  • 6 Institute of Molecular Enzymology, School of Biology and Basic Medical Sciences, Suzhou Medical College, Soochow University, Suzhou 215123, China.
  • 7 Suzhou Key Laboratory of Pathogen Bioscience and Anti-Infective Medicine, Suzhou Medical College, Soochow University, Suzhou 215123, China.
PMID: 37509615 DOI: 10.3390/biomedicines11071975
Abstract

Tuberculosis (TB) is a leading infectious disease with serious Antibiotic resistance. The benzothiazinone (BTZ) scaffold PBTZ169 kills Mycobacterium tuberculosis (Mtb) through the inhibition of the essential cell wall Enzyme decaprenylphosphoryl-β-D-ribose 2'-oxidase (DprE1). PBTZ169 shows anti-TB potential in animal models and pilot clinical tests. Although highly potent, the BTZ type DprE1 inhibitors in general show extremely low aqueous solubility, which adversely affects the drug-like properties. To improve the compounds physicochemical properties, we generated a series of BTZ analogues. Several optimized compounds had MIC values against Mtb lower than 0.01 µM. The representative compound 37 displays improved solubility and bioavailability compared to the lead compound. Additionally, compound 37 shows Mtb-killing ability in an acute Infection mouse model.

Keywords

DprE1 inhibitor; anti-tubercular agents; in vivo activity; structure activity relationship.

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