Side Chain-Modified Benzothiazinone Derivatives with Anti-Mycobacterial Activity
Dongguang Fan,
Bin Wang,
Giovanni Stelitano,
Karin Savková,
Olga Riabova,
Rui Shi,
Xiaomei Wu,
Laurent R. Chiarelli,
Katarína Mikušová,
Vadim Makarov,
Yu Lu,
Yuzhi Hong,
Chunhua Qiao
Affiliations
Dongguang Fan
College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China
Bin Wang
Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Department of Pharmacology, Beijing Tuberculosis and Thoracic Tumor Research, Beijing Chest Hospital, Beijing 101149, China
Giovanni Stelitano
Department of Biology and Biotechnology, University of Pavia, 27100 Pavia, Italy
Karin Savková
Department of Biochemistry, Faculty of Natural Sciences, Comenius University in Bratislava, 84215 Bratislava, Slovakia
Olga Riabova
Research Center of Biotechnology of the Russian Academy of Sciences, Moscow 119071, Russia
Rui Shi
College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China
Xiaomei Wu
College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China
Laurent R. Chiarelli
Department of Biology and Biotechnology, University of Pavia, 27100 Pavia, Italy
Katarína Mikušová
Department of Biochemistry, Faculty of Natural Sciences, Comenius University in Bratislava, 84215 Bratislava, Slovakia
Vadim Makarov
Research Center of Biotechnology of the Russian Academy of Sciences, Moscow 119071, Russia
Yu Lu
Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Department of Pharmacology, Beijing Tuberculosis and Thoracic Tumor Research, Beijing Chest Hospital, Beijing 101149, China
Yuzhi Hong
Institute of Molecular Enzymology, School of Biology and Basic Medical Sciences, Suzhou Medical College, Soochow University, Suzhou 215123, China
Chunhua Qiao
College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China
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.
