2. Academic Validation
  3. The optimization and characterization of functionalized sulfonamides derived from sulfaphenazole against Mycobacterium tuberculosis with reduced CYP 2C9 inhibition

The optimization and characterization of functionalized sulfonamides derived from sulfaphenazole against Mycobacterium tuberculosis with reduced CYP 2C9 inhibition

  • Bioorg Med Chem Lett. 2021 May 15:40:127924. doi: 10.1016/j.bmcl.2021.127924.
Hui Chen 1,  Bin Wang 2,  Peng Li 3,  Hong Yan 1,  Gang Li 4,  Haihong Huang 5,  Yu Lu 6
Affiliations

Affiliations

  • 1 Beijing Key Laboratory of Environmental and Viral Oncology, College of Life Science and Bio-engineering, Beijing University of Technology, Beijing 100124, PR China.
  • 2 Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Department of Pharmacology, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing 101149, PR China.
  • 3 Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation & Chinese Academy of Medical Sciences Key Laboratory of Anti-DR TB Innovative Drug Research, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, PR China.
  • 4 Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation & Chinese Academy of Medical Sciences Key Laboratory of Anti-DR TB Innovative Drug Research, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, PR China. Electronic address: [email protected].
  • 5 Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation & Chinese Academy of Medical Sciences Key Laboratory of Anti-DR TB Innovative Drug Research, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, PR China. Electronic address: [email protected].
  • 6 Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Department of Pharmacology, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing 101149, PR China. Electronic address: [email protected].
PMID: 33705901 DOI: 10.1016/j.bmcl.2021.127924
Abstract

In this study, a series of sulfonamide compounds was designed and synthesized through the systematic optimization of the Antibacterial agent sulfaphenazole for the treatment of Mycobacterium tuberculosis (M. tuberculosis). Preliminary results indicate that the 4-aminobenzenesulfonamide moiety plays a key role in maintaining antimycobacterial activity. Compounds 10c, 10d, 10f and 10i through the optimization on phenyl ring at the R2 site on the pyrazole displayed promising antimycobacterial activity paired with low cytotoxicity. In particular, compound 10d displayed good activity (MIC = 5.69 μg/mL) with low inhibition of CYP 2C9 (IC50 > 10 μM), consequently low potential risk of drug-drug interaction. These promising results provide new insight into the combination regimen using sulfonamide as one component for the treatment of M. tuberculosis.

Keywords

Antimycobacterial activity; CYP 2C9; Cytotoxicity; Optimization; Sulfonamide compounds.

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