Design, Synthesis, and Characterization of TNP-2198, a Dual-Targeted Rifamycin-Nitroimidazole Conjugate with Potent Activity against Microaerophilic and Anaerobic Bacterial Pathogens

  • J Med Chem. 2022 Mar 24;65(6):4481-4495. doi: 10.1021/acs.jmedchem.1c02045.
Zhenkun Ma  1 ,  Shijie He  1 ,  Ying Yuan  1 ,  Zhijun Zhuang  1 ,  Yu Liu  1 ,  Huan Wang  1 ,  Jing Chen  1 ,  Xiangyi Xu  1 ,  Charles Ding  1 ,  Vadim Molodtsov  2 ,  Wei Lin  2 ,  Gregory T Robertson  3 ,  William J Weiss  4 ,  Mark Pulse  4 ,  Phung Nguyen  4 ,  Leonard Duncan  5 ,  Timothy Doyle  5 ,  Richard H Ebright  2 ,  Anthony Simon Lynch  1
Affiliations
  • 1. TenNor Therapeutics Ltd, 218 Xinghu Street, Suzhou Industrial Park, Suzhou 215123, China.
  • 2. Waksman Institute and Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey 08854, United States.
  • 3. Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, 80523-1682, United States.
  • 4. HSC College of Pharmacy, University of North Texas, Fort Worth, Texas 76107, United States.
  • 5. JMI Laboratories, North Liberty, Iowa 52317, United States.
PMID: 35175750 DOI: 10.1021/acs.jmedchem.1c02045
Abstract

TNP-2198, a stable conjugate of a rifamycin pharmacophore and a nitroimidazole pharmacophore, has been designed, synthesized, and evaluated as a novel dual-targeted Antibacterial agent for the treatment of microaerophilic and anaerobic Bacterial infections. TNP-2198 exhibits greater activity than a 1:1 molar mixture of the parent drugs and exhibits activity against strains resistant to both rifamycins and nitroimidazoles. A crystal structure of TNP-2198 bound to a Mycobacterium tuberculosis RNA polymerase transcription initiation complex reveals that the rifamycin portion of TNP-2198 binds to the rifamycin binding site on RNAP and the nitroimidazole portion of TNP-2198 interacts directly with the DNA template-strand in the RNAP active-center cleft, forming a hydrogen bond with a base of the DNA template strand. TNP-2198 is currently in Phase 2 clinical development for the treatment of Helicobacter pylori Infection, Clostridioides difficile Infection, and Bacterial vaginosis.

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