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

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

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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