2. Academic Validation
  3. Antitubercular and Antiparasitic 2-Nitroimidazopyrazinones with Improved Potency and Solubility

Antitubercular and Antiparasitic 2-Nitroimidazopyrazinones with Improved Potency and Solubility

  • J Med Chem. 2020 Dec 24;63(24):15726-15751. doi: 10.1021/acs.jmedchem.0c01372.
Chee Wei Ang 1,  Lendl Tan 2 3,  Melissa L Sykes 4,  Neda AbuGharbiyeh 5,  Anjan Debnath 5,  Janet C Reid 1,  Nicholas P West 2 3,  Vicky M Avery 4,  Matthew A Cooper 1 3,  Mark A T Blaskovich 1 3
Affiliations

Affiliations

  • 1 Centre for Superbug Solutions, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland 4072, Australia.
  • 2 School of Chemistry and Molecular Bioscience, The University of Queensland, St. Lucia, Queensland 4072, Australia.
  • 3 Australian Infectious Diseases Research Centre, St. Lucia, Queensland 4067, Australia.
  • 4 Discovery Biology, Griffith University, Nathan, Queensland 4111, Australia.
  • 5 Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California 92093, United States.
PMID: 33151678 DOI: 10.1021/acs.jmedchem.0c01372
Abstract

Following the approval of delamanid and pretomanid as new drugs to treat drug-resistant tuberculosis, there is now a renewed interest in bicyclic nitroimidazole scaffolds as a source of therapeutics against infectious diseases. We recently described a nitroimidazopyrazinone bicyclic subclass with promising antitubercular and antiparasitic activity, prompting additional efforts to generate analogs with improved solubility and enhanced potency. The key pendant aryl substituent was modified by (i) introducing polar functionality to the methylene linker, (ii) replacing the terminal phenyl group with less lipophilic heterocycles, or (iii) generating extended biaryl side chains. Improved antitubercular and antitrypanosomal activity was observed with the biaryl side chains, with most analogs achieved 2- to 175-fold higher activity than the monoaryl parent compounds, with encouraging improvements in solubility when pyridyl groups were incorporated. This study has contributed to understanding the existing structure-activity relationship (SAR) of the nitroimidazopyrazinone scaffold against a panel of disease-causing organisms to support future lead optimization.

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