Evolution of Small Molecule Inhibitors of <i>Mycobacterium tuberculosis</i> Menaquinone Biosynthesis
A dire need exists for novel drugs to treat <i>Mycobacterium tuberculosis</i> infection. In an effort to build on our early efforts targeting the MenG enzyme within the menaquinone biosynthetic pathway, we have pursued the optimization of diaryl amide JSF-2911 to address its poor metabolic stability and modest <i>in vitro</i> potency. A hit evolution campaign focused on modification of the amine substructure within this hit compound, resulting in a range of analogues that have been profiled extensively. Among these derivatives, JSF-4536 and JSF-4898 demonstrated significantly improved biological profiles, notably offering submicromolar MIC values versus <i>M. tuberculosis</i> and promising values characterizing the mouse liver microsome stability, aqueous solubility, and mouse pharmacokinetic profile. JSF-4898 enhanced the efficacy of rifampicin in a subacute model of <i>M. tuberculosis</i> infection in mice. The findings suggest a rationale for the further optimization of MenG inhibitors to provide a novel therapeutic strategy to address <i>M. tuberculosis</i> infection.
Authors
- Paridhi Sukheja
- Shraddha Suryavanshi
- Kholiswa Tsotetsi
- Steven Park (ORCID: https://orcid.org/0000-0002-6757-1559)
- Shaogang Li
- Andrew M. Nelson
- Kayunta Johnson
- Joel S. Freundlich (ORCID: https://orcid.org/0000-0002-3411-3455)
- Matthew Zimmerman (ORCID: https://orcid.org/0000-0002-4390-3555)
- Jansy Passiflora Sarathy (ORCID: https://orcid.org/0000-0002-1532-146X)
- Riccardo Russo (ORCID: https://orcid.org/0000-0002-2900-0659)
- David Alland (ORCID: https://orcid.org/0000-0001-5196-1571)
- Suyapa Penalva-Lopez
- Vijeta Sharma (ORCID: https://orcid.org/0000-0003-2760-3365)
- Quan Jiang
- Pradeep Kumar (ORCID: https://orcid.org/0000-0002-8320-1494)
- Elaine Morrison
- Pankaj Sharma (ORCID: https://orcid.org/0009-0004-1223-4653)
- Parul Singh
- Julianna Cangialosi
- Srinivas Thadkapally
- Elissa Ocke
Institutions
- Rutgers, The State University of New Jersey (US)
- Hackensack Meridian Health (US)
- Center for Discovery (US)
- Rutgers New Jersey Medical School (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-03-04
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c03156
- Citations
- 4
- Primary Topic
- Tuberculosis Research and Epidemiology
- Type
- article
- Field-Weighted Citation Impact
- 5.58
Funders
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases