Design, Synthesis, and Biological Evaluation of Mono- and Diamino-Substituted Squaramide Derivatives as Potent Inhibitors of Mycobacterial Adenosine Triphosphate (ATP) Synthase
Amides of squaric acid are new drug candidates with activity against mycobacteria. Like the approved drug bedaquiline, these compounds achieve efficacy by inhibiting mycobacterial ATP synthase. However, squaramides have a different binding site than bedaquiline and possess the potential to inhibit bedaquiline-resistant strains. We developed an optimized synthesis for monoamino-substituted squaric acid analogues. Guided by an atomic model of a squaramide compound bound to its target, we synthesized 31 new monoamino/diamino-substituted squaric acid derivates. The efficacy of these compounds was determined in whole-cell assays against <i>Mycobacterium tuberculosis</i> and <i>Mycobacterium avium</i>. The molecular target was confirmed with measurement of inhibition of <i>Mycobacterium smegmatis</i> ATP synthase and by using <i>M. tuberculosis</i> strains that modulate the expression of ATP synthase. Compared to earlier squaramides, several analogues demonstrated micromolar activity against <i>M. tuberculosis</i>, improved microsomal stability <i>in vitro</i>, and reduced cytotoxicity. These properties contribute to the preclinical development of this class of compound.
Authors
- Shipra Grover (ORCID: https://orcid.org/0000-0001-7094-6879)
- Rana Abdelaziz (ORCID: https://orcid.org/0000-0002-9581-604X)
- Lea Mann
- Karin Bartel (ORCID: https://orcid.org/0000-0002-6634-547X)
- Norbert Reiling (ORCID: https://orcid.org/0000-0001-6673-4291)
- Dirk Schnappinger
- John L. Rubinstein (ORCID: https://orcid.org/0000-0003-0566-2209)
- Peter Imming (ORCID: https://orcid.org/0000-0003-2178-3887)
- Paul R. Palme
- Andreas M. Kany (ORCID: https://orcid.org/0000-0001-7580-3658)
- Adrian Richter (ORCID: https://orcid.org/0000-0002-0062-7896)
- Lindsay Sonnenkalb (ORCID: https://orcid.org/0000-0002-8827-772X)
- Anna K. H. Hirsch (ORCID: https://orcid.org/0000-0001-8734-4663)
- Lina Ouologuem (ORCID: https://orcid.org/0009-0007-4648-3641)
Institutions
- University of Toronto (CA)
- American Association of Colleges of Pharmacy (US)
- Cornell University (US)
- Hospital for Sick Children (CA)
- Hai phong University Of Medicine and Pharmacy (VN)
- Bioscience Research (US)
- University of Pharmacy Mandalay (MM)
- German Center for Infection Research (DE)
- Helmholtz Centre for Infection Research (DE)
- Research Center Borstel - Leibniz Lung Center (DE)
- Institute of Biophysics (BG)
- Helmholtz Institute for Pharmaceutical Research Saarland (DE)
- Institute of Molecular Biology and Biophysics (RU)
- Institute of Experimental Pharmacology and Toxicology of the Slovak Academy of Sciences (SK)
- Interface (United Kingdom) (GB)
- Instytut Farmaceutyczny (PL)
- Martin Luther University Halle-Wittenberg (DE)
- Ludwig-Maximilians-Universität München (DE)
- Saarland University (DE)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-11-24
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c02284
- Citations
- 1
- Primary Topic
- ATP Synthase and ATPases Research
- Type
- article
- Field-Weighted Citation Impact
- 0.81