2. Academic Validation
  3. Design, Synthesis, and Biological Evaluation of Mono- and Diamino-Substituted Squaramide Derivatives as Potent Inhibitors of Mycobacterial Adenosine Triphosphate (ATP) Synthase

Design, Synthesis, and Biological Evaluation of Mono- and Diamino-Substituted Squaramide Derivatives as Potent Inhibitors of Mycobacterial Adenosine Triphosphate (ATP) Synthase

  • J Med Chem. 2025 Dec 11;68(23):25274-25289. doi: 10.1021/acs.jmedchem.5c02284.
Paul R Palme 1,  Shipra Grover 2,  Rana Abdelaziz 3,  Lea Mann 1,  Andreas M Kany 4 5,  Lina Ouologuem 6,  Karin Bartel 6,  Lindsay Sonnenkalb 7,  Norbert Reiling 8 9,  Anna K H Hirsch 4 5 10,  Dirk Schnappinger 2,  John L Rubinstein 3 11,  Peter Imming 1,  Adrian Richter 1
Affiliations

Affiliations

  • 1 Pharmaceutical Chemistry, Institute of Pharmacy, Martin-Luther-Universität Halle-Wittenberg, Halle (Saale) 06120, Germany.
  • 2 Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York 10065, United States.
  • 3 Molecular Medicine Program, The Hospital for Sick Children, Toronto, ON M5G1H3, Canada.
  • 4 Helmholtz Institute for Pharmaceutical Research Saarland (HIPS)-Helmholtz Centre for Infection Research (HZI), Saarbrücken 66123, Germany.
  • 5 PharmaScienceHub, Saarbrücken 66123, Germany.
  • 6 Department of Pharmacy, Faculty of Chemistry and Pharmacy, Ludwig Maximilian University of Munich, Munich 81377, Germany.
  • 7 Molecular and Experimental Mycobacteriology, Research Center Borstel, Leibniz Lung Center, Borstel 23845, Germany.
  • 8 Microbial Interface Biology, Research Center Borstel, Leibniz Lung Center, Borstel 23845, Germany.
  • 9 German Center for Infection Research, DZIF, Partner Site Hamburg-Lübeck-Borstel-Riems, Borstel 23845, Germany.
  • 10 Department of Pharmacy, Campus E8.1, Saarland University, Saarbrücken 66123, Germany.
  • 11 Departments of Biochemistry and Medical Biophysics, The University of Toronto, Toronto, ON M5G 1L7, Canada.
PMID: 41277442 DOI: 10.1021/acs.jmedchem.5c02284
Abstract

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 Mycobacterium tuberculosis and Mycobacterium avium. The molecular target was confirmed with measurement of inhibition of Mycobacterium smegmatis ATP Synthase and by using M. tuberculosis strains that modulate the expression of ATP Synthase. Compared to earlier squaramides, several analogues demonstrated micromolar activity against M. tuberculosis, improved microsomal stability in vitro, and reduced cytotoxicity. These properties contribute to the preclinical development of this class of compound.

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