2. Academic Validation
  3. Second-Generation Anti-Tubercular Squaramides Targeting Complex V of the Respiratory Chain of Mycobacterium tuberculosis Displaying Enhanced Metabolic Stability

Second-Generation Anti-Tubercular Squaramides Targeting Complex V of the Respiratory Chain of Mycobacterium tuberculosis Displaying Enhanced Metabolic Stability

  • J Med Chem. 2026 May 14;69(9):10213-10239. doi: 10.1021/acs.jmedchem.5c03274.
Nada Mosallam 1,  Paul M O'Neill 1,  Monika Lisauskaitė 1,  Christopher M Woodley 1,  Alison Ardrey 2,  Laura N Jeffreys 2,  Ilinca Memelis 2 3,  Deepak Almeida 4,  Jin Lee 4,  Paul J Converse 4,  Daire Cantillon 2 3,  Eric L Nuermberger 4,  Dirk Bald 5,  Giancarlo A Biagini 2 3,  W David Hong 1,  Neil G Berry 1,  Gemma L Nixon 1
Affiliations

Affiliations

  • 1 Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, U.K.
  • 2 Centre for Drugs & Diagnostics, Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Liverpool L3 5QA, U.K.
  • 3 Centre for Tuberculosis Research, Liverpool School of Tropical Medicine, Liverpool L3 5QA, U.K.
  • 4 Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, United States.
  • 5 Department of A-LIFE, AIMMS, Faculty of Science, Vrije Universiteit Amsterdam De Boelelaan 1108, Amsterdam 1081 HZ, The Netherlands.
PMID: 42023742 DOI: 10.1021/acs.jmedchem.5c03274
Abstract

Squaramides (SQA) were reported as potent antituberculosis drugs through inhibition of the mycobacterial enzyme adenosine triphosphate (ATP) synthase, which is critical for ATP synthesis. However, squaramide compounds showed high metabolic clearance (CL) despite their promising potency and selectivity. Herein, we describe lead optimization efforts to improve the potency and metabolic stability of previous lead 1f. Multiple squaramide analogues exhibited improved potency. The most potent analogue 20j expressed enhanced potency of 51 nM and moderate metabolic stability. SQA 6k displayed optimum balance of potency and metabolic stability both in vitro and in vivo. Notably, against bedaquiline-resistant Rv0678 mutants, a modest 2-fold increase in 6k minimum inhibitory concentration (MIC) was observed─reversed by complementation─versus a 16-fold shift in bedaquiline (BDQ) MIC. In a chronic tuberculosis (TB) mouse model, 6k coadministered with 1-aminobenzotriazole (ABT) exhibited bactericidal activity. These findings provide key strategies for improving potency and pharmacokinetic properties toward a tractable preclinical candidate.

Figures
Products