Second-Generation Anti-Tubercular Squaramides Targeting Complex V of the Respiratory Chain of Mycobacterium tuberculosis Displaying Enhanced Metabolic Stability
Nada Mosallam·Gemma L. Nixon·Monika Lisauskaitė·Christopher M. Woodley·Alison Ardrey·Laura N. Jeffreys·Ilinca Memelis·Jin Lee·Paul J. Converse·Dirk Bald·W. David Hong·Neil G. Berry·Deepak Almeida·Daire Cantillon·Eric L. Nuermberger·Giancarlo A. Biagini·Paul M. O’Neill
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 <b>1f</b>. Multiple squaramide analogues exhibited improved potency. The most potent a