Lead Optimization of 1,4-Azaindoles as Antimycobacterial Agents

TLDR

1,4‑Azaindoles were identified as potent antimycobacterial agents targeting DprE1, but their development was hampered by rapid mouse metabolism and PDE6 off‑target activity. The study optimized the series to yield metabolically stable, PDE6‑free compounds with robust pharmacokinetics, aiming for in‑vivo combination and safety evaluations. The optimized compounds showed potent activity and were effective in a rat chronic TB infection model.

Abstract

In a previous report, we described the discovery of 1,4-azaindoles, a chemical series with excellent in vitro and in vivo antimycobacterial potency through noncovalent inhibition of decaprenylphosphoryl-β-d-ribose-2′-epimerase (DprE1). Nevertheless, high mouse metabolic turnover and phosphodiesterase 6 (PDE6) off-target activity limited its advancement. Herein, we report lead optimization of this series, culminating in potent, metabolically stable compounds that have a robust pharmacokinetic profile without any PDE6 liability. Furthermore, we demonstrate efficacy for 1,4-azaindoles in a rat chronic TB infection model. We believe that compounds from the 1,4-azaindole series are suitable for in vivo combination and safety studies.