Antitubercular and Antiparasitic 2‑Nitroimidazopyrazinones with Improved Potency and Solubility

Following the approval of delamanid and pretomanid as new drugs
to treat drug-resistant tuberculosis, there is now a renewed interest
in bicyclic nitroimidazole scaffolds as a source of therapeutics against
infectious diseases. We recently described a nitroimidazopyrazinone
bicyclic subclass with promising antitubercular and antiparasitic
activity, prompting additional efforts to generate analogs with improved
solubility and enhanced potency. The key pendant aryl substituent
was modified by (i) introducing polar functionality to the methylene
linker, (ii) replacing the terminal phenyl group with less lipophilic
heterocycles, or (iii) generating extended biaryl side chains. Improved
antitubercular and antitrypanosomal activity was observed with the
biaryl side chains, with most analogs achieved 2- to 175-fold higher
activity than the monoaryl parent compounds, with encouraging improvements
in solubility when pyridyl groups were incorporated. This study has
contributed to understanding the existing structure–activity
relationship (SAR) of the nitroimidazopyrazinone scaffold against
a panel of disease-causing organisms to support future lead optimization.