Cubane and Cyclooctatetraene Pirfenidones – Synthesis and Biological Evaluation

Pirfenidone, an oral anti-fibrotic and anti-inflammatory medication used for the treatment of idiopathic pulmonary fibrosis (IPF), has been proposed to treat post-COVID pneumonia pulmonary fibrosis (PF). However, pirfenidone displays side effects which include hepatotoxicity and anorexia. Cubane and cyclooctatetraene (COT) derivatives of pirfenidone were prepared as bioisostere/biomotif replacements of the phenyl ring to explore potential changes in activity. The key intermediate, aminocubane, enabled the synthesis of both the cubane and cyclooctatetraene (COT) derived pirfenidone analogues in 6 steps. The COT derivative was observed to display similar activity and cytotoxicity with pirfenidone in an anti-virus and ACE2 inhibition assay, although limited effect was observed from pirfenidone and the analogues described herein.