Cubane and Cyclooctatetraene Pirfenidones – Synthesis and Biological Evaluation

Abstract

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.