Synthesis and bioactivity of phenyl substituted furan and oxazole carboxylic acid derivatives as potential PDE4 inhibitors

In this present study, a series of 5-phenyl-2-furan and 4-phenyl-2-oxazole derivatives were designed and synthesized as phosphodiesterase type 4 (PDE4) inhibitors. In vitro results showed that the synthesized compounds exhibited considerable inhibitory activity against PDE4B and blockade of LPS-induced TNF-α release. Among the designed compounds, Compound 5j exhibited lower IC50 value (1.4 μM) against PDE4 than parent rolipram (2.0 μM) in in vitro enzyme assay, which also displayed good in vivo activity in animal models of asthma/COPD and sepsis induced by LPS. Docking results suggested that introduction of methoxy group at para-position of phenyl ring, demonstrated good interaction with metal binding pocket domain of PDE4B, which was helpful to enhance inhibitory activity. [Display omitted] •Novel 5-phenyl-2-furan and 4-phenyl-2-oxazole derivatives were synthesized.•The title compounds as selective PDE4B inhibitors exhibited strong activity.•2-cyanoimino-1,3-thiazolidine moiety was effective and favored the inhibitory activity.•SAR and molecular simulation studies were conducted.