Dialkyloxyphenyl hybrids as PDE4B inhibitors: Design, synthesis, in vitro/in vivo anti-inflammatory activity and in silico insights

A series of novel dialkyloxyphenyl hybrids 11a-11h and 12a-12c were designed and synthesized as PDE4 inhibitors with anti-inflammatory activity. All compounds demonstrated nanomolar-range inhibitory activity against both PDE4B and PDE4D isoforms with notable selectivity for PDE4B. The 3,4-dimethoxyphenyl derivative 11e exhibited superior PDE4B inhibitory activity (IC₅₀ = 2.82 nM), with nine-fold selectivity compared to 1.5 of Rolipram. In TNF-α inhibition assays, 11e demonstrated remarkable potency (IC₅₀ = 7.20 nM), comparable to roflumilast, followed by 11d (IC₅₀ = 15.54 nM) and 11b (IC₅₀ = 28.52 nM). In vivo evaluation using LPS-induced sepsis model revealed that 11e achieved the highest inhibition of both TNF-α (52.19 %) and neutrophilia (56.47 %) compared to reference compounds. Molecular docking and dynamics studies revealed that hybrids 11b, 11d, and 11e exhibit a characteristic binding mode within the PDE4 active sites, rationalizing their activity through specific interactions, and demonstrating higher stability in the active site compared to Roflumilast.