Synthesis, Biological Evaluation,and Molecular Modelingof New 3-(Cyclopentyloxy)-4-methoxybenzaldehyde O-(2-(2,6-Dimethylmorpholino)-2-oxoethyl) Oxime (GEBR-7b) RelatedPhosphodiesterase 4D (PDE4D) Inhibitors.

A new series of 3-(cyclopentyloxy)-4-methoxyphenylderivatives,structurally related to our hit GEBR-4a (1) and GEBR-7b(2), has been designed by changing length and functionalityof the chain linking the catecholic moiety to the terminal cycloamineportion. Among the numerous molecules synthesized, compounds 8, 10a, and 10bshowed increasedpotency as PDE4D enzyme inhibitors with respect to 2anda good selectivity against PDE4A4, PDE4B2, and PDE4C2 enzymes, withoutboth cytotoxic and genotoxic effects. The ability to enhance cAMPlevel in neuronal cells was assessed for compound 8.SAR considerations, also confirmed by in silico docking simulations,evidenced that both chain and amino terminal function characterizedby higher hydrophilicity are required for a good and selective inhibitor–catalyticpocket interaction. [ABSTRACT FROM AUTHOR]