A series of novel rutaecarpine derivatives were synthesized and subjected to pharmacological evaluation as PDE5 inhibitors. The structure–activity relationships were discussed and their binding conformation and simultaneous interaction mode were further clarified by the molecular docking studies. Among the 25 analogues, compound 8i exhibited most potent PDE5 inhibition with IC50 values about 0.086 μM. Moreover, it also produced good effects against scopolamine-induced cognitive impairment in vivo. These results might bring significant instruction for further development of potential PDE5 inhibitors derived from rutaecarpine as a good candidate drug for the treatment of Alzheimer's disease. © 2020 Elsevier Ltd