Structure-based design, synthesis and biological evaluation of diphenylmethylamine derivatives as novel Akt1 inhibitors

:•A rational strategy was applied by combination of virtual evaluation and experimental feedback.•A novel modification site on diphenylmethylamine derivatives was identified.•A total of 23 compounds were designed, synthesized and biologically evaluated.•A promising compound 22c with potent and good selectivity profiles was discovered.

A series of diphenylmethylamine derivatives were rationally designed, synthesized and biologically evaluated. Most of them exhibited moderate to good Akt1 inhibitory activities, as well as promising anti-proliferative efficacy against cancer cell lines. Besides, molecular docking studies were carried out to probe their binding modes with Akt1. Further kinase selectivity studies of compound 22c were performed, indicating its excellent selectivity against Aurora A, Drak, IKKβ, GSK3β, SYK and JAK2, and moderate selectivity against PKC and BRAF. Finally, a refined pharmacophore model was generated using the most active compounds 2, 12c and 22c via application of HipHop program.

Graphical abstractA total of 23 compounds were rationally designed, synthesized and biologically evaluated. Several promising novel Akt1 inhibitors were identified.Figure optionsDownload full-size imageDownload as PowerPoint slide