A small chemical library of 2-aminoimidazole derivatives as BACE-1 inhibitors: Structure-based design, synthesis, and biological evaluation

In this work, we report a rational structure-based approach aimed at the discovery of new 2-aminoimidazoles as β-secretase inhibitors. Taking advantage of a microwave-assisted synthetic protocol, a small library of derivatives was obtained and biologically evaluated. Two compounds showed promising activities in both enzymatic and cellular assays. Moreover, one of them exhibited the capability to cross the blood–brain barrier as assessed by the parallel artificial membrane permeability assay. [Display omitted] ► BACE-1 inhibition as a validated AD modifying therapy. ► Rational structure-based design toward the discovery of new BACE-1 inhibitors. ► Application of a synthetic protocol amenable to parallel synthesis. ► Synthesis and biological evaluation of a small library of 2-aminoimidazoles. ► Compound 7 has emerged as a promising anti-BACE-1 hit compound.