Searching for the Multi-Target-Directed Ligands against Alzheimer’s disease: Discovery of quinoxaline-based hybrid compounds with AChE, H3R and BACE 1 inhibitory activities

A novel series of quinoxaline derivatives, as Multi-Target-Directed Ligands (MTDLs) for AD treatment, were designed by lending the core structural elements required for H3R antagonists and hybridizing BACE 1 inhibitor 1 with AChE inhibitor BYYT-25. A virtual database consisting of quinoxaline derivatives was first screened on a pharmacophore model of BACE 1 inhibitors, and then filtered by a molecular docking model of AChE. Seventeen quinoxaline derivatives with high score values were picked out, synthesized and evaluated for their biological activities. Compound 11a, the most effective MTDL, showed the potent activity to H3R/AChE/BACE 1 (H3R antagonism, IC50=280.0±98.0nM; H3R inverse agonism, IC50=189.3±95.7nM; AChE, IC50=483±5nM; BACE 1, 46.64±2.55% inhibitory rate at 20μM) and high selectivity over H1R/H2R/H4R. Furthermore, the protein binding patterns between 11a and AChE/BACE 1 showed that it makes several essential interactions with the enzymes.