Inhibition of Alzheimer's BACE-1 by 2,6-dialkyl-4-chromon-3-yl-1,4-dihydropyridine-3,5-dicarboxylates

Alzheimer's disease is the most common cause of dementia in the elderly, and no disease-modifying therapy is yet available for this devastating pathology. Deposition of different physicochemical forms of amyloid-beta peptides is a critical phase in the pathogenesis of Alzheimer's disease. beta-Site amyloid precursor protein cleaving enzyme 1 (BACE-1) is a major enzyme responsible for amyloid-beta production; therefore, inhibition of this enzyme represents a promising approach for the discovery of amyloid-beta-lowering agents. In this study, a series of novel 2,6-dialkyl-4-chromon-3-yl-1,4-dihydropyridine-3,5-dicarboxylates (14-23) were synthesized and assessed as BACE-1 inhibitors using the Forster resonance energy transfer-based enzyme assay. Synthesized dihydropyridines exhibited weak-to-relatively-good BACE-1 inhibitory activities. Enzyme inhibitory activities ranged from 6.84 +/- A 6.62 (23) to 51.32 +/- A 1.04 (14) percent enzyme inhibitions at the concentration of 10 mu M. The structure-activity relationship study showed that the presence of 4-[7-(ethanoyloxy)-4-oxo-4H-chromen-3-yl] moiety at C4 position of dihydropyridine ring (14, 16 and 18) confers higher activity compared with other substitutions at this position. Docking simulation predicted a key H-bond interaction between Asp32 residue and dihydropyridine NH group. Moreover, all docked dihydropyridines made good hydrophobic contacts with S1 and S2 subpockets of BACE-1. A good correlation between estimated binding affinities (pK(i)) and experimental BACE-1 inhibitory activities at 10 mu M was obtained (R (2) = 0.639). The findings of this study suggested that 2,6-dialkyl-4-chromon-3-yl-1,4-dihydropyridine-3,5-dicarboxylates could be promising scaffolds for the discovery of novel BACE-1 inhibitors for management of Alzheimer's disease.