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

Abstract

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-b peptides is a critical phase in the pathogenesis of Alzheimer's disease. b-Site amyloid precursor protein cleaving enzyme 1 (BACE- 1) is a major enzyme responsible for amyloid-b production; therefore, inhibition of this enzyme represents a promising approach for the discovery of amyloid-b-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 reso- nance energy transfer-based enzyme assay. Synthesized di- hydropyridines exhibited weak-to-relatively-good BACE-1 inhibitory activities. Enzyme inhibitory activities ranged from 6.84 ± 6.62 (23) to 51.32 ± 1.04 (14) percent enzyme inhi- bitions at the concentration of 10 lM. 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 (pKi) and experimental BACE-1 inhibitory activities at 10 lM 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.