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8324332 
Journal Article 
Inhibition of Alzheimer's BACE-1 by 2,6-dialkyl-4-chromon-3-yl-1,4-dihydropyridine-3,5-dicarboxylates 
Razzaghi-Asl, N; Aggarwal, N; Srivastava, S; Parmar, VS; Prasad, AK; Miri, R; Saso, L; Firuzi, O 
2015 
Medicinal Chemistry Research
ISSN: 1054-2523
EISSN: 1554-8120 
Birkhauser Boston 
24 
3230-3241 
English 
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-β peptides is a critical phase in the pathogenesis of Alzheimer's disease. β-Site amyloid precursor protein cleaving enzyme 1 (BACE-1) is a major enzyme responsible for amyloid-β production; therefore, inhibition of this enzyme represents a promising approach for the discovery of amyloid-β-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 Förster resonance energy transfer-based enzyme assay. Synthesized dihydropyridines 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 inhibitions at the concentration of 10 μM. 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 μM 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. © 2015 Springer Science+Business Media New York. 
Alzheimer; BACE-1; Dihydropyridine; Inhibitor