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.

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, V. S.; Prasad, A. K.; Miri, R.; Saso, L.; Firuzi, O.. - In: MEDICINAL CHEMISTRY RESEARCH. - ISSN 1054-2523. - STAMPA. - 24:8(2015), pp. 3230-3241. [10.1007/s00044-015-1367-z]

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

Saso, L.;
2015

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-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
alzheimer; bace-1; dihydropyridine; inhibitor
01 Pubblicazione su rivista::01a Articolo in rivista
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, V. S.; Prasad, A. K.; Miri, R.; Saso, L.; Firuzi, O.. - In: MEDICINAL CHEMISTRY RESEARCH. - ISSN 1054-2523. - STAMPA. - 24:8(2015), pp. 3230-3241. [10.1007/s00044-015-1367-z]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1096211
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