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 H(3)R 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 H(3)R/AChE/BACE 1 (H(3)R antagonism, IC(50)=280.0 ± 98.0 nM; H(3)R inverse agonism, IC(50)=189.3 ± 95.7 nM; AChE, IC(50)=483 ± 5 nM; BACE 1, 46.64±2.55% inhibitory rate at 20 μM) and high selectivity over H(1)R/H(2)R/H(4)R. Furthermore, the protein binding patterns between 11a and AChE/BACE 1 showed that it makes several essential interactions with the enzymes.
ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zijingang Campus, Zhejiang University, Hangzhou 310058, China.
Wenhai
W
Huang
Li
L
Tang
Ying
Y
Shi
Shufang
S
Huang
Lei
L
Xu
Rong
R
Sheng
Peng
P
Wu
Jia
J
Li
Naiming
N
Zhou
Yongzhou
Y
Hu
D000110:Acetylcholinesterase / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D054828:Histamine H3 Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D011810:Quinoxalines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D018100:Receptors, Histamine H3 / Q000378:metabolism; D013329:Structure-Activity Relationship
D002800:Cholinesterase Inhibitors; D054828:Histamine H3 Antagonists; D008024:Ligands; D011810:Quinoxalines; D018100:Receptors, Histamine H3; D000110:Acetylcholinesterase; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human