2,4-Disubstituted quinazolines as amyloid-β aggregation inhibitors with dual cholinesterase inhibition and antioxidant properties: Development and structure-activity relationship (SAR) studies

“…In this respect, design, synthesis, and biological evaluation of multi-target heterocycles have been the center of attention to develop potent and novel anti-AD drugs [10 -12] as well as diagnostic applications. [13,14] Focusing on the cholinesterase inhibitory activity of heterocycles, design and synthesis of a wide range of compounds such as coumarins, [15] 1,2,3-triazoles, [16][17][18][19] isoxazoles, [19,20] imidazoles, [21] pyrazoles, [22] and quinazolines, [23] etc., have been developed. In this work, following anti-ChE activity of our previously reported isoxazole derivatives A and B, [19,20] synthesis and biological evaluation of novel isoxazoles connected to phenylpiperazine moiety were reported ( Figure 2).…”

Section: Introductionmentioning

confidence: 99%

Design and Synthesis of Selective Acetylcholinesterase Inhibitors: Arylisoxazole‐Phenylpiperazine Derivatives

Saeedi

Mohtadi-Haghighi

Mirfazli

et al. 2019

Chemistry & Biodiversity

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In this work, a novel series of arylisoxazole-phenylpiperazines were designed, synthesized, and evaluated toward acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Our results revealed that [5-(2chlorophenyl)-1,2-oxazol-3-yl](4-phenylpiperazin-1-yl)methanone (5c) was the most potent AChE inhibitor with IC 50 of 21.85 μM. It should be noted that most of synthesized compounds showed no BChE inhibitory activity and [5-(2-fluorophenyl)-1,2-oxazol-3-yl](4-phenylpiperazin-1-yl)methanone (5a) was the most active anti-BChE derivative (IC 50 = 51.66 μM). Also, kinetic studies for the AChE and BChE inhibitory activity of compounds 5c and 5a confirmed that they have simultaneously bound to the catalytic site (CS) and peripheral anionic site (PAS) of both AChE and BChE. Furthermore, docking study of compound 5c showed desired interactions of that compound with amino acid residues located in the active and peripheral anionic sites. Compound 5c was also evaluated for its BACE1 inhibitory activity and demonstrated IC 50 = 76.78 μM. Finally, neuroprotectivity of compound 5c on Aβ-treated neurotoxicity in PC12 cells depicted low activity.

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“…This includes: (a) GSK‐3β and tau aggregation inhibitors (Gandini et al, ), (b) AChE and monoamine oxidase B inhibitors, (Xu et al, ) (c) beta‐secretase 1 (BACE‐1) and glycogen synthase kinase 3 (GSK‐3β), (Prati et al, ) (d) the hybridization of AChE inhibitor and serotonergic subtype 4 receptor (5‐HT4R) activator (Rochais et al, ), (e) the introduction of antioxidant selenium into the Aβ‐aggregation inhibitor (Wang et al, ), and (f) the modifications of multifunctional anti‐AD curcumin scaffold (Di Martino et al, ). Despite these prior efforts, Aβ and cholinesterases remain to be of paramount significance (Mohamed & Rao, ; Panek, Wichur, Godyń, Pasieka, & Malawska, ; Tonelli et al, ). Presently, the only pharmacological therapy for AD apart from N‐methyl d ‐aspartate receptor antagonist memantine, are the cholinesterase inhibitors, that is, donepezil, rivastigmine, and galantamine (Figure ).…”

Section: Introductionmentioning

confidence: 99%

“…Despite these prior efforts, Aβ and cholinesterases remain to be of paramount significance (Mohamed & Rao, 2017;Panek, Wichur, Gody n, Pasieka, & Malawska, 2017;Tonelli et al, 2015). Presently, the only pharmacological therapy for AD apart from N-methyl Daspartate receptor antagonist memantine, are the cholinesterase inhibitors, that is, donepezil, rivastigmine, and galantamine ( Figure 2).…”

mentioning

confidence: 99%

Dual targeting of cholinesterase and amyloid beta with pyridinium/isoquinolium derivatives

Chakravarty¹,

Ju²,

Wen-hua

et al. 2019

Drug Development Research

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With the surge in the cases of Alzheimer's disease (AD) over the years, several targets have been explored to curb the disease. Cholinesterases, namely acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), remain to be the available targets that are amendable to currently approved treatments. In this study, a series of novel compounds based on tramiprosate, a highly specific amyloid beta (Aβ) inhibitor, was designed to inhibit AChE, BuChE, and Aβ aggregation. In particular, the addition of a pyridinium/isoquinolinium ring to the tramiprosate moiety (to give compounds 3a–j) led to an increase in the binding affinity for the catalytic active site of cholinesterase, which was hampered by the presence of sulfonic acid. Exclusion of the sulfonic acid moiety led to a novel but effective class of cholinesterase inhibitors (9a–w). in vitro Aβ aggregation inhibition assay indicated that compounds 3a–j, 9e–f, 9i–l, 9q, 9r, 9u–w, and 12 could inhibit over 10% Aβ aggregation at 1 mM concentration. Cholinesterase inhibition assay suggested that compounds 9g, 9h, 9o, and 9q–t exhibit over 70% inhibition on both AChE and BuChE at a concentration of 100 μM. Amongst the designed molecules, compound 9r (ca 18% at 1 mM) showed comparable inhibitory effect on the inhibition of Aβ aggregation with tramiprosate (ca 20% at 1 mM), along with impressive cholinesterase inhibitory potential (AChE IC50 = 13 μM and BuChE IC50 = 12 μM), acceptable toxicity and ability to pass through blood brain barrier, which could be used to ameliorate the phenotypes of AD in preclinical models.

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2,4-Disubstituted quinazolines as amyloid-β aggregation inhibitors with dual cholinesterase inhibition and antioxidant properties: Development and structure-activity relationship (SAR) studies

Cited by 78 publications

References 57 publications

Design, synthesis and evaluation of scutellarein- O -acetamidoalkylbenzylamines as potential multifunctional agents for the treatment of Alzheimer's disease

Design, synthesis and evaluation of scutellarein- O -acetamidoalkylbenzylamines as potential multifunctional agents for the treatment of Alzheimer's disease

Design and Synthesis of Selective Acetylcholinesterase Inhibitors: Arylisoxazole‐Phenylpiperazine Derivatives

Dual targeting of cholinesterase and amyloid beta with pyridinium/isoquinolium derivatives

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