Novel quinazoline-urea analogues as modulators for A beta-induced mitochondrial dysfunction: Design, synthesis, and molecular docking study

Authors
Elkamhawy, AhmedLee, JiyounPark, Beoung-GeonPark, InsunPae, Ae NimRoh, Eun Joo
Issue Date
2014-09-12
Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
Citation
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v.84, pp.466 - 475
Abstract
A novel series of twenty-six quinazoline-urea derivatives was designed and synthesized. Their blocking activities against beta-amyloid peptide (A beta) induced mitochondrial permeability transition pore (mPTP) opening were evaluated by JC-1 assay which measured the change of mitochondrial membrane potential. Seven compounds showed better inhibitory activities than the standard Cyclosporin A (CsA). The most active analogues were tested by MTT assay to evaluate their toxicity on the cellular survival; they revealed excellent cellular viability. To explain the difference in inhibitory activity, molecular docking study using (GOLD) program was performed for selected sets of the most active and inactive compounds on cyclophilin D (CypD) receptor as a major component of mPTP. Moreover, ADME profiling, in silico toxicity, drug-likeness, and drug-score studies were discussed. From these results, we report compound 31 as the most active nonpeptidyl mPTP blocker possessing quinazoline-urea scaffold; 2 folds of CsA activity, which would constitute a new direction for the design of novel mPTP modulators. (C) 2014 Elsevier Masson SAS. All rights reserved.
Keywords
ALZHEIMERS-DISEASE; PERMEABILITY TRANSITION; AMYLOID-BETA; COGNITIVE DECLINE; CYCLOPHILIN; DERIVATIVES; DEMENTIA; ALZHEIMERS-DISEASE; PERMEABILITY TRANSITION; AMYLOID-BETA; COGNITIVE DECLINE; CYCLOPHILIN; DERIVATIVES; DEMENTIA; Mitochondrial permeability transition pore (mPTP); Alzheimer' s disease (AD); Quinazoline-urea; Cyclophilin D (CypD); beta-amyloid peptide (A beta); Molecular docking
ISSN
0223-5234
URI
https://pubs.kist.re.kr/handle/201004/126352
DOI
10.1016/j.ejmech.2014.07.027
Appears in Collections:
KIST Article > 2014
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