title: Novel quinazoline-urea analogues as modulators for Aβ-induced mitochondrial dysfunction: design, synthesis, and molecular docking study.
abstract: A novel series of twenty-six quinazoline-urea derivatives was designed and synthesized. Their blocking activities against β-amyloid peptide (Aβ) 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.
authors: Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST), Seoul 136-791, South Korea; Department of Biological Chemistry, Korea University of Science and Technology (UST), Daejeon 305-350, South Korea.
authors: Ahmed
authors: A
authors: Elkamhawy
authors: Department of Global Medical Science, Sungshin Women's University, Seoul 142-732, South Korea.
authors: Jiyoun
authors: J
authors: Lee
authors: School of Life Sciences and Biotechnology, Korea University, Seoul 136-701, South Korea; Center of Neuromedicine, Korea Institute of Science and Technology (KIST), Seoul 136-791, South Korea.
authors: Beoung-Geon
authors: BG
authors: Park
authors: Center of Neuromedicine, Korea Institute of Science and Technology (KIST), Seoul 136-791, South Korea; Department of Biotechnology, Yonsei University, Seoul 120-749, South Korea.
authors: Insun
authors: I
authors: Park
authors: Center of Neuromedicine, Korea Institute of Science and Technology (KIST), Seoul 136-791, South Korea.
authors: Ae Nim
authors: AN
authors: Pae
authors: Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST), Seoul 136-791, South Korea; Department of Biological Chemistry, Korea University of Science and Technology (UST), Daejeon 305-350, South Korea. Electronic address: jennyej105@hotmail.com.
authors: Eun Joo
authors: EJ
authors: Roh
mesh_terms: D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D011799:Quinazolines; D014508:Urea
keywords: Alzheimer's disease (AD); Cyclophilin D (CypD); Mitochondrial permeability transition pore (mPTP); Molecular docking; Quinazoline-urea; β-amyloid peptide (Aβ)