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

• This study is concerned with design and synthesis of novel nonpeptidyl mPTP blockers with quinazoline-urea scaffold.
• Seven compounds displayed superior activity to CsA with excellent cell viability.
• Docking study using GOLD software was performed to explain the in vitro activity.
• Compound 31 is regarded as the most active nonpeptidyl mPTP blocker with quinazoline-urea scaffold.

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.

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