Medicinal Plants Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, 14155, Tehran, Iran.
Persian Medicine and Pharmacy Research Center, Tehran University of Medical Sciences, 14155, Tehran, Iran.
Chem Biodivers. 2020 May;17(5):e1900746. doi: 10.1002/cbdv.201900746. Epub 2020 Apr 15.
A novel series of hybrid arylisoxazole-chromenone carboxamides were designed, synthesized, and evaluated for their cholinesterase (ChE) inhibitory activity based on the modified Ellman's method. Among synthesized compounds, 5-(3-nitrophenyl)-N-{4-[(2-oxo-2H-1-benzopyran-7-yl)oxy]phenyl}-1,2-oxazole-3-carboxamide depicted the most acetylcholinesterase (AChE) inhibitory activity (IC =1.23 μm) and 5-(3-chlorophenyl)-N-{4-[(2-oxo-2H-1-benzopyran-7-yl)oxy]phenyl}-1,2-oxazole-3-carboxamide was found to be the most potent butyrylcholinesterase (BChE) inhibitor (IC =9.71 μm). 5-(3-Nitrophenyl)-N-{4-[(2-oxo-2H-1-benzopyran-7-yl)oxy]phenyl}-1,2-oxazole-3-carboxamide was further investigated for its BACE1 inhibitory activity as well as neuroprotectivity and metal chelating ability as important factors involved in onset and progress of Alzheimer's disease. It could inhibit BACE1 by 48.46 % at 50 μm. It also showed 6.4 % protection at 25 μm and satisfactory chelating ability toward Zn , Fe , and Cu ions. Docking studies of 5-(3-nitrophenyl)-N-{4-[(2-oxo-2H-1-benzopyran-7-yl)oxy]phenyl}-1,2-oxazole-3-carboxamide and 5-(3-chlorophenyl)-N-{4-[(2-oxo-2H-1-benzopyran-7-yl)oxy]phenyl}-1,2-oxazole-3-carboxamide confirmed desired interactions with those amino acid residues of the AChE and BChE, respectively.
基于改良的 Ellman 法，我们设计、合成了一系列新型的芳基异恶唑-色满酮混合酰胺，并评估了它们对胆碱酯酶（ChE）的抑制活性。在所合成的化合物中，5-(3-硝基苯基）-N-{4-[(2-氧代-2H-1-苯并吡喃-7-基）氧基]苯基}-1,2-恶唑-3-甲酰胺对乙酰胆碱酯酶（AChE）的抑制活性最强（IC =1.23 μm），而 5-(3-氯苯基）-N-{4-[(2-氧代-2H-1-苯并吡喃-7-基）氧基]苯基}-1,2-恶唑-3-甲酰胺对丁酰胆碱酯酶（BChE）的抑制活性最强（IC =9.71 μm）。我们进一步研究了 5-(3-硝基苯基）-N-{4-[(2-氧代-2H-1-苯并吡喃-7-基）氧基]苯基}-1,2-恶唑-3-甲酰胺对 BACE1 的抑制活性以及神经保护作用和金属螯合能力，因为这些因素与阿尔茨海默病的发生和发展有关。它在 50 μm 时可以抑制 BACE1 活性达 48.46%。在 25 μm 时，它也表现出 6.4%的保护作用，并对 Zn、Fe 和 Cu 离子具有良好的螯合能力。5-(3-硝基苯基）-N-{4-[(2-氧代-2H-1-苯并吡喃-7-基）氧基]苯基}-1,2-恶唑-3-甲酰胺和 5-(3-氯苯基）-N-{4-[(2-氧代-2H-1-苯并吡喃-7-基）氧基]苯基}-1,2-恶唑-3-甲酰胺的对接研究证实了它们与 AChE 和 BChE 的相应氨基酸残基的预期相互作用。
