Adsorption to the Surface of Hemozoin Crystals: Structure-Based Design and Synthesis of Amino-Phenoxazine β-Hematin Inhibitors.
Adsorption to the Surface of Hemozoin Crystals: Structure-Based Design and Synthesis of Amino-Phenoxazine β-Hematin Inhibitors.
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DOI：
10.1002/cmdc.202200139
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发表时间：
2022-05-18
期刊：
影响因子：
3.4
通讯作者：
中科院分区：
文献类型：
--
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在硅吸附中，8种抑制β-血红素（合成血色素）形成的抗疟药物在（001）表面发现了一个主要的结合位点，该位点主要通过π-π相互作用的形成来容纳抑制剂。吸附能与β-血红素抑制活性的对数之间存在良好的相关性（r2 = 0.64, P = 0.017）。在53种单环、双环和三环支架中，后者的吸附能最好。基于吸附行为，研究了5种新的氨基-苯恶嗪类化合物作为β-血红素抑制剂。2-取代苯恶嗪对3D7菌株表现出良好至中度的β-血红素抑制活性（< 100 μM）和恶性疟原虫血期活性。N1，N1-二乙基- n4 -（10h -苯恶嗪-2-基）戊烷-1,4-二胺（P2a）的IC50值分别为4.7±0.6 μM和0.64±0.05 μM，是最有希望的hit。吸附能可以预测β-血红素抑制活性，因此，基于硅的方法是基于结构开发新的非喹啉抑制剂的有益工具。53个环支架在β-血红蛋白晶体的最快（001）表面上的硅吸附鉴定了吩恶嗪支架的进一步衍生化。合成了一个具有预测β-血红素抑制活性的2-和3-取代氨基-苯恶嗪化合物文库。P2a显示出最有希望的β-血红素抑制和抗疟原虫活性。
In silico adsorption of eight antimalarials that inhibit β-hematin (synthetic hemozoin) formation identified a primary binding site on the (001) face, which accommodates inhibitors via formation of predominantly π-π interactions. A good correlation (r2 = 0.64, P = 0.017) between adsorption energies and the logarithm of β-hematin inhibitory activity was found for this face. Of 53 monocyclic, bicyclic and tricyclic scaffolds, the latter yielded the most favorable adsorption energies. Five new amino-phenoxazine compounds were pursued as β-hematin inhibitors based on adsorption behaviour. The 2-substituted phenoxazines show good to moderate β-hematin inhibitory activity (< 100 μM) and Plasmodium falciparum blood stage activity against the 3D7 strain. N1,N1-diethyl-N4-(10H-phenoxazin-2-yl)pentane-1,4-diamine (P2a) is the most promising hit with IC50 values of 4.7 ± 0.6 and 0.64 ± 0.05 μM, respectively. Adsorption energies are predictive of β-hematin inhibitory activity, and thus the in silico approach is a beneficial tool for structure-based development of new non-quinoline inhibitors. The in silico adsorption of 53 cyclic scaffolds to the fastest-growing (001) face of a β-hematin crystal identified the phenoxazine scaffold for further derivatization. A small library of 2- and 3-substituted amino-phenoxazine compounds with predicted β-hematin inhibitory activity were synthesized. P2a shows the most promising β-hematin inhibition and antiplasmodium activity.
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影响因子：
4.2
作者：
Ge, Jian-Feng;Arai, Chika;Ihara, Masataka
通讯作者：
Ihara, Masataka
影响因子：
18.3
作者：
de Villiers KA;Egan TJ
通讯作者：
Egan TJ
DOI：
10.1039/b914359a
发表时间：
2010-02-07
期刊：
Dalton transactions (Cambridge, England : 2003)
影响因子：
--
作者：
Hoang AN;Ncokazi KK;de Villiers KA;Wright DW;Egan TJ
通讯作者：
Egan TJ
影响因子：
3.8
作者：
Buller, R;Peterson, ML;Leiserowitz, L
通讯作者：
Leiserowitz, L
影响因子：
2.1
作者：
Gamble, Allan B.;Garner, James;Keller, Paul A.
通讯作者：
Keller, Paul A.