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New synthetic 1,2,4-triazole derivatives: Cholinesterase inhibition and molecular docking studies
Results in Chemistry Pub Date : 2020-04-14 , DOI: 10.1016/j.rechem.2020.100041
Naheed Riaz , Muhammad Iftikhar , Muhammad Saleem , Aziz-ur-Rehman , Safdar Hussain , Fatima Rehmat , Zainab Afzal , Saba Khawar , Muhammad Ashraf , Mariya al-Rashida

Two series of new N-aryl derivatives (9a-j; 10a-j) of 2-(4-ethyl-5-(3-chlorophenyl)-4H-1,2,4-triazol-3-ylthio)acetamide and 2-(4-phenyl-5-(3-chlorophenyl)-4H-1,2,4-triazol-3-ylthio)acetamide were synthesized by the successive conversions of 3-chlorobenzoic acid (a) into its respective ester (1) hydrazide (2), and into N-substituted 1,2,4-triazole (5, 6) via 3 and 4, respectively. The target compounds (9a-j; 10a-j) were obtained by the reaction of N-substituted 1,2,4-triazole (5, 6) with various electrophiles (8a-j), in N,N-dimethyl formamide (DMF) and sodium hydride (NaH). The synthesized analogues were characterized by using FTIR, 1H, 13C NMR spectroscopy, EIMS and HREIMS spectrometry. All the synthesized compounds, 9a-j and 10a-j, were evaluated for their inhibitory potential against acetylcholinesterase (AChE) and butyrylcholinestrase (BChE), where these compounds showed moderate to good activities against the tested enzymes. Compounds 9j and 10f displayed potent inhibitory potential (IC50 5.41 ± 0.24 & 13.57 ± 0.31 μM, respectively) against AChE while compound 9j exhibited potent inhibitory activity (IC50 7.52 ± 0.18 μM) against BChE. Other compounds showed good to moderate inhibitory activities against the said enzymes in the range of IC50 14.29–43.94 μM for AChE and IC50 21.59–41.54 μM for BChE. To rationalize the binding site interactions, docking studies were carried out. All docked compounds were found to bind in the active site with similar binding orientation and favorable binding interactions with the surrounding amino acids.



中文翻译:

新的合成1,2,4-三唑衍生物:抑制胆碱酯酶和分子对接研究

2-(4-乙基-5-(3-氯苯基)-4H-1,2,4-三唑-3-基硫基)乙酰胺和2的两个系列的新N-芳基衍生物(9a - j ; 10a - j)通过将3-氯苯甲酸(a)依次转化为其相应的酯(1),合成了-(4-苯基-5-(3-氯苯基)-4H-1,2,4-三唑-3-基硫基)乙酰胺酰肼(2),并进入ñ取代的1,2,4-三唑(56孔)34分别。目标化合物(9a - j ; 10a - j)通过反应获得Ñ取代1,2,4-三唑(56)与各种亲电体(图8a - Ĵ),在Ññ -二甲基甲酰胺(DMF)和氢化钠(NaH)。通过使用FTIR,1 H,13 C NMR光谱,EIMS和HREIMS光谱来表征合成的类似物。所有合成的化合物9a - j10a - j评估了它们对乙酰胆碱酯酶(AChE)和丁酰胆碱酯酶(BChE)的抑制潜力,其中这些化合物对测试的酶显示出中等至良好的活性。化合物9j10f表现出对AChE的有效抑制潜力(分别为IC 50 5.41±0.24和13.57±0.31μM),而化合物9j表现出了对BChE的有效抑制活性(IC 50 7.52±0.18μM)。其他化合物对AChE和IC 50的IC 50为14.29-43.94μM,对上述酶表现出良好至中等的抑制活性BChE为21.59–41.54μM。为了合理化结合位点相互作用,进行了对接研究。发现所有对接的化合物都以相似的结合方向和与周围氨基酸的有利结合相互作用结合在活性位点。

更新日期:2020-04-14
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