Hakimi Arash Modarres, Lashgari Negar, Mahernia Shabnam, Ziarani Ghodsi Mohammadi, Amanlou Massoud
Drug Design & Development Research Centre and Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, I.R. Iran.
School of Chemistry, College of Science, University of Tehran, Tehran, I.R. Iran.
Res Pharm Sci. 2017 Oct;12(5):353-363. doi: 10.4103/1735-5362.213980.
In the current study, a series of 3,4-dihydro-2-pyridone derivatives were synthesized in a one-pot fourcomponent reaction of Meldrum's acid, benzaldehyde derivatives, methyl acetoacetate, and ammonium acetate. SiO2-Pr-SO3H was used as an efficient catalyst for the synthesis of the target compounds under solvent-free conditions. The most probable mechanism for this reaction has been discussed. The advantages of this methodology are high product yields, being environmentally benign, short reaction times, and easy handling. Eight 2-pyridinone derivatives were evaluated for their inhibitory activities against Jack bean urease. Molecular docking study of the synthesized compounds was also evaluated. All compounds showed good activities against urease and among them, 4-(4-nitrophenyl)-5-methoxycarbonyl-6-methyl-3,4-dihydropyridone () showed the most potent activity (IC = 29.12 µM), more potent than hydroxyurea as the reference drug (IC = 100.0 µM). Also, the results from docking studies were in good agreement with those obtained with assay. According to the docking studies methionine (Met) 637 and nitro phenyl ring cause n-π interaction between lone pair of sulfur atom and π aromatic ring. Moreover, hydrophobic interactions existed between compound and alanine (ALA) 636, ALA 440, and isoleucine 411. The results indicated that the inhibitory activities increased with the increase of electron withdrawing ability of the groups despite a less important role of lipophilicity in increasing the inhibitory activity.
在当前研究中，通过丙二酸亚异丙酯、苯甲醛衍生物、乙酰乙酸甲酯和乙酸铵的一锅四组分反应合成了一系列3,4-二氢-2-吡啶酮衍生物。SiO2-Pr-SO3H被用作在无溶剂条件下合成目标化合物的高效催化剂。已讨论了该反应最可能的机理。该方法的优点是产物收率高、环境友好、反应时间短且易于操作。评估了八种2-吡啶酮衍生物对刀豆脲酶的抑制活性。还对合成化合物进行了分子对接研究。所有化合物均显示出良好的脲酶抑制活性，其中4-(4-硝基苯基)-5-甲氧基羰基-6-甲基-3,4-二氢吡啶酮（）表现出最强的活性（IC = 29.12 µM），比作为参考药物的羟基脲（IC = 100.0 µM）更有效。此外，对接研究的结果与实验获得的结果高度一致。根据对接研究，甲硫氨酸（Met）637和硝基苯环导致硫原子孤对与π芳香环之间的n-π相互作用。此外，化合物与丙氨酸（ALA）636、ALA 440和异亮氨酸411之间存在疏水相互作用。结果表明，尽管亲脂性在增加抑制活性方面的作用较小，但抑制活性随着基团吸电子能力的增加而增强。
