Das Anindya, Adak Avijit K, Ponnapalli Kalyankumar, Lin Chien-Hung, Hsu Kai-Cheng, Yang Jinn-Moon, Hsu Tsu-An, Lin Chun-Cheng
Department of Chemistry, National Tsing Hua University, 101, Section 2, Kuang-Fu Road, Hsinchu 30013, Taiwan.
Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
Eur J Med Chem. 2016 Nov 10;123:397-406. doi: 10.1016/j.ejmech.2016.07.064. Epub 2016 Jul 28.
The design of potent metabolically stable neuraminidase (NA) inhibitors represents an attractive approach for treating influenza virus infection. In this study, we describe the exploitation of the 150-cavity in the active site of group 1 NA for the design, synthesis, and in vitro evaluation of new triazole-containing N-acyl derivatives related to Zanamivir. Inhibition studies with influenza virus NAs of group 1 (H1N1) and group 2 (H3N2) revealed that several of them are good inhibitors, with IC50 values in the low nanomolar (2.3 nM-31 nM) range. Substituents that form stable van der Waals interaction with the 150-cavity residues play crucial roles in NA inhibition as demonstrated by the potency of 6a (H1N1 IC50 = 2.3 nM, and H3N2 IC50 = 2.9 nM). Docking studies indicated that the cyclohexane-substituted triazole ring extended toward the hydrophobic region in the active site of group 1 NA in open form. The high potency observed for inhibitor 6a may be attributable to the highly favorable hydrophobic interactions in this region.
设计高效代谢稳定的神经氨酸酶（NA）抑制剂是治疗流感病毒感染的一种有吸引力的方法。在本研究中，我们描述了利用1型NA活性位点中的150腔来设计、合成和体外评估与扎那米韦相关的含新三唑的N-酰基衍生物。对1型（H1N1）和2型（H3N2）流感病毒NA的抑制研究表明，其中几种是良好的抑制剂，IC50值在低纳摩尔（2.3 nM - 31 nM）范围内。如6a的效力所示，与150腔残基形成稳定范德华相互作用的取代基在NA抑制中起关键作用（H1N1的IC50 = 2.3 nM，H3N2的IC50 = 2.9 nM）。对接研究表明，环己烷取代的三唑环以开放形式向1型NA活性位点的疏水区域延伸。观察到抑制剂6a具有高效力可能归因于该区域高度有利的疏水相互作用。
