Çınar Gözde, Alikadıoğlu Zeynep, Soylu-Eter Özge, Naesens Lieve, Cihan-Üstündağ Gökçe
Institute of Health Sciences, Istanbul University, Istanbul, Turkey.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Istanbul Health and Technology University, Istanbul, Turkey.
Drug Dev Res. 2025 Apr;86(2):e70080. doi: 10.1002/ddr.70080.
Hemagglutinin (HA) is a viral glycoprotein that mediates influenza virus entry into the host cell and is considered a relevant viral target. We here report the identification of a class of 4-tert-butylphenyl-substituted spirothiazolidinones as HA-mediated fusion inhibitors with specific activity against influenza A/H3N2 virus. The novel spirocyclic compounds were achieved by using one-pot cyclocondensation method and the chemical structures were characterized by IR, H NMR, C NMR, and elemental analysis. Compound 2c, bearing methyl substitutions at positions 2- and 8- of the spiro ring displayed an EC value against influenza A/H3N2 virus of 1.3 μM and an antiviral selectivity index of 30. The fusion-inhibiting effect of compound 2c was revealed in the polykaryon assay which is based on cell-cell fusion when influenza virus H3 HA-transfected cells are exposed to low pH. Computer-aided docking was performed to predict the possible binding pocket in the H3 HA trimer. Resistance data and in silico studies indicated that compound 2c has an overlapping binding pocket in the stem region of H3 HA with the known fusion inhibitors TBHQ and arbidol.
血凝素（HA）是一种病毒糖蛋白，介导流感病毒进入宿主细胞，被认为是一个相关的病毒靶点。我们在此报告了一类4-叔丁基苯基取代的螺噻唑烷酮作为HA介导的融合抑制剂，对甲型H3N2流感病毒具有特异性活性。这些新型螺环化合物通过一锅环缩合方法制备，其化学结构通过红外光谱（IR）、氢核磁共振（H NMR）、碳核磁共振（C NMR）和元素分析进行表征。在螺环的2-位和8-位带有甲基取代基的化合物2c对甲型H3N2流感病毒的半数有效浓度（EC）值为1.3 μM，抗病毒选择性指数为30。在多核体试验中揭示了化合物2c的融合抑制作用，该试验基于当转染流感病毒H3 HA的细胞暴露于低pH值时的细胞间融合。进行了计算机辅助对接以预测H3 HA三聚体中可能的结合口袋。耐药性数据和计算机模拟研究表明，化合物2c在H3 HA的茎区与已知的融合抑制剂特丁基对苯二酚（TBHQ）和阿比多尔具有重叠的结合口袋。
