Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Joan XXIII, s/n, Barcelona, E-08028, Spain.
Department of Biosciences and National Research Council (CNR) Biophysics Institute (IBF), University of Milan, Via Celoria 26, 20133 Milan, Italy.
Eur J Med Chem. 2015;96:318-29. doi: 10.1016/j.ejmech.2015.04.030. Epub 2015 Apr 14.
Two new polycyclic scaffolds were synthesized and evaluated as anti-influenza A compounds. The 5-azapentacyclo[6.4.0.0(2,10).0(3,7).0(9,11)]dodecane derivatives were only active against the wild-type M2 channel in the low-micromolar range. However, some of the 14-azaheptacyclo[8.6.1.0(2,5).0(3,11).0(4,9).0(6,17).0(12,16)]heptadecane derivatives were dual inhibitors of the wild-type and the V27A mutant M2 channels. The antiviral activity of these molecules was confirmed by cell culture assays. Their binding mode was analysed through molecular dynamics simulations, which showed the existence of distinct binding modes in the wild type M2 channel and its V27A variant.
两种新的多环支架被合成并评估为抗流感 A 化合物。5-氮杂戊烷衍生物仅在低微摩尔范围内对野生型 M2 通道表现出活性。然而，一些 14-氮杂庚烷衍生物是野生型和 V27A 突变型 M2 通道的双重抑制剂。这些分子的抗病毒活性通过细胞培养实验得到证实。通过分子动力学模拟分析了它们的结合模式，结果表明在野生型 M2 通道及其 V27A 变体中存在不同的结合模式。
