Sun Aiming, Prussia Andrew, Zhan Weiqiang, Murray Ernest E, Doyle Joshua, Cheng Li-Ting, Yoon Jeong-Joong, Radchenko Eugene V, Palyulin Vladimir A, Compans Richard W, Liotta Dennis C, Plemper Richard K, Snyder James P
Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, USA.
J Med Chem. 2006 Aug 24;49(17):5080-92. doi: 10.1021/jm0602559.
Measles virus (MV) is one of the most infectious pathogens known. Despite the existence of a vaccine, over 500,000 deaths/year result from MV or associated complications. Anti-measles compounds could conceivably reverse these statistics. Previously, we described a homology model of the MV fusion protein trimer and a putative binding site near the head-neck region. The resulting model permitted the identification of two nonpeptidic entry inhibitors. Here, we present the design, synthesis, and bioevaluation of several series of fusion inhibitors and describe their structure-activity relationships (SAR). Five simply substituted anilides show low-microM blockade of the MV, one of which (AS-48) exhibits IC50 = 0.6-3.0 microM across a panel of wild-type MV strains found in the field. Molecular field topology analysis (MFTA), a 2D QSAR approach based on local molecular properties (atomic charges, hydrogen-bonding capacity and local lipophilicity), applied to the anilide series suggests structural modifications to improve potency.
麻疹病毒（MV）是已知传染性最强的病原体之一。尽管有疫苗存在，但每年仍有超过50万例死亡由麻疹病毒或相关并发症导致。可以想象，抗麻疹化合物可能会扭转这些统计数据。此前，我们描述了麻疹病毒融合蛋白三聚体的同源模型以及头颈部区域附近的一个假定结合位点。由此产生的模型使得能够鉴定出两种非肽类进入抑制剂。在此，我们展示了几系列融合抑制剂的设计、合成及生物评估，并描述了它们的构效关系（SAR）。五种简单取代的苯胺类化合物对麻疹病毒表现出低微摩尔浓度的阻断作用，其中一种（AS - 48）在一组野外发现的野生型麻疹病毒株中表现出IC50 = 0.6 - 3.0微摩尔。应用于苯胺类系列的分子场拓扑分析（MFTA），一种基于局部分子性质（原子电荷、氢键能力和局部亲脂性）的二维定量构效关系方法，表明可通过结构修饰来提高效力。
