Design, synthesis, and Multivariate quantitative structure-activity relationship of Salicylanilides-Potent inhibitors of type III secretion in Yersinia
Design, synthesis, and Multivariate quantitative structure-activity relationship of Salicylanilides-Potent inhibitors of type III secretion in Yersinia
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DOI：
10.1021/jm070741b
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发表时间：
2007-11-29
影响因子：
7.3
通讯作者：
Elofsson, Mikael
中科院分区：
文献类型：
--
作者：
Dahlgren, Markus K.;Kauppi, Anna M.;Elofsson, Mikael
水杨酰苯胺N-（4-氯苯基）-2-乙酰氧基-3，5-二碘苯甲酰胺，1a，在耶尔森氏菌的III型分泌（T3 S）的抑制剂的类似物，选择，合成，并在三个周期的生物学评价。首先，合成了一组在水杨酸环部分具有变化的类似物以探测可能的结构变化。建立了基本的构效关系，然后用于从水杨酰苯胺的主成分分析得分图中挑选化合物以生成第二组。使用D-最优洋葱设计设计具有增加的生物活性可能性的第三组。使用与T3 S抑制%相关的结构单元的PLS评分向量作为响应，计算使用分层偏最小二乘回归潜在结构（Hi-PLS）的定量结构-活性关系模型。使用与Hi-PLS模型相同的描述符集推导出PLS判别分析（PLS-DA）模型。这两个模型都用外部测试集进行了验证。
Analogues to the salicylanilide N-(4-Chlorophenyl)-2-acetoxy-3,5-diiodobenzamide, 1a, an inhibitor of type III secretion (T3S) in Yersinia, were selected, synthesized, and biologically evaluated in three cycles. First, a set of analogues with variations in the salicylic acid ring moiety was synthesized to probe possible structural variation. A basic structure-activity relationship was established and then used to cherry-pick compounds from a principal component analysis score plot of salicylanilides to generate a second set. A third set with increased likelihood of biological activity was designed using D-optimal onion design. A quantitative structure-activity relationship model using hierarchical partial least-square regression to latent structures (Hi-PLS) was computed using PLS score vectors of building blocks correlated to the % inhibition of T3S as a response. A PLS discriminant analysis (PLS-DA) model was derived using the same descriptor set as that for the Hi-PLS model. Both models were validated with an external test set.