Lipkowitz K B, McCracken R O
Department of Chemistry, Indiana University-Purdue University, Indianapolis 46205.
J Parasitol. 1991 Dec;77(6):998-1005.
The structural and electronic features of a narrow-spectrum benzimidazole anthelmintic triclabendazole (TCZ, 6-chloro-5-[2,3-dichlorophenoxy]-2-methylthio-benzimidazole) and its 2 main metabolites triclabendazole sulfoxide (TCZ sulfoxide, 6-chloro-5-[2,3-dichlorophenoxyl]-2-methylsulfonyl-benzimidazole) and triclabendazole sulfone (TCZ sulfone, 6-chloro-5-[2,3-dichlorophenoxy]-2-methylsulfonyl-benzimidazole) have been determined using a combination of quantum mechanics, molecular graphics, and molecular modeling techniques. Using conformational analyses and quantum mechanics, 2 important differences were found between TCZ sulfoxide, the purported active species, and the broad-spectrum benzimidazole anthelmintics. The first distinguishing feature is the shape of the molecule; the substituent at the 2 position of TCZ sulfoxide is nonplanar. All other broad-spectrum benzimidazole anthelmintics, regardless of substituent at the 2 position (methyl carbamate or thiazolyl group), are flat. The second distinguishing feature is the net atomic charge on the substituent at the 2 position of TCZ sulfoxide; it is an order of magnitude larger than the net atomic charges on the other anthelmintics. Thus the nonplanar shape of the methysulfinyl group at the 2 position of TCZ sulfoxide is different (as is its net charge), suggesting that this may be the origin of its narrow spectrum of activity.
利用量子力学、分子图形学和分子建模技术相结合的方法，已确定了窄谱苯并咪唑驱虫药三氯苯达唑（TCZ，6-氯-5-[2,3-二氯苯氧基]-2-甲硫基苯并咪唑）及其2种主要代谢产物三氯苯达唑亚砜（TCZ亚砜，6-氯-5-[2,3-二氯苯氧基]-2-甲磺酰基苯并咪唑）和三氯苯达唑砜（TCZ砜，6-氯-5-[2,3-二氯苯氧基]-2-甲磺酰基苯并咪唑）的结构和电子特征。通过构象分析和量子力学发现，推测的活性物质TCZ亚砜与广谱苯并咪唑驱虫药之间存在2个重要差异。第一个显著特征是分子形状；TCZ亚砜2位的取代基是非平面的。所有其他广谱苯并咪唑驱虫药，无论2位的取代基（氨基甲酸甲酯或噻唑基）如何，都是平面的。第二个显著特征是TCZ亚砜2位取代基上的净原子电荷；它比其他驱虫药上的净原子电荷大一个数量级。因此，TCZ亚砜2位甲亚磺酰基的非平面形状不同（其净电荷也是如此），这表明这可能是其窄谱活性的起源。
