Department of Chemistry, Wichita State University, Wichita, KS 67260, USA.
Bioorg Med Chem. 2012 Jul 1;20(13):4140-8. doi: 10.1016/j.bmc.2012.04.055. Epub 2012 May 10.
Dengue and West Nile viruses (WNV) are mosquito-borne members of flaviviruses that cause significant morbidity and mortality. There is no approved vaccine or antiviral drugs for human use to date. In this study, a series of functionalized meta and para aminobenzamide derivatives were synthesized and subsequently screened in vitro against Dengue virus and West Nile virus proteases. Four active compounds were identified which showed comparable activity toward the two proteases and shared in common a meta or para(phenoxy)phenyl group. The inhibition constants (K(i)) for the most potent compound 7n against Dengue and West Nile virus proteases were 8.77 and 5.55 μM, respectively. The kinetics data support a competitive mode of inhibition of both proteases by compound 7n. This conclusion is further supported by molecular modeling. This study reveals a new chemical scaffold which is amenable to further optimization to yield potent inhibitors of the viral proteases via the combined utilization of iterative medicinal chemistry/structure-activity relationship studies and in vitro screening.
登革热和西尼罗河病毒（WNV）是蚊媒传播的黄病毒属成员，可导致严重的发病率和死亡率。迄今为止，尚无针对人类使用的经批准的疫苗或抗病毒药物。在这项研究中，合成了一系列功能化的间位和对位氨基苯甲酰胺衍生物，并随后在体外对登革热病毒和西尼罗河病毒蛋白酶进行了筛选。鉴定出四种活性化合物，它们对两种蛋白酶表现出相当的活性，并且共同具有间位或对位（苯氧基）苯基。最有效的化合物 7n 对登革热和西尼罗河病毒蛋白酶的抑制常数（K（i））分别为 8.77 和 5.55 μM。动力学数据支持化合物 7n 通过竞争模式抑制两种蛋白酶。这一结论得到了分子建模的进一步支持。这项研究揭示了一种新的化学支架，通过迭代药物化学/构效关系研究和体外筛选的联合利用，可进一步优化生成针对病毒蛋白酶的有效抑制剂。
