Saudi Milind, Zmurko Joanna, Kaptein Suzanne, Rozenski Jef, Gadakh Bharat, Chaltin Patrick, Marchand Arnaud, Neyts Johan, Van Aerschot Arthur
KU Leuven, Rega Institute for Medical Research, Medicinal Chemistry, Minderbroedersstraat 10, 3000 Leuven, Belgium.
KU Leuven, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Minderbroedersstraat 10, 3000 Leuven, Belgium.
Eur J Med Chem. 2016 Oct 4;121:158-168. doi: 10.1016/j.ejmech.2016.05.043. Epub 2016 May 21.
High-throughput screening of a subset of the CD3 chemical library (Centre for Drug Design and Discovery; KU Leuven) provided us with a lead compound 1, displaying low micromolar potency against dengue virus and yellow fever virus. Within a project aimed at discovering new inhibitors of flaviviruses, substitution of its central imidazole ring led to synthesis of variably substituted pyrazine dicarboxylamides and phthalic diamides, which were evaluated in cell-based assays for cytotoxicity and antiviral activity against the dengue virus (DENV) and yellow fever virus (YFV). Fourteen compounds inhibited DENV replication (EC50 ranging between 0.5 and 3.4 μM), with compounds 6b and 6d being the most potent inhibitors (EC50 0.5 μM) with selectivity indices (SI) > 235. Compound 7a likewise exhibited anti-DENV activity with an EC50 of 0.5 μM and an SI of >235. In addition, good antiviral activity of seven compounds in the series was also noted against the YFV with EC50 values ranging between 0.4 and 3.3 μM, with compound 6n being the most potent for this series with an EC50 0.4 μM and a selectivity index of >34. Finally, reversal of one of the central amide bonds as in series 13 proved deleterious to the inhibitory activity.
对CD3化学文库的一个子集（药物设计与发现中心；鲁汶大学）进行高通量筛选，为我们提供了一种先导化合物1，它对登革热病毒和黄热病毒显示出低微摩尔效力。在一个旨在发现黄病毒新抑制剂的项目中，对其中心咪唑环进行取代，导致合成了各种取代的吡嗪二甲酰胺和邻苯二甲酰胺，并在基于细胞的试验中对它们针对登革热病毒（DENV）和黄热病毒（YFV）的细胞毒性和抗病毒活性进行了评估。14种化合物抑制了DENV复制（EC50在0.5至3.4 μM之间），化合物6b和6d是最有效的抑制剂（EC50为0.5 μM），选择性指数（SI）>235。化合物7a同样表现出抗DENV活性，EC50为0.5 μM，SI>235。此外，该系列中的7种化合物对YFV也具有良好的抗病毒活性，EC50值在0.4至3.3 μM之间，化合物6n是该系列中最有效的，EC50为0.4 μM，选择性指数>34。最后，如系列13中那样反转一个中心酰胺键被证明对抑制活性有害。
