Venkatesham Akkaladevi, Saudi Milind, Kaptein Suzanne, Neyts Johan, Rozenski Jef, Froeyen Mathy, Van Aerschot Arthur
KU Leuven, Rega Institute for Medical Research, Medicinal Chemistry, Herestraat 49, 3000 Leuven, Belgium.
KU Leuven, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Herestraat 49, 3000 Leuven, Belgium.
Eur J Med Chem. 2017 Jan 27;126:101-109. doi: 10.1016/j.ejmech.2016.10.008. Epub 2016 Oct 5.
Previous efforts led to dicarboxamide derivatives like 1.3, comprising either an imidazole, pyrazine or fenyl ring as the central scaffold, with many congeners displaying strong inhibitory effects against dengue virus (DENV) in cell-based assays. Following up on some literature reports, the rationale was borne out to preserve the pending groups, now attached to either a 2,6-diaminopurine or 2,4-diaminoquinazoline scaffold. Synthetic efforts turned out less straightforward than expected, but yielded some new derivatives with low micromolar anti-DENV activity, albeit not devoid of cellular toxicity. The purine 14 proved the most potent compound for this series with an EC50 of 1.9 μM and a selectivity index of 58, while the quinazoline 18a displayed an EC50 of 2.6 μM with SI of only 2.
先前的研究成果产生了二羧酰胺衍生物，如1.3，其包含咪唑、吡嗪或苯基环作为中心骨架，许多同类物在基于细胞的试验中对登革热病毒（DENV）表现出强烈的抑制作用。根据一些文献报道，保留现在连接到2,6-二氨基嘌呤或2,4-二氨基喹唑啉骨架上的悬垂基团的基本原理得到了证实。合成工作比预期的要复杂一些，但产生了一些具有低微摩尔抗DENV活性的新衍生物，尽管并非没有细胞毒性。嘌呤14被证明是该系列中最有效的化合物，EC50为1.9 μM，选择性指数为58，而喹唑啉18a的EC50为2.6 μM，SI仅为2。
