Division of Pharmaceutical Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, Athens 15771, Greece.
Molecular Virology Laboratory, Hellenic Pasteur Institute, 127 Vas. Sofias ave., 11521 Athens, Greece.
Bioorg Chem. 2020 May;98:103580. doi: 10.1016/j.bioorg.2020.103580. Epub 2020 Jan 28.
The design and synthesis of a number of new imidazo[4,5-b]pyridines is described. The heterocyclic scaffold possesses 6-chloro- or 5,6-dichloro-substitution and bears various 2-alkylamino-methyl or ethyl groups. The corresponding N and N-tosylates are also presented. The anti-HBV activity of the compounds was evaluated in HBV infectious system at the level of HBV rcDNA secretion and CC, EC and selectivity index values were determined. The tosylates showed low antiviral potency and relatively high cytotoxicity, on the contrary, a number of 2,5 and/or-6-substituted imidazopyridines, mainly those belonging to the 6-chloroimidazo[4,5-b]pyridine series, were endowed with a very interesting profile and were further investigated. The most promising among them, along with the reduction of the secreted HBV rcDNA, also caused a reduction in HBV cccDNA and pgRNA levels, with a concomitant accumulation of the intracellular encapsidated rcDNA. Surprisingly, the most active 2-diethylaminoethyl-substituted derivative (21d), was highly competitive to interferon.
描述了一系列新型咪唑并[4,5-b]吡啶的设计和合成。该杂环支架具有 6-氯或 5,6-二氯取代基，并带有各种 2-烷氨基甲基或乙基取代基。还呈现了相应的 N 和 N-对甲苯磺酸盐。在 HBV 感染系统中，在 HBV rcDNA 分泌水平上评估了化合物的抗 HBV 活性，并确定了 CC、EC 和选择性指数值。甲苯磺酸盐显示出低抗病毒效力和相对高细胞毒性，相反，许多 2,5 和/或-6 取代的咪唑并吡啶，主要属于 6-氯咪唑并[4,5-b]吡啶系列，具有非常有趣的特性，并进一步进行了研究。其中最有前途的化合物，除了减少分泌的 HBV rcDNA 外，还导致 HBV cccDNA 和 pgRNA 水平降低，同时细胞内包裹的 rcDNA 积累。令人惊讶的是，最有效的 2-二乙氨基乙基取代衍生物（21d），与干扰素具有很强的竞争力。
