A persistent latent reservoir of virus in CD4+ T cells is a major barrier to cure HIV. Activating viral transcription in latently infected cells using small molecules is one strategy being explored to eliminate latency. We previously described the use of a FlpIn.FM HEK293 cellular assay to identify and then optimize the 2-acylaminothiazole class to exhibit modest activation of HIV gene expression. Here, we implement two strategies to further improve the activation of viral gene expression and physicochemical properties of this class. Firstly, we explored rigidification of the central oxy-carbon linker with a variety of saturated heterocycles, and secondly, investigated bioisosteric replacement of the 2-acylaminothiazole moiety. The optimization process afforded lead compounds (74 and 91) from the 2-piperazinyl thiazolyl urea and the imidazopyridine class. The lead compounds from each class demonstrate potent activation of HIV gene expression in the FlpIn.FM HEK293 cellular assay (both with LTR EC50s of 80 nM) and in the Jurkat Latency 10.6 cell model (LTR EC50 220 and 320 nM respectively), but consequently activate gene expression non-specifically in the FlpIn.FM HEK293 cellular assay (CMV EC50 70 and 270 nM respectively) manifesting in cellular cytotoxicity. The lead compounds have potential for further development as novel latency reversing agents.

中文翻译：

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优化5取代的噻唑基脲和6取代的咪唑并吡啶作为潜在的HIV-1潜伏期逆转剂。

CD4 + T细胞中病毒的持久性潜在贮藏库是治愈HIV的主要障碍。使用小分子激活潜伏感染细胞中的病毒转录是探索消除潜伏期的一种策略。我们先前描述了使用FlpIn.FM HEK293细胞分析法来鉴定然后优化2-酰基氨基噻唑类以显示适度激活HIV基因表达的用途。在这里，我们实施两种策略来进一步改善此类病毒基因表达的激活和理化特性。首先，我们探索了各种饱和杂环对中央氧碳连接基的刚性作用，其次，研究了2-酰基氨基噻唑部分的生物等位取代。优化过程从2-哌嗪基噻唑基尿素和咪唑并吡啶类中获得了先导化合物（74和91）。在FlpIn.FM HEK293细胞试验（LTR EC50为80 nM）和Jurkat Latency 10.6细胞模型（分别为LTR EC50 220和320 nM）中，每种类别的先导化合物均显示出HIV基因表达的有效激活。激活FlpIn.FM HEK293细胞试验（分别为CMV EC50 70和270 nM）中表现出细胞毒性的基因表达。铅化合物作为新型潜伏期逆转剂具有潜在的进一步开发潜力。6细胞模型（分别为LTR EC50 220和320 nM），但因此在FlpIn.FM HEK293细胞分析（分别为CMV EC50 70和270 nM）中非特异性激活基因表达，表现出细胞毒性。铅化合物作为新型潜伏期逆转剂具有潜在的进一步开发潜力。6细胞模型（分别为LTR EC50 220和320 nM），但因此在FlpIn.FM HEK293细胞分析（分别为CMV EC50 70和270 nM）中非特异性激活基因表达，表现出细胞毒性。铅化合物作为新型潜伏期逆转剂具有潜在的进一步开发潜力。