6-(1-Benzyl-1H-pyrrol-2-yl)-2,4-dioxo-5-hexenoic Acids as Dual Inhibitors of Recombinant HIV-1 Integrase and Ribonuclease H, Synthesized by a Parallel Synthesis Approach

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• 作者：Roberta Costi ; Mathieu M茅tifiot ; Francesca Esposito ; Giuliana Cuzzucoli Crucitti ; Luca Pescatori ; Antonella Messore ; Luigi Scipione ; Silvano Tortorella ; Luca Zinzula ; Ettore Novellino ; Yves Pommier ; Enzo Tramontano ; Christophe Marchand ; Roberto Di Santo
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：November 14, 2013
• 年：2013
• 卷：56
• 期：21
• 页码：8588-8598
• 全文大小：357K
• 年卷期：v.56,no.21(November 14, 2013)
• ISSN：1520-4804

文摘

The increasing efficiency of HAART has helped to transform HIV/AIDS into a chronic disease. Still, resistance and drug鈥揹rug interactions warrant the development of new anti-HIV agents. We previously discovered hit 6, active against HIV-1 replication and targeting RNase H in vitro. Because of its diketo-acid moiety, we speculated that this chemotype could serve to develop dual inhibitors of both RNase H and integrase. Here, we describe a new series of 1-benzyl-pyrrolyl diketohexenoic derivatives, 7a鈥?b>y and 8a鈥?b>y, synthesized following a parallel solution-phase approach. Those 50 analogues have been tested on recombinant enzymes (RNase H and integrase) and in cell-based assays. Approximately half (22) exibited inhibition of HIV replication. Compounds 7b, 7u, and 8g were the most active against the RNase H activity of reverse-transcriptase, with IC₅₀ values of 3, 3, and 2.5 渭M, respectively. Compound 8g was also the most potent integrase inhibitor with an IC₅₀ value of 26 nM.