A Parallel Synthesis Approach to the Identification of Novel Diheteroarylamide-Based Compounds Blocking HIV Replication: Potential Inhibitors of HIV-1 Pre-mRNA Alternative Splicing

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• 作者：Peter K. Cheung ; David Horhant ; Laura E. Bandy ; Maryam Zamiri ; Safwat M. Rabea ; Stoyan K. Karagiosov ; Mitra Matloobi ; Steven McArthur ; P. Richard Harrigan ; Benoit Chabot ; David S. Grierson
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：March 10, 2016
• 年：2016
• 卷：59
• 期：5
• 页码：1869-1879
• 全文大小：597K
• ISSN：1520-4804

文摘

A 256-compound library was evaluated in an anti-HIV screen to identify structural “mimics” of the fused tetracyclic indole compound 1 (IDC16) that conserve its anti-HIV activity without associated cytotoxicity. Four diheteroarylamide-type compounds, containing a common 5-nitroisobenzothiazole motif, were identified as active. In subsequent screens, the most potent compound 9 (1C8) was active against wild-type HIV-1_IIIB (subtype B, X4-tropic) and HIV-1 97USSN54 (subtype A, R5-tropic) with EC₅₀’s of 0.6 and 0.9 μM, respectively. Compound 9 also inhibited HIV strains resistant to drugs targeting HIV reverse transcriptase, protease, integrase, and coreceptor CCR5 with EC₅₀’s ranging from 0.9 to 1.5 μM. The CC₅₀ value obtained in a cytotoxicity assay for compound 9 was >100 μM, corresponding to a therapeutic index (CC₅₀/EC₅₀) of approximately 100. Further comparison studies revealed that, whereas the anti-HIV activity for compound 9 and the parent molecule 1 are similar, the cytotoxic effect for compound 9 was, as planned, markedly suppressed.