Oxoquinoline acyclonucleoside phosphonate analogues as a new class of specific inhibitors of human immunodeficiency virus type 1

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• 作者：Let¨ªcia V. Faro ; J¨¦ssica M. de Almeida ; Cl¨¢udio C. Cirne-Santos ; Viveca A. Giongo ; Lu¨ªs R. Castello-Branco ; Ingrid de B. Oliveira ; Juliana E.F. Barbosa ; Anna C. Cunha ; V¨ªtor F. Ferreira ; Marcos C. de Souza ; Izabel C.N.P. Paix?o ; Maria Cec¨ªlia B.V. de Souza
• 关键词：Oxoquinoline ; Acyclonucleoside phosphonate ; Antiviral ; Anti-HIV-1
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 出版时间：1 August, 2012
• 年：2012
• 卷：22
• 期：15
• 页码：5055-5058
• 全文大小：276 K

文摘

The emergence of a multidrug-resistant HIV-1 strain and the toxicity of anti-HIV-1 compounds approved for clinical use are the most significant problems facing antiretroviral therapies. Therefore, it is crucial to find new agents to overcome these issues. In this study, we synthesized a series of new oxoquinoline acyclonucleoside phosphonate analogues (ethyl 1-[(diisopropoxyphosphoryl)methyl]-4-oxo-1,4-dihydroquinoline-3-carboxylates g class=""boldFont"">3ag>-g class=""boldFont"">3kg>), which contained different substituents at the C6 or C7 positions of the oxoquinoline nucleus and an N1-bonded phosphonate group. We subsequently investigated these compounds¡¯ in vitro inhibitory effects against HIV-1-infected peripheral blood mononuclear cells (PBMCs). The most active compounds were the fluoro-substituted derivatives g class=""boldFont"">3fg> and g class=""boldFont"">3gg>, which presented excellent EC₅₀ values of 0.4 ¡À 0.2 ¦ÌM (g class=""boldFont"">3fg>) and 0.2 ¡À 0.005 ¦ÌM (g class=""boldFont"">3gg>) and selectivity index values (SI) of 6240 and 14675, respectively.