Oxoquinoline acyclonucleoside phosphonate analogues as a new class of specific inhibitors of human immunodeficiency virus type 1 |
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| Authors: | Letícia V Faro Jéssica M de Almeida Cláudio C Cirne-Santos Viveca A Giongo Luís R Castello-Branco Ingrid de B Oliveira Juliana E F Barbosa Anna C Cunha Vítor F Ferreira Marcos C de Souza Izabel C N P Paixão Maria Cecília B V de Souza |
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| Institution: | 1. Departamento de Química Orgânica, Instituto de Química, Universidade Federal Fluminense, Outeiro de São João Batista s/n, centro, Niterói, Programa de Pós-graduação em Química, Rio de Janeiro 24020-150, Brazil;2. Departamento de Biologia Celular e Molecular, Instituto de Biologia, Universidade Federal Fluminense, Outeiro de São João Batista s/n, centro, Niterói, Programa de Pós-graduação em Biologia das Interações, Rio de Janeiro 24020-150, Brazil;3. Laboratório de Imunologia Clínica, IOC/Instituto Oswaldo Cruz e Fundação, Fundação Ataulpho de Paiva IOC/FIOCRUZ, Brazil;4. Departamento de Biologia Marinha, Instituto de Biologia, Universidade Federal Fluminense, Outeiro de São João Batista s/n, centro, Niterói, Programa de Pós-graduação em Biologia das Interações, Rio de Janeiro 24020-150, Brazil |
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| Abstract: | 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 3a-3k), 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 3f and 3g, which presented excellent EC(50) values of 0.4±0.2 μM (3f) and 0.2±0.005 μM (3g) and selectivity index values (SI) of 6240 and 14675, respectively. |
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