RESUMEN
1,6-Naphthyridine-2-carboxylic acid benzylamides are potent anti-HCMV compounds. Replacement of the amide moiety by other groups containing internal hydrogen bonds was undertaken to extend the SAR. Our results indicated that the urca derivatives showed very good activity.
Asunto(s)
Antivirales/síntesis química , Citomegalovirus/efectos de los fármacos , Naftiridinas/farmacología , Tioamidas/farmacología , Antivirales/farmacología , Supervivencia Celular/efectos de los fármacos , Diseño de Fármacos , Enlace de Hidrógeno , Concentración 50 Inhibidora , Naftalenos/química , Naftiridinas/síntesis química , Relación Estructura-Actividad , Tioamidas/síntesis química , Tioamidas/químicaRESUMEN
Substituted 1,6-naphthyridine derivatives, a new class of human cytomegalovirus inhibitors, were prepared to demonstrate the role of intramolecular hydrogen bonds to maintain the compounds in their active conformation.
Asunto(s)
Antivirales/química , Antivirales/farmacología , Citomegalovirus/efectos de los fármacos , Naftiridinas/química , Naftiridinas/farmacología , Citomegalovirus/química , Humanos , Concentración 50 Inhibidora , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Conformación Molecular , Relación Estructura-ActividadRESUMEN
Structure-activity relationship studies on our newly identified anti-HCMV compounds, the 1,6-naphthyridines led to the identification of isoquinoline-6-carboxamides as potent and selective anti-HCMV agents.
Asunto(s)
Antivirales/farmacología , Citomegalovirus/efectos de los fármacos , Isoquinolinas/farmacología , Antivirales/química , Isoquinolinas/química , Pruebas de Sensibilidad Microbiana , Relación Estructura-ActividadAsunto(s)
Antivirales/síntesis química , Citomegalovirus/efectos de los fármacos , Naftiridinas/síntesis química , Antivirales/química , Antivirales/farmacología , Antivirales/toxicidad , Línea Celular , Humanos , Concentración 50 Inhibidora , Naftiridinas/química , Naftiridinas/farmacología , Naftiridinas/toxicidad , Relación Estructura-ActividadRESUMEN
Pyrido [1,2a] indole derivatives were identified as potent inhibitors of human immunodeficiency virus type 1 (HIV-1) replication during a random screening programme. The compounds showed no antiviral activity against HIV-2 or in cells chronically infected with HIV-1, but had good inhibitory effect against purified HIV-1 reverse transcriptase (RT) in an in vitro assay. They were therefore classified as non-nucleoside RT inhibitors (NNRTI). The synthesis of additional compounds of the same class revealed a structure-activity relationship. The most potent compound of the series, BCH-1, had similar antiviral activity to the licensed NNRTI nevirapine against laboratory strains of HIV-1 cultured in cell lines and primary clinical isolates of HIV-1 cultured in peripheral blood mononuclear cells. However, BCH-1 showed greater cytotoxicity, providing a narrow selectivity index in the order of 35. BCH-1 had equivalent antiviral activity against viruses resistant to the nucleoside RT inhibitors zidovudine, didanosine and lamivudine and maintained better activity (less than threefold change in IC50) than nevirapine against viruses resistant to a range of NNRTIs with the single amino acid changes L100I, K103N, E138K or Y181C in the RT. Viruses with single V106A or Y188C amino acid changes showed five- and 10-fold resistance to BCH-1, respectively, in contrast to nevirapine, which had a > 100-fold change in IC50. However, virus with both V106A and Y188C amino acid changes showed higher level resistance (> 15-fold) to BCH-1. Virus with > 10-fold resistance to BCH-1 was rapidly selected for after growth in increasing concentrations of compound and was shown to be cross-resistant to nevirapine. Sequencing of this virus revealed two amino acid changes at positions 179 (V to D) and 181 (Y to C) in the RT. BCH-1 represents a new class of NNRTI, which may act as a lead to identify more selective compounds.