RESUMEN
Influenza A virus (IAV) causes great morbidity and mortality worldwide every year. However, there are only a limited number of drugs clinically available against IAV infection. Further, emergence of drug-resistant strains can render those drugs ineffective. Thus there is an unmet medical need to develop new anti-influenza agents. In this study, we show that punicalagin from plants possesses strong anti-influenza activity with a low micromolar IC50 value in tissue culture. Using a battery of bioassays such as single-cycle replication assay, neuraminidase (NA) inhibition assay, and virus yield reduction assay, we demonstrate that the primary mechanism of action (MOA) of punicalagin is the NA-mediated viral release. Moreover, punicalagin can inhibit replication of different strains of influenza A and B viruses, including oseltamivir-resistant virus (NA/H274Y), indicating that punicalagin is a broad spectrum antiviral against both IAV and IBV. Further, although punicalagin targets NA like oseltamivir, it has a different MOA. These results suggest that punicalagin is an influenza NA inhibitor that may be further developed as a novel antiviral against influenza viruses.
Asunto(s)
Antivirales/farmacología , Inhibidores Enzimáticos/farmacología , Taninos Hidrolizables/farmacología , Virus de la Influenza A/efectos de los fármacos , Virus de la Influenza B/efectos de los fármacos , Neuraminidasa/antagonistas & inhibidores , Extractos Vegetales/farmacología , Animales , Perros , Virus de la Influenza A/enzimología , Concentración 50 Inhibidora , Células de Riñón Canino Madin Darby , Replicación Viral/efectos de los fármacosRESUMEN
A series of novel 5-alkyl-6-Adamantylmethylpyrimidin-4(3H)-ones bearing various substituents at the C-2 position of the pyrimidinone ring were synthesized using a facile route and evaluated for their anti-HIV activity in MT-4 cells. The biological results demonstrated that the majority of the newly designed compounds possessed moderate efficiency in inhibiting the replication of the wild-type (WT) HIV-1 strain (IIIB ) with EC50 values in the range from 0.10 to 5.39 µm. Among them, 5b1 and 5b3 proved to be the two most active inhibitors against WT HIV-1 with EC50 values of 0.10 and 0.12 µm, respectively, which were more active than nevirapine (NVP) in the same assay. In addition, HIV-1 reverse-transcriptase (RT) inhibition assay indicated that the representative compound 5b1 showed affinity to WT HIV-1 RT, and inhibited the activity of RT with an IC50 value superior to the reference drug NVP. Moreover, the preliminary structure-activity relationship (SAR) and the molecular modeling analysis of these new derivatives are also discussed.
Asunto(s)
Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacología , Diseño de Fármacos , VIH-1/efectos de los fármacos , Pirimidinas/farmacología , Inhibidores de la Transcriptasa Inversa/química , Inhibidores de la Transcriptasa Inversa/farmacología , Fármacos Anti-VIH/síntesis química , Línea Celular , Evaluación Preclínica de Medicamentos , Humanos , Pirimidinas/química , Inhibidores de la Transcriptasa Inversa/síntesis químicaRESUMEN
A series of novel S-DABO derivatives with the substituted 1,2,3-triazole moiety on the C-2 side chain were synthesized using the simple and efficient CuAAC reaction, and biologically evaluated as inhibitors of HIV-1. Among them, the most active HIV-1 inhibitor was compound 4-((4-((4-(2,6-dichlorobenzyl)-5-methyl-6-oxo-1,6-dihydropyrimidin-2-ylthio)methyl)-1H-1,2,3-triazol-1-yl)methyl)benzenesulfonamide (B5b7), which exhibited similar HIV-1 inhibitory potency (EC50 = 3.22 µm) compared with 3TC (EC50 = 2.24 µm). None of these compounds demonstrated inhibition against HIV-2 replication. The preliminary structure-activity relationship (SAR) of these new derivatives was discussed briefly.