RESUMO
Aim: The purpose of this study is to design and synthesize a new series of sulfamethazine derivatives as potent neuraminidase inhibitors. Materials & methods: A sulfamethazine lead compound, ZINC670537, was first identified by structure-based virtual screening technique, then some novel inhibitors X1-X10 based on ZINC670537 were designed and synthesized. Results: Compound X3 exerts the most good potency in inhibiting the wild-type H5N1 NA (IC50 = 6.74 µM) and the H274Y mutant NA (IC50 = 21.09 µM). 150-cavity occupation is very important in determining activities of these inhibitors. The sulfamethazine moiety also plays an important role. Conclusion: Compound X3 maybe regard as a good anti-influenza candidate to preform further study.
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Assuntos
Antivirais , Desenho de Fármacos , Inibidores Enzimáticos , Virus da Influenza A Subtipo H5N1 , Neuraminidase , Sulfametazina , Neuraminidase/antagonistas & inibidores , Neuraminidase/metabolismo , Sulfametazina/farmacologia , Sulfametazina/síntese química , Sulfametazina/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Antivirais/farmacologia , Antivirais/síntese química , Antivirais/química , Virus da Influenza A Subtipo H5N1/efeitos dos fármacos , Virus da Influenza A Subtipo H5N1/enzimologia , Relação Estrutura-Atividade , Humanos , Estrutura Molecular , Simulação de Acoplamento MolecularRESUMO
Neuraminidase (NA) is an ideal target for the development of anti-influenza drugs. In this paper, ZINC06057848 was screened out as a hit compound by docking-based virtual screening and molecular dynamics (MD) simulation. The modification and optimization of hit ZINC06057848 resulted in the discovery of a series of novel 1,3,4-triazole-containing NA inhibitors (5a-5j). Compound 5c exerts the best inhibitory activity (IC50 = 0.11 µM) against NA, which is comparable to the positive control oseltamivir carboxylate (OSC) (IC50 = 0.10 µM). Molecular docking analysis indicates that the good efficacy of inhibitor 5c may be attributed to the furan and triazole rings extending into 430-cavity and the ethylbenzene part occupying the active site. The results of this work may help in the development of new NA inhibitors.
Assuntos
Acetamidas/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Neuraminidase/antagonistas & inibidores , Triazóis/farmacologia , Acetamidas/síntese química , Acetamidas/química , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Estrutura Molecular , Neuraminidase/metabolismo , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/químicaRESUMO
Neuraminidase (NA) is an important target for the treatment of influenza. In this study, a new lead NA inhibitor, 4 (ZINC01121127), was discovered by pharmacophore-based virtual screening and molecular dynamic (MD) simulation. Some novel NA inhibitors containing thiophene ring were synthesized by optimizing the skeleton of the lead compound 4. Compound 4b had the most potent inhibitory activity against NA (IC50 = 0.03 µM), which was better than the positive control oseltamivir carboxylate (IC50 = 0.06 µM). 4b (EC50 = 1.59 µM) also exhibits excellent antiviral activity against A/chicken/Hubei/327/2004 (H5N1-DW), which is superior to the reference drug OSC (EC50 = 5.97 µM). Molecular docking study shows that the thiophene moiety plays an essential role in compound 4b, which can bind well to the active site of NA. The good activity of 4b may be also ascribed to the extending of quinoline ring into the 150-cavity. The results of this study may provide an insightful help for the development of new NA inhibitors.