RESUMO
Antiviral drug resistance in influenza infections has been a major threat to public health. To develop a broad-spectrum inhibitor of influenza to combat the problem of drug resistance, we previously identified the highly conserved E339...R416 salt bridge of the nucleoprotein trimer as a target and compound 1 as an inhibitor disrupting the salt bridge with an EC50 = 2.7 µM against influenza A (A/WSN/1933). We have further modified this compound via a structure-based approach and performed antiviral activity screening to identify compounds 29 and 30 with EC50 values of 110 and 120 nM, respectively, and without measurable host cell cytotoxicity. Compared to the clinically used neuraminidase inhibitors, these two compounds showed better activity profiles against drug-resistant influenza A strains, as well as influenza B, and improved survival of influenza-infected mice.
Assuntos
Compostos de Anilina/farmacologia , Antivirais/farmacologia , Vírus da Influenza A/química , Multimerização Proteica/efeitos dos fármacos , Proteínas de Ligação a RNA/metabolismo , Tiazóis/farmacologia , Proteínas do Core Viral/metabolismo , Compostos de Anilina/síntese química , Compostos de Anilina/metabolismo , Animais , Antivirais/síntese química , Antivirais/metabolismo , Sítios de Ligação/efeitos dos fármacos , Feminino , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Estrutura Molecular , Proteínas do Nucleocapsídeo , Ligação Proteica , Eletricidade Estática , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/metabolismoRESUMO
Ethyne-linked naphthyridine-aniline conjugated molecules are selective sensors of decylguanine in dichloromethane and guanosine monophosphate in water (Kass = 16,000 M(-1)). The 2-acetamido-1,8-naphthyridine moiety binds with guanine in a DAA-ADD triply hydrogen-bonded motif. The aniline moiety enhances an electron-donating effect, and the substituent is tuned to attain extra hydrogen bonds, π-π stacking, and electrostatic interactions. The proposed binding modes are supported by a Job plot, ESI-MS, (1)H NMR, UV-vis, and fluorescence spectral analyses.
Assuntos
Acetamidas/química , Compostos de Anilina/química , Guanina/química , Guanosina Monofosfato/química , Naftiridinas/química , Fluorescência , Ligação de Hidrogênio , Imageamento por Ressonância Magnética , Estrutura MolecularRESUMO
New fluorescent molecular sensors for 9-alkylguanines were constructed by conjugation of 2-acetamido-1,8-naphthyridine with N-Boc-pyrrole, N-Boc-pyreno[2,1-b]pyrrole, or acetanilide moieties via an ethynyl bridge. In combination with the triple hydrogen-bonding motif of 2-acetamidonaphthyridine toward alkylguanine, an additional binding site was provided by the substituent properly located on the pyrrole or aniline ring to enhance the affinity of these receptor molecules. Besides the ESI-MS analyses, the binding events were readily monitored by the absorption and fluorescence changes in the visible region.
