RESUMO
Enterovirus infections are common in humans, yet there are no approved antiviral treatments. In this study we concentrated on inhibition of one of the Enterovirus B (EV-B), namely Coxsackievirus A9 (CVA9), using a combination of medicinal chemistry, virus inhibition assays, structure determination from cryogenic electron microscopy and molecular modeling, to determine the structure activity relationships for a promising class of novel N-phenylbenzylamines. Of the new 29 compounds synthesized, 10 had half maximal effective concentration (EC50) values between 0.64-10.46 µM, and of these, 7 had 50% cytotoxicity concentration (CC50) values higher than 200 µM. In addition, this new series of compounds showed promising physicochemical properties and act through capsid stabilization, preventing capsid expansion and subsequent release of the genome.
Assuntos
Antivirais , Capsídeo , Enterovirus Humano B , Antivirais/farmacologia , Antivirais/química , Antivirais/síntese química , Relação Estrutura-Atividade , Enterovirus Humano B/efeitos dos fármacos , Capsídeo/efeitos dos fármacos , Capsídeo/metabolismo , Capsídeo/química , Humanos , Proteínas do Capsídeo/metabolismo , Proteínas do Capsídeo/química , Proteínas do Capsídeo/antagonistas & inibidores , Modelos Moleculares , Chlorocebus aethiopsRESUMO
Pharmacophore-based structural identification, synthesis, and structure-activity relationships of a new class of muscarinic M3 receptor antagonists, the diaryl imidazolidin-2-one derivatives, are described. The versatility of the discovered scaffold allowed for several structural modifications that resulted in the discovery of two distinct classes of compounds, specifically a class of tertiary amine derivatives (potentially useful for the treatment of overactive bladder by oral administration) and a class of quaternary ammonium salt derivatives (potentially useful for the treatment of respiratory diseases by the inhalation route of administration). In this paper, we describe the synthesis and biological activity of tertiary amine derivatives. For these compounds, selectivity for the M3 receptor toward the M2 receptor was crucial, because the M2 receptor subtype is mainly responsible for adverse systemic side effects of currently marketed muscarinic antagonists. Compound 50 showed the highest selectivity versus M2 receptor, with binding affinity for M3 receptor Ki = 4.8 nM and for M2 receptor Ki = 1141 nM. Functional in vitro studies on selected compounds confirmed the antagonist activity toward the M3 receptor and functional selectivity toward the M2 receptor.
Assuntos
Imidazolidinas/síntese química , Receptor Muscarínico M3/antagonistas & inibidores , Administração Oral , Animais , Função Atrial/efeitos dos fármacos , Células CHO , Células CACO-2 , Permeabilidade da Membrana Celular , Cricetinae , Cricetulus , Feminino , Humanos , Imidazolidinas/química , Imidazolidinas/farmacologia , Técnicas In Vitro , Masculino , Camundongos , Microssomos/metabolismo , Modelos Moleculares , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Ensaio Radioligante , Ratos , Receptor Muscarínico M2/antagonistas & inibidores , Relação Estrutura-Atividade , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/fisiologiaRESUMO
Synthesis and biological activity of a novel class of quaternary ammonium salt muscarinic M3 receptor antagonists, showing high selectivity versus the M2 receptor, are described. Selected compounds exhibited potent anticholinergic properties, in isolated guinea-pig trachea, and good functional selectivity for trachea over atria. In vivo, the same compounds potently inhibited acetylcholine-induced bronchoconstriction after intratracheal administration in the guinea pig.