RESUMEN
Despite the rising threat of fatal coronaviruses, there are no general proven effective antivirals to treat them. 2-Aminoquinazolin-4(3H)-one derivatives were newly designed, synthesized, and investigated to show the inhibitory effects on SARS-CoV-2 and MERS-CoV. Among the synthesized derivatives, 7-chloro-2-((3,5-dichlorophenyl)amino)quinazolin-4(3H)-one (9g) and 2-((3,5-dichlorophenyl)amino)-5-hydroxyquinazolin-4 (3H)-one (11e) showed the most potent anti-SARS-CoV-2 activities (IC50 < 0.25 µM) and anti-MERS-CoV activities (IC50 < 1.1 µM) with no cytotoxicity (CC50 > 25 µM). In addition, both compounds showed acceptable results in metabolic stabilities, hERG binding affinities, CYP inhibitions, and preliminary PK studies.
Asunto(s)
Antivirales/síntesis química , Diseño de Fármacos , Coronavirus del Síndrome Respiratorio de Oriente Medio/efectos de los fármacos , Quinazolinonas/farmacología , SARS-CoV-2/efectos de los fármacos , Animales , Antivirales/farmacocinética , Antivirales/farmacología , Antivirales/uso terapéutico , COVID-19/virología , Línea Celular , Supervivencia Celular/efectos de los fármacos , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/virología , Sistema Enzimático del Citocromo P-450/química , Sistema Enzimático del Citocromo P-450/metabolismo , Semivida , Humanos , Concentración 50 Inhibidora , Ratones , Microsomas/metabolismo , Coronavirus del Síndrome Respiratorio de Oriente Medio/aislamiento & purificación , Quinazolinonas/química , Quinazolinonas/metabolismo , Quinazolinonas/uso terapéutico , Ratas , SARS-CoV-2/aislamiento & purificación , Relación Estructura-Actividad , Tratamiento Farmacológico de COVID-19RESUMEN
Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) continues to spread worldwide, with 25 million confirmed cases and 800 thousand deaths. Effective treatments to target SARS-CoV-2 are urgently needed. In the present study, we have identified a class of cyclic sulfonamide derivatives as novel SARS-CoV-2 inhibitors. Compound 13c of the synthesized compounds exhibited robust inhibitory activity (IC50 = 0.88 µM) against SARS-CoV-2 without cytotoxicity (CC50 > 25 µM), with a selectivity index (SI) of 30.7. In addition, compound 13c exhibited high oral bioavailability (77%) and metabolic stability with good safety profiles in hERG and cytotoxicity studies. The present study identified that cyclic sulfonamide derivatives are a promising new template for the development of anti-SARS-CoV-2 agents.