ABSTRACT
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.
Subject(s)
Antiviral Agents/chemical synthesis , Drug Design , Middle East Respiratory Syndrome Coronavirus/drug effects , Quinazolinones/pharmacology , SARS-CoV-2/drug effects , Animals , Antiviral Agents/pharmacokinetics , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/virology , Cell Line , Cell Survival/drug effects , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Cytochrome P-450 Enzyme System/chemistry , Cytochrome P-450 Enzyme System/metabolism , Half-Life , Humans , Inhibitory Concentration 50 , Mice , Microsomes/metabolism , Middle East Respiratory Syndrome Coronavirus/isolation & purification , Quinazolinones/chemistry , Quinazolinones/metabolism , Quinazolinones/therapeutic use , Rats , SARS-CoV-2/isolation & purification , Structure-Activity Relationship , COVID-19 Drug TreatmentABSTRACT
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.