Stephania tetrandra and other related species of Menispermaceae are the major sources of the bis-benzylisoquinoline alkaloids tetrandrine (TET), fangchinoline (FAN), and cepharanthine (CEP). Although the pharmacological properties of these compounds include anticancer and anti-inflammatory activities, the antiviral effects of these compounds against human coronavirus (HCoV) remain unclear. Hence, the aims of the current study were to assess the antiviral activities of TET, FAN, and CEP and to elucidate the underlying mechanisms in HCoV-OC43-infected MRC-5 human lung cells. These compounds significantly inhibited virus-induced cell death at the early stage of virus infection. TET, FAN, and CEP treatment dramatically suppressed the replication of HCoV-OC43 as well as inhibited viral S and N protein expression. The virus-induced host response was reduced by compound treatment as compared with the vehicle control. Taken together, these findings demonstrate that TET, FAN, and CEP are potential natural antiviral agents for the prevention and treatment of HCoV-OC43 infection.

We previously reported the potent antiviral effect of the 2-aminoquinazolin-4-(3H)-one 1, which shows significant activity (IC₅₀ = 0.23 μM) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with no cytotoxicity. However, it is necessary to improve the in vivo pharmacokinetics of compound 1 because its area under the curve (AUC) and maximum plasma concentration are low. Here, we designed and synthesized N-substituted quinazolinone derivatives that had good pharmacokinetics and that retained their inhibitory activity against SARS-CoV-2. These compounds were conveniently prepared on a large scale through a one-pot reaction using Dimroth rearrangement as a key step. The synthesized compounds showed potent inhibitory activity, low binding to hERG channels, and good microsomal stability. In vivo pharmacokinetic studies showed that compound 2b had the highest exposure (AUC_24h = 41.57 μg∙h/mL) of the synthesized compounds. An in vivo single-dose toxicity evaluation of compound 2b at 250 and 500 mg/kg in rats resulted in no deaths and an approximate lethal dose greater than 500 mg/kg. This study shows that N-acetyl 2-aminoquinazolin-4-(3H)-one 2b is a promising lead compound for developing anti-SARS-CoV-2 agents.

Background/Objectives: The rise in methicillin-resistant Staphylococcus aureus (MRSA) demands new therapeutic strategies. In this study, a series of 2-(amino)quinazolin-4(3H)-one derivatives were synthesized and evaluated for antistaphylococcal activity. Methods/Results: Through screening against S. aureus ATCC25923 and USA300 JE2, several submicromolar inhibitors were identified. Among them, compound 6l, which contains a 7-chloro substituent on the key parental scaffold, exhibited strong overall antibacterial activity (MIC₅₀: 1.0 µM, ATCC25923; 0.6 µM, JE2) and served as a lead for further structural optimization. Structure–activity relationship analysis showed that substitution at the 2-position was critical, with its optimized analog 6y (3,4-difluorobenzylamine) exhibiting the highest potency (MIC₅₀: 0.36 µM, ATCC25923; 0.02 µM, JE2). Cytotoxicity assays in HepG2 cells revealed six compounds with IC₅₀ values above 20 µM, yielding efficacy windows greater than 10. Compound 6y exhibited an exceptional index (~885). Consistently, in an H460 lung epithelial infection model mimicking MRSA pneumonia, 6y significantly reduced intracellular bacterial loads with minimal host cell damage, outperforming comparator compounds. Conclusions: These findings highlight 2-(amino)quinazolin-4(3H)-one derivatives, particularly 6y, as promising leads for the development of new antistaphylococcal agents.