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.
Subject(s)
Antiviral Agents/pharmacology , Drug Discovery , SARS-CoV-2/drug effects , Sulfonamides/pharmacology , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Cell Line , Chlorocebus aethiops , Cricetulus , Dogs , Dose-Response Relationship, Drug , Humans , Mice , Microbial Sensitivity Tests , Molecular Structure , Rats , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , COVID-19 Drug TreatmentABSTRACT
Streptococcus pneumoniae is one of Gram-positive pathogen that causes invasive pneumococcal disease. Nowadays, many S. pneumoniae strains are resistant to commonly used antibiotics such as ß-lactams and macrolides. 3-Acyl-2-phenylamino-1,4-dihydroquinolin-4-one (APDQ) derivatives are known as novel chemicals having anti-pneumococcal activity against S. pneumoniae. The underlying mechanism of the anti-pneumococcal activity of this inhibitor remains unknown. Therefore, we tried to find the anti-pneumococcal mechanism of APDQ230122, one of the APDQ derivatives active against S. pneumoniae. We performed transcriptomic analysis (RNA-Seq) and proteomic analysis (LC-MS/MS analysis) to get differentially expressed genes (DEG) and differentially expressed proteins (DEP) of S. pneumoniae 521 treated with sub-inhibitory concentrations of APDQ230122 and elucidated the comprehensive expression changes of genes and proteins using multi-omics analysis. As a result, genes or proteins of peptidoglycan biosynthesis and DNA replication were significantly down-regulated. Electron microscopy analysis revealed that the structure of peptidoglycan was damaged by APDQ230122 in a chemical concentration-dependent manner. Therefore, we suggest peptidoglycan biosynthesis is a major target of APDQ230122. Multi-omics analysis can provide us useful information to elucidate anti-pneumococcal activity of APDQ230122.
Subject(s)
Anti-Bacterial Agents/pharmacology , Streptococcus pneumoniae/drug effects , Streptococcus pneumoniae/genetics , DNA Replication/drug effects , DNA Replication/genetics , Down-Regulation/drug effects , Down-Regulation/genetics , Gene Expression/drug effects , Gene Expression/genetics , Microbial Sensitivity Tests/methods , Peptidoglycan/genetics , Proteomics/methods , Transcriptome/drug effects , Transcriptome/geneticsABSTRACT
Based on the interhemispheric inhibition model of unilateral visuospatial neglect (USN) after stroke, the effects of dual-mode transcranial direct current stimulation (tDCS) over the parietal cortices were assessed in a double-blind random-order cross-over experiment. Ten chronic right hemispheric stroke patients (4 men; mean age: 62.6 years) with USN were recruited. All participants underwent three randomly arranged tDCS sessions: (1) dual-mode, anodal tDCS over the right posterior parietal cortex (PPC) and cathodal tDCS over the left PPC; (2) single-mode, anodal tDCS over the right PPC; and (3) sham mode. Each session lasted 20min. Before and immediately after the stimulation, a line bisection test and star cancelation test were carried out. In the line bisection test, significant improvements were observed after both the dual- and the single-mode tDCS (p<0.05), but not after sham stimulation. Statistical analysis showed a significant interaction between time and tDCS mode, where the dual tDCS had a stronger effect than the single or sham stimulation modes (p<0.05). The star cancelation test did not show any significant change. These results suggest that dual tDCS over the bilateral PPC is an effective method for the treatment of USN in stroke patients.
