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1.
Int J Mol Sci ; 22(20)2021 Oct 12.
Article in English | MEDLINE | ID: covidwho-1480791

ABSTRACT

Novel xanthine and imidazolone derivatives were synthesized based on oxazolone derivatives 2a-c as a key intermediate. The corresponding xanthine 3-5 and imidazolone derivatives 6-13 were obtained via reaction of oxazolone derivative 2a-c with 5,6-diaminouracils 1a-e under various conditions. Xanthine compounds 3-5 were obtained by cyclocondensation of 5,6-diaminouracils 1a-c with different oxazolones in glacial acetic acid. Moreover, 5,6-diaminouracils 1a-e were reacted with oxazolones 2a-c in presence of drops of acetic acid under fused condition yielding the imidazolone derivatives 6-13. Furthermore, Schiff base of compounds 14-16 were obtained by condensing 5,6-diaminouracils 1a,b,e with 4-dimethylaminobenzaldehyde in acetic acid. The structural identity of the resulting compounds was resolved by IR, 1H-, 13C-NMR and Mass spectral analyses. The novel synthesized compounds were screened for their antifungal and antibacterial activities. Compounds 3, 6, 13 and 16 displayed the highest activity against Escherichia coli as revealed from the IC50 values (1.8-1.9 µg/mL). The compound 16 displayed a significant antifungal activity against Candia albicans (0.82 µg/mL), Aspergillus flavus (1.2 µg/mL) comparing to authentic antibiotics. From the TEM microgram, the compounds 3, 12, 13 and 16 exhibited a strong deformation to the cellular entities, by interfering with the cell membrane components, causing cytosol leakage, cellular shrinkage and irregularity to the cell shape. In addition, docking study for the most promising antimicrobial tested compounds depicted high binding affinity against acyl carrier protein domain from a fungal type I polyketide synthase (ACP), and Baumannii penicillin- binding protein (PBP). Moreover, compound 12 showed high drug- likeness, and excellent pharmacokinetics, which needs to be in focus for further antimicrobial drug development. The most promising antimicrobial compounds underwent theoretical investigation using DFT calculation.


Subject(s)
Anti-Infective Agents/chemical synthesis , Imidazoles/chemistry , Uracil/chemistry , Xanthines/chemistry , Animals , Anti-Infective Agents/metabolism , Anti-Infective Agents/pharmacology , Binding Sites , Candida albicans/drug effects , Cell Survival/drug effects , Chlorocebus aethiops , DNA Gyrase/chemistry , DNA Gyrase/metabolism , Density Functional Theory , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Half-Life , Imidazoles/metabolism , Imidazoles/pharmacology , Microbial Sensitivity Tests , Molecular Docking Simulation , Polyketide Synthases/chemistry , Polyketide Synthases/metabolism , Structure-Activity Relationship , Thermodynamics , Vero Cells
2.
Biomed Res Int ; 2021: 6614000, 2021.
Article in English | MEDLINE | ID: covidwho-1327769

ABSTRACT

Chloroquine (CQ) and hydroxychloroquine (HCQ) have shown the ability to inhibit in vitro viral replications of coronaviridae viruses such as SARS-CoV and SARS-CoV-2. However, clinical trial outcomes have been disparate, suggesting that CQ and HCQ antiviral mechanisms are not fully understood. Based on three-dimensional structural similarities between HCQ and the known ACE2 specific inhibitor MLN-4760, we compared their modulation on ACE2 activity. Here we describe, for the first time, in a cell-free in vitro system that HCQ directly and dose-dependently inhibits the activity of recombinant human ACE2, with a potency similar to the MLN-4760. Further analysis suggests that HCQ binds to a noncompetitive site other than the one occupied by MLN-4760. We also determined that the viral spike glycoprotein segment that comprises the RBD segment has no effect on ACE2 activity but unexpectedly was able to partially reverse the inhibition induced by HCQ but not that by MLN-4760. In summary, here we demonstrate the direct inhibitory action of HCQ over the activity of the enzyme ACE2. Then, by determining the activity of ACE2, we reveal that the interaction with the spike protein of SARS-CoV-2 leads to structural changes that at least partially displace the interaction of the said enzyme with HCQ. These results may help to explain why the effectiveness of HCQ in clinical trials has been so variable. Additionally, this knowledge could be used for to develop techniques for the detection of SARS-CoV-2.


Subject(s)
Angiotensin-Converting Enzyme 2 , Antiviral Agents , COVID-19/drug therapy , Hydroxychloroquine , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Humans , Hydroxychloroquine/chemistry , Hydroxychloroquine/metabolism , Hydroxychloroquine/pharmacology , Imidazoles/chemistry , Imidazoles/metabolism , Imidazoles/pharmacology , Leucine/analogs & derivatives , Leucine/chemistry , Leucine/metabolism , Leucine/pharmacology , Recombinant Proteins/chemistry , Recombinant Proteins/metabolism , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism
3.
Proteins ; 89(11): 1425-1441, 2021 11.
Article in English | MEDLINE | ID: covidwho-1281247

ABSTRACT

The novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) still has serious negative effects on health, social life, and economics. Recently, vaccines from various companies have been urgently approved to control SARS-CoV-2 infections. However, any specific antiviral drug has not been confirmed so far for regular treatment. An important target is the main protease (Mpro ), which plays a major role in replication of the virus. In this study, Gaussian and residue network models are employed to reveal two distinct potential allosteric sites on Mpro that can be evaluated as drug targets besides the active site. Then, Food and Drug Administration (FDA)-approved drugs are docked to three distinct sites with flexible docking using AutoDock Vina to identify potential drug candidates. Fourteen best molecule hits for the active site of Mpro are determined. Six of these also exhibit high docking scores for the potential allosteric regions. Full-atom molecular dynamics simulations with MM-GBSA method indicate that compounds docked to active and potential allosteric sites form stable interactions with high binding free energy (∆Gbind ) values. ∆Gbind values reach -52.06 kcal/mol for the active site, -51.08 kcal/mol for the potential allosteric site 1, and - 42.93 kcal/mol for the potential allosteric site 2. Energy decomposition calculations per residue elucidate key binding residues stabilizing the ligands that can further serve to design pharmacophores. This systematic and efficient computational analysis successfully determines ivermectine, diosmin, and selinexor currently subjected to clinical trials, and further proposes bromocriptine, elbasvir as Mpro inhibitor candidates to be evaluated against SARS-CoV-2 infections.


Subject(s)
Antiviral Agents/metabolism , Benzofurans/chemistry , Coronavirus 3C Proteases/metabolism , Drug Repositioning/methods , Imidazoles/chemistry , Allosteric Site , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Benzofurans/metabolism , Benzofurans/pharmacology , Binding Sites , Bromocriptine/chemistry , Bromocriptine/metabolism , Bromocriptine/pharmacology , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus 3C Proteases/chemistry , Diosmin/chemistry , Diosmin/metabolism , Hydrazines/chemistry , Hydrazines/metabolism , Hydrazines/pharmacology , Imidazoles/metabolism , Imidazoles/pharmacology , Ivermectin/chemistry , Ivermectin/metabolism , Ivermectin/pharmacology , Ligands , Molecular Docking Simulation , Molecular Dynamics Simulation , Triazoles/chemistry , Triazoles/metabolism , Triazoles/pharmacology , United States , United States Food and Drug Administration
4.
J Pharmacol Sci ; 147(1): 62-71, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1240460

ABSTRACT

Owing to the urgent need for therapeutic interventions against the SARS-coronavirus 2 (SARS-CoV-2) pandemic, we employed an in silico approach to evaluate the SARS-CoV-2 inhibitory potential of newly synthesized imidazoles. The inhibitory potentials of the compounds against SARS-CoV-2 drug targets - main protease (Mpro), spike protein (Spro) and RNA-dependent RNA polymerase (RdRp) were investigated through molecular docking analysis. The binding free energy of the protein-ligand complexes were estimated, pharmacophore models were generated and the absorption, distribution, metabolism, excretion and toxicity (ADMET) properties of the compounds were determined. The compounds displayed various levels of binding affinities for the SARS-CoV-2 drug targets. Bisimidazole C2 scored highest against all the targets, with its aromatic rings including the two imidazole groups contributing to the binding. Among the phenyl-substituted 1H-imidazoles, C9 scored highest against all targets. C11 scored highest against Spro and C12 against Mpro and RdRp among the thiophene-imidazoles. The compounds interacted with HIS 41 - CYS 145 and GLU 288 - ASP 289 - GLU 290 of Mpro, ASN 501 of Spro receptor binding motif and some active site amino acids of RdRp. These novel imidazole compounds could be further developed as drug candidates against SARS-CoV-2 following lead optimization and experimental studies.


Subject(s)
Computational Biology/methods , Enzyme Inhibitors/pharmacology , Imidazoles/pharmacology , Molecular Docking Simulation/methods , SARS-CoV-2/drug effects , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , Humans , Imidazoles/chemistry , Imidazoles/metabolism , Protein Binding/physiology , Protein Structure, Secondary , Protein Structure, Tertiary , SARS-CoV-2/chemistry , SARS-CoV-2/metabolism
5.
Protein Cell ; 12(11): 877-888, 2021 11.
Article in English | MEDLINE | ID: covidwho-1188202

ABSTRACT

A new coronavirus (SARS-CoV-2) has been identified as the etiologic agent for the COVID-19 outbreak. Currently, effective treatment options remain very limited for this disease; therefore, there is an urgent need to identify new anti-COVID-19 agents. In this study, we screened over 6,000 compounds that included approved drugs, drug candidates in clinical trials, and pharmacologically active compounds to identify leads that target the SARS-CoV-2 papain-like protease (PLpro). Together with main protease (Mpro), PLpro is responsible for processing the viral replicase polyprotein into functional units. Therefore, it is an attractive target for antiviral drug development. Here we discovered four compounds, YM155, cryptotanshinone, tanshinone I and GRL0617 that inhibit SARS-CoV-2 PLpro with IC50 values ranging from 1.39 to 5.63 µmol/L. These compounds also exhibit strong antiviral activities in cell-based assays. YM155, an anticancer drug candidate in clinical trials, has the most potent antiviral activity with an EC50 value of 170 nmol/L. In addition, we have determined the crystal structures of this enzyme and its complex with YM155, revealing a unique binding mode. YM155 simultaneously targets three "hot" spots on PLpro, including the substrate-binding pocket, the interferon stimulating gene product 15 (ISG15) binding site and zinc finger motif. Our results demonstrate the efficacy of this screening and repurposing strategy, which has led to the discovery of new drug leads with clinical potential for COVID-19 treatments.


Subject(s)
Coronavirus Papain-Like Proteases/chemistry , High-Throughput Screening Assays/methods , Protease Inhibitors/chemistry , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Antiviral Agents/therapeutic use , Binding Sites , COVID-19/drug therapy , COVID-19/virology , Coronavirus Papain-Like Proteases/genetics , Coronavirus Papain-Like Proteases/metabolism , Crystallography, X-Ray , Drug Evaluation, Preclinical , Drug Repositioning , Humans , Imidazoles/chemistry , Imidazoles/metabolism , Imidazoles/therapeutic use , Inhibitory Concentration 50 , Molecular Dynamics Simulation , Mutagenesis, Site-Directed , Naphthoquinones/chemistry , Naphthoquinones/metabolism , Naphthoquinones/therapeutic use , Protease Inhibitors/metabolism , Protease Inhibitors/therapeutic use , Protein Structure, Tertiary , Recombinant Proteins/biosynthesis , Recombinant Proteins/chemistry , Recombinant Proteins/isolation & purification , SARS-CoV-2/isolation & purification
6.
Virology ; 554: 48-54, 2021 02.
Article in English | MEDLINE | ID: covidwho-989369

ABSTRACT

The COVID-19 pandemic has urged for the repurposing of existing drugs for rapid management and treatment. Renin inhibitors down regulation of ACE2, which is an essential receptor for SARS-CoV-2 infection that is responsible for COVID-19, in addition to their ability to act as protease inhibitors were encouraging aspects for their investigation as possible inhibitors of main protease of SARS-CoV-2 via computational studies. A Pharmacophore model was generated using the newly released SARS-COV-2 main protease inhibitors. Virtual screening was performed on renin inhibitors, and Drug likeness filter identified remikiren and 0IU as hits. Molecular docking for both compounds showed that the orally active renin inhibitor remikiren (Ro 42-5892) of Hoffmann-La Roche exhibited good molecular interaction with Cys145 and His41 in the catalytic site of SARS-CoV-2 main protease. Molecular dynamics simulation suggested that the drug is stable in the active site of the enzyme.


Subject(s)
Coronavirus 3C Proteases/antagonists & inhibitors , Drug Repositioning , Protease Inhibitors/pharmacology , Renin/antagonists & inhibitors , SARS-CoV-2/drug effects , COVID-19/drug therapy , COVID-19/virology , Catalytic Domain , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/metabolism , Imidazoles/chemistry , Imidazoles/metabolism , Imidazoles/pharmacology , Models, Molecular , Protease Inhibitors/chemistry , Protease Inhibitors/metabolism , Protein Binding , SARS-CoV-2/enzymology
7.
Pharmacol Res ; 163: 105297, 2021 01.
Article in English | MEDLINE | ID: covidwho-922113

ABSTRACT

Necrostatin-1 (Nec-1) is a RIP1-targeted inhibitor of necroptosis, a form of programmed cell death discovered and investigated in recent years. There are already many studies demonstrating the essential role of necroptosis in various diseases, including inflammatory diseases, cardiovascular diseases and neurological diseases. However, the potential of Nec-1 in diseases has not received much attention. Nec-1 is able to inhibit necroptosis signaling pathway and thus ameliorate necroptotic cell death in disease development. Recent research findings indicate that Nec-1 could be applied in several types of diseases to alleviate disease development or improve prognosis. Moreover, we predict that Nec-1 has the potential to protect against the complications of coronavirus disease 2019 (COVID-19). This review summarized the effect of Nec-1 in disease models and the underlying molecular mechanism, providing research evidence for its future application.


Subject(s)
Anti-Inflammatory Agents/pharmacology , COVID-19/drug therapy , Imidazoles/pharmacology , Indoles/pharmacology , Lung/drug effects , Necroptosis/drug effects , SARS-CoV-2/pathogenicity , Animals , COVID-19/metabolism , COVID-19/pathology , COVID-19/virology , Disease Models, Animal , Host-Pathogen Interactions , Humans , Imidazoles/metabolism , Indoles/metabolism , Lung/metabolism , Lung/pathology , Lung/virology , Signal Transduction
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