Pyrrolo[2,3-b]quinoxalines in attenuating cytokine storm in COVID-19: their sonochemical synthesis and in silico / in vitro assessment

Chemboli, Raviteja; Kapavarapu, Ravikumar; Kolli, Deepti; Prasad, K. R. S.; Reddy, Alugubelli Gopi; Kumar, Abbaraju Venkata Durga Nagendra; Rao, Mandava V. Basaveswara; Pal, Manojit

doi:10.1016/j.molstruc.2020.129868

Cited by 34 publications

(14 citation statements)

References 33 publications

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“…For example, Rolipram and Roflumilast were both shown to inhibit viral replication ( 58 , 59 ). In addition, compounds with properties of PDE4 inhibition were suggested to bind to N-terminal RNA-binding domain of SARS-CoV-2 N-protein, a critical component of the viral replication and genome packaging machinery that may affect viral replication ( 60 , 61 ). By analogy with other PDE4 inhibitors, it is tempting to speculate that Tanimilast may be helpful in COVID-19 pneumonia not only by regulating the inflammatory balance but also by directly reducing viral replication and load.…”

Section: Discussionmentioning

confidence: 99%

The PDE4 Inhibitor Tanimilast Blunts Proinflammatory Dendritic Cell Activation by SARS-CoV-2 ssRNAs

Nguyen¹,

Schioppa²,

Tiberio³

et al. 2022

Front. Immunol.

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Phosphodiesterase 4 (PDE4) inhibitors are immunomodulatory drugs approved to treat diseases associated with chronic inflammatory conditions, such as COPD, psoriasis and atopic dermatitis. Tanimilast (international non-proprietary name of CHF6001) is a novel, potent and selective inhaled PDE4 inhibitor in advanced clinical development for the treatment of COPD. To begin testing its potential in limiting hyperinflammation and immune dysregulation associated to SARS-CoV-2 infection, we took advantage of an in vitro model of dendritic cell (DC) activation by SARS-CoV-2 genomic ssRNA (SCV2-RNA). In this context, Tanimilast decreased the release of pro-inflammatory cytokines (TNF-α and IL-6), chemokines (CCL3, CXCL9, and CXCL10) and of Th1-polarizing cytokines (IL-12, type I IFNs). In contrast to β-methasone, a reference steroid anti-inflammatory drug, Tanimilast did not impair the acquisition of the maturation markers CD83, CD86 and MHC-II, nor that of the lymph node homing receptor CCR7. Consistent with this, Tanimilast did not reduce the capability of SCV2-RNA-stimulated DCs to activate CD4+ T cells but skewed their polarization towards a Th2 phenotype. Both Tanimilast and β-methasone blocked the increase of MHC-I molecules in SCV2-RNA-activated DCs and restrained the proliferation and activation of cytotoxic CD8+ T cells. Our results indicate that Tanimilast can modulate the SCV2-RNA-induced pro-inflammatory and Th1-polarizing potential of DCs, crucial regulators of both the inflammatory and immune response. Given also the remarkable safety demonstrated by Tanimilast, up to now, in clinical studies, we propose this inhaled PDE4 inhibitor as a promising immunomodulatory drug in the scenario of COVID-19.

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Section: Discussionmentioning

confidence: 99%

The PDE4 Inhibitor Tanimilast Blunts Proinflammatory Dendritic Cell Activation by SARS-CoV-2 ssRNAs

Nguyen¹,

Schioppa²,

Tiberio³

et al. 2022

Front. Immunol.

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“…Molecular modelling using docking [41][42][43][44] has been considered as an important computational tool to predict the binding interactions of the ligands with the active site of protein in search of their mode of action against SARS CoV-2 [45][46][47][48][49][50][51][52]. In this context, we have performed the molecular docking in the search of potent SARS CoV-2 inhibitors using the obtained hypothesis model.…”

Section: Molecular Dockingmentioning

confidence: 99%

Systematic virtual screening in search of SARS CoV-2 inhibitors against spike glycoprotein: pharmacophore screening, molecular docking, ADMET analysis and MD simulations

2022

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In the absence of efficient anti-viral medications, the coronavirus disease 2019 (COVID-19), stemming from severe acute respiratory syndrome coronavirus-2 (SARS CoV-2), has spawned a worldwide catastrophe and global emergency. Amidst several anti-viral targets of COVID-19, spike glycoprotein has been recognized as an essential target for the viral entry into the host cell. In the search of effective SARS CoV-2 inhibitors acting against spike glycoprotein, the virtual screening of 175,851 ligands from the 2020.1 Asinex BioDesign library has been performed using in silico tools like SiteMap analysis, pharmacophore-based screening, molecular docking using different levels of precision, such as high throughput virtual screening, standard precision and extra precision, followed by absorption, distribution, metabolism, excretion and toxicity analysis, and molecular dynamics (MD) simulation. Following a molecular docking study, seventeen molecules (with a docking score of less than − 6.0) were identified having the substantial interactions with the catalytic amino acid and nucleic acid residues of spike glycoprotein at the binding site. In investigations using MD simulations for 10 ns, the hit molecules ( 1 and 2 ) showed adequate compactness and uniqueness, as well as satisfactory stability. These computational research findings have offered a key starting point in the field of design and development of novel SARS CoV-2 entry inhibitors with appropriate drug likeliness. Graphical abstract Supplementary Information The online version contains supplementary material available at 10.1007/s11030-022-10394-9.

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“…The results of research on the synthesis of a series of new norcantharimide-derived molecules revealed that these molecules (12) showed physicochemical properties that could be considered as orally active drug candidates, while docking studies indicated that they exhibited good theoretical affinity for M pro [281]. Chemboli and co-workers reported research on the synthesis of 2-substituted pyrrolo [2,3-b]quinoxalines as potent cytokine storm attenuating agents in COVID-19 [282]. Most of the compounds showed reasonable and significant inhibition of TNF-α and acceptable toxicity in vitro as a result of the structure-activity study.…”

Section: Synthesis Of New Molecular Structures Against Covid-19mentioning

confidence: 99%

A Multidisciplinary Approach to Coronavirus Disease (COVID-19)

Ertürk

Şahin

et al. 2021

Molecules

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Since December 2019, humanity has faced an important global threat. Many studies have been published on the origin, structure, and mechanism of action of the SARS-CoV-2 virus and the treatment of its disease. The priority of scientists all over the world has been to direct their time to research this subject. In this review, we highlight chemical studies and therapeutic approaches to overcome COVID-19 with seven different sections. These sections are the structure and mechanism of action of SARS-CoV-2, immunotherapy and vaccine, computer-aided drug design, repurposing therapeutics for COVID-19, synthesis of new molecular structures against COVID-19, food safety/security and functional food components, and potential natural products against COVID-19. In this work, we aimed to screen all the newly synthesized compounds, repurposing chemicals covering antiviral, anti-inflammatory, antibacterial, antiparasitic, anticancer, antipsychotic, and antihistamine compounds against COVID-19. We also highlight computer-aided approaches to develop an anti-COVID-19 molecule. We explain that some phytochemicals and dietary supplements have been identified as antiviral bioproducts, which have almost been successfully tested against COVID-19. In addition, we present immunotherapy types, targets, immunotherapy and inflammation/mutations of the virus, immune response, and vaccine issues.

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Pyrrolo[2,3-b]quinoxalines in attenuating cytokine storm in COVID-19: their sonochemical synthesis and in silico / in vitro assessment

Cited by 34 publications

References 33 publications

The PDE4 Inhibitor Tanimilast Blunts Proinflammatory Dendritic Cell Activation by SARS-CoV-2 ssRNAs

The PDE4 Inhibitor Tanimilast Blunts Proinflammatory Dendritic Cell Activation by SARS-CoV-2 ssRNAs

Systematic virtual screening in search of SARS CoV-2 inhibitors against spike glycoprotein: pharmacophore screening, molecular docking, ADMET analysis and MD simulations

A Multidisciplinary Approach to Coronavirus Disease (COVID-19)

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