Synthesis and In Vitro Study of Antiviral Activity of Glycyrrhizin Nicotinate Derivatives against HIV-1 Pseudoviruses and SARS-CoV-2 Viruses

When developing drugs against SARS-CoV-2, it is important to consider the characteristics of patients with different co-morbidities. People infected with HIV-1 are a particularly vulnerable group, as they may be at a higher risk than the general population of contracting COVID-19 with clinical complications. For such patients, drugs with a broad spectrum of antiviral activity are of paramount importance. Glycyrrhizinic acid (Glyc) and its derivatives are promising biologically active compounds for the development of such broad-spectrum antiviral agents. In this work, derivatives of Glyc obtained by acylation with nicotinic acid were investigated. The resulting preparation, Glycyvir, is a multi-component mixture containing mainly mono-, di-, tri- and tetranicotinates. The composition of Glycyvir was characterized by HPLC-MS/MS and its toxicity assessed in cell culture. Antiviral activity against three strains of SARS-CoV-2 was tested in vitro on Vero E6 cells by MTT assay. Glycyvir was shown to inhibit SARS-CoV-2 replication in vitro (IC502–8 μM) with an antiviral activity comparable to the control drug Remdesivir. In addition, Glycyvir exhibited marked inhibitory activity against HIV pseudoviruses of subtypes B, A6 and the recombinant form CRF63_02A (IC50 range 3.9–27.5 µM). The time-dependence of Glycyvir inhibitory activity on HIV pseudovirus infection of TZM-bl cells suggested that the compound interfered with virus entry into the target cell. Glycyvir is a promising candidate as an agent with low toxicity and a broad spectrum of antiviral action.

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Preliminary in vitro study of anti-oxidant activity and anti-diabetic potential of plant extracts from 4 herbal substances not traditionally used for treatment of diabetes mellitus

Pharmacia ◽

10.3897/pharmacia.68.e72769 ◽

2021 ◽

Vol 68 (4) ◽

pp. 755-762

Author(s):

Dora Trifonova ◽

Anna Gavrilova ◽

Galina Dyakova ◽

Genadi Gavrilov ◽

Maya Yotova ◽

...

Keyword(s):

Diabetes Mellitus ◽

Inhibitory Activity ◽

In Vitro Study ◽

Biologically Active ◽

Total Phenolic ◽

Water Extracts ◽

Sambucus Ebulus ◽

Anti Oxidant ◽

Treatment Of Diabetes

The focus of the presented study is the in vitro anti-oxidant activity and anti-diabetic potential of water extracts from the following four herbal substances, not traditionally used for treatment of diabetes mellitus – leaves of Sambucus ebulus L. and Prunus mahaleb L., and flowering stems of Cichorium intybus L. and Satureja kitaibelii Wierzb. ex Heuff. The water extracts are obtained through ultrasonication. The extract of S. kitaibelii stands out due to its highest values in all studied indicators – total phenolic content, scavenging potential (DPPH, ABTS) and α-glucosidase inhibitory activity which was six times higher than acarbose. The extract of C. intybus also showed significant α-glucosidase inhibitory activity compared to acarbose. The flowering stems of both species are promising sources of biologically active substances for blood sugar control in diabetes mellitus.

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Evaluation of Antiviral Activities of Curcumin Derivatives against HSV-1 in Vero Cell Line

Natural Product Communications ◽

10.1177/1934578x1000501220 ◽

2010 ◽

Vol 5 (12) ◽

pp. 1934578X1000501 ◽

Cited By ~ 6

Author(s):

Keivan Zandi ◽

Elissa Ramedani ◽

Khosro Mohammadi ◽

Saeed Tajbakhsh ◽

Iman Deilami ◽

...

Keyword(s):

Cell Culture ◽

Antiviral Activity ◽

Vero Cell ◽

Cell Line ◽

Antiviral Agents ◽

Antiviral Drug ◽

In Vitro Study ◽

Vero Cell Line ◽

Hsv 1

Antiviral drug resistance is one of the most common problems in medicine, and, therefore, finding new antiviral agents, especially from natural resources, seems to be necessary. This study was designed to assay the antiviral activity of curcumin and its new derivatives like gallium-curcumin and Cu-curcumin on replication of HSV-1 in cell culture. The research was performed as an in vitro study in which the antiviral activity of different concentrations of three substances including curcumin, Gallium-curcumin and Cu-curcumin were tested on HSV-1. The cytotoxicity of the tested compounds was also evaluated on the Vero cell line. The CC50 values for curcumin, gallium-curcumin and Cu-curcumin were 484.2 μg/mL, 255.8 μg/mL and 326.6 μg/mL, respectively, and the respective IC50 values 33.0 μg/mL, 13.9 μg/mL and 23.1 μg/mL. The calculated SI values were 14.6, 18.4 and 14.1, respectively. The results showed that curcumin and its new derivatives have remarkable antiviral effects on HSV-1 in cell culture.

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In Vitro Antiviral Activity of Doxycycline against SARS-CoV-2

Molecules ◽

10.3390/molecules25215064 ◽

2020 ◽

Vol 25 (21) ◽

pp. 5064 ◽

Cited By ~ 2

Author(s):

Mathieu Gendrot ◽

Julien Andreani ◽

Priscilla Jardot ◽

Sébastien Hutter ◽

Océane Delandre ◽

...

Keyword(s):

Antiviral Activity ◽

Broad Spectrum ◽

In Vitro Study ◽

Experimental Models ◽

In Vivo Evaluation ◽

Study Results ◽

Anti Inflammatory ◽

Approved Drugs

In December 2019, a new severe acute respiratory syndrome coronavirus (SARS-CoV-2), causing coronavirus disease 2019 (COVID-19), emerged in Wuhan, China. Despite containment measures, SARS-CoV-2 spread in Asia, Southern Europe, then in America and currently in Africa. Identifying effective antiviral drugs is urgently needed. An efficient approach to drug discovery is to evaluate whether existing approved drugs can be efficient against SARS-CoV-2. Doxycycline, which is a second-generation tetracycline with broad-spectrum antimicrobial, antimalarial and anti-inflammatory activities, showed in vitro activity on Vero E6 cells infected with a clinically isolated SARS-CoV-2 strain (IHUMI-3) with median effective concentration (EC50) of 4.5 ± 2.9 µM, compatible with oral uptake and intravenous administrations. Doxycycline interacted both on SARS-CoV-2 entry and in replication after virus entry. Besides its in vitro antiviral activity against SARS-CoV-2, doxycycline has anti-inflammatory effects by decreasing the expression of various pro-inflammatory cytokines and could prevent co-infections and superinfections due to broad-spectrum antimicrobial activity. Therefore, doxycycline could be a potential partner of COVID-19 therapies. However, these results must be taken with caution regarding the potential use in SARS-CoV-2-infected patients: it is difficult to translate in vitro study results to actual clinical treatment in patients. In vivo evaluation in animal experimental models is required to confirm the antiviral effects of doxycycline on SARS-CoV-2 and more trials of high-risk patients with moderate to severe COVID-19 infections must be initiated.

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(Z)- and (E)-2-(Hydroxymethylcyclopropylidene)-Methylpurines and Pyrimidines as Antiviral Agents

Antiviral Chemistry and Chemotherapy ◽

10.1177/095632029800900406 ◽

1998 ◽

Vol 9 (4) ◽

pp. 57-68 ◽

Cited By ~ 27

Author(s):

Y-L Qiu ◽

RG Ptak ◽

JM Breitenbach ◽

J-S Lin ◽

Y-C Cheng ◽

...

Keyword(s):

Antiviral Activity ◽

Antiviral Agents ◽

Human Herpesvirus ◽

Murine Cytomegalovirus ◽

Strong Inhibitor ◽

Varicella Zoster ◽

Daudi Cells ◽

Hiv 1 ◽

Hsv 1

Several Z- and E-methylenecyclopropane nucleoside analogues were synthesized and evaluated for antiviral activity. Reaction of the Z- and E-2-amino-6-chloropurine methylenecyclopropanes with ammonia or cyclopropylamine gave 2,6-diamino or 2-amino-6-cyclopropylamino analogues. Alkylation elimination of N4-acetylcytosine with ethyl Z- and E-2-bromo-2-bromomethylcyclopropane-1-carboxylates gave a mixture of the Z-and E-methylenecyclopropane derivatives of cytosine. Reduction furnished a mixture of syncytol and the E isomer. Benzoylation led to the respective N4-benzoyl derivatives which were separated by chromatography. Debenzoylation afforded pure syncytol and the E isomer. Alkylation of 2,4-bis-O-trimethylsilylthymine with ethyl Z- and E-2-bromo-2-bromomethylcyclopropane-1-carboxylates gave the corresponding Z- and E-1-bromo-cyclopropylmethylderivatives of thymine. Base-catalysed elimination of HBr gave Z- and E-methylenecyclopropane carboxylic esters. Reduction furnished, after chromatographic separation, synthymol and the E isomer. The Z/E isomeric assignment of the obtained products followed from 1H NMR spectroscopy. The methylenecyclopropane analogues were tested for antiviral activity in vitro against human and murine cytomegalovirus (HCMV, MCMV), Epstein–Barr virus (EBV), varicella zoster virus (VZV), hepatitis B virus (HBV), herpes simplex virus types 1 and 2 (HSV-1, HSV-2), human herpesvirus 6 (HHV-6) and human immunodeficiency virus type 1 (HIV-1). The Z-2-amino-6-cyclopropylaminopurine analogue was the most effective agent against HCMV (EC50 or EC90 0.4–2 μM) followed by syncytol and the Z-2,6-diaminopurine analogues (EC50 or EC90 3.4–29 and 11–24 μM, respectively). The latter compound was also a strong inhibitor of MCMV (EC50 0.6 μM). Syncytol was the most potent against EBV (EC50 <0.41 and 2.5 μM) followed by the Z-2,6-diaminopurine (EC50 1.5 and 6.9 μM) and the Z-2-amino-6-cyclopropylaminopurine derivative (EC50 11.8 μM). Syncytol was also most effective against VZV (EC50 3.6 μM). Activity against HSV-1, HSV-2 and HHV-6 was generally lower; synthymol had an EC50 of 2 μM against HSV-1 (ELISA) and 1.3 μM against EBV in Daudi cells but was inactive in other assays. The 2-amino-6-cyclopropylamino analogue displayed EC50 values between 215 and >74 μM in HSV-1 and HSV-2 assays. 2-Amino-6-cyclopropylaminopurine and 2,6-diaminopurine derivatives were effective against HBV (EC50 2 and 10 μM, respectively), whereas none of the analogues inhibited HIV-1 at a higher virus load. Syncytol and the E isomer were equipotent against EBV in Daudi cells but the E isomer was much less effective in DNA hybridization assays. The E-2,6-diaminopurine analogue and E isomer of synthymol were devoid of antiviral activity.

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An Historic Overview of Biological Response Modifiers as Antiviral Agents

Canadian Journal of Infectious Diseases ◽

10.1155/1992/979517 ◽

1992 ◽

Vol 3 (suppl b) ◽

pp. 34-40 ◽

Cited By ~ 1

Author(s):

Page S Morahan ◽

Aangelo J Pinto

Keyword(s):

Antiviral Activity ◽

Broad Spectrum ◽

Antiviral Agents ◽

Biological Response ◽

Natural Resistance ◽

Biological Response Modifiers ◽

Protective Effects ◽

Small Molecular Weight

A wide variety ofimmunomodulators/biological response modifiers (BRMs) has been demonstrated to provide broad spectrum antiviral activity against both RNA and DNA viruses in several animal species. Dramatic decreases in mortality, reduced virus titres in tissues and reduced histopathology can be produced. The antivirally effective agents include microbially derived materials, polyanions, cytokines and chemically diverse small molecular weight chemicals. The greatest protective effects are observed with prophylactic treatment. although early therapeutic treatment can also be effective. Little direct antiviral activity can be observed in vitro. The findings suggest induction by BRMs of antiviral mediators in vivo early in the course of viral pathogenesis, before the virus has become sequestered in a privileged site or too much infectious virus has been produced for natural resistance to have an impact, immunomodulators are pleiotropic in their immunomodulatory effects, and it has been difficult to establish whether one cell type or mediator is critical for the observed broad spectrum antiviral activity. Therefore, the mechanisms of antiviral action of immunomodulators remain unclear for most systems, but probably involve enhancement of natural immune responses. While no unified antiviral mechanism among different immunomodulators has yet emerged, interferon induction remains a major hypothesis.

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Limonoids Containing a C1–O–C29 Moiety: Isolation, Structural Modification, and Antiviral Activity

Marine Drugs ◽

10.3390/md16110434 ◽

2018 ◽

Vol 16 (11) ◽

pp. 434 ◽

Cited By ~ 4

Author(s):

Jing-Ling Ren ◽

Xiao-Peng Zou ◽

Wan-Shan Li ◽

Li Shen ◽

Jun Wu

Keyword(s):

Antiviral Activity ◽

Inhibitory Activity ◽

Influenza A ◽

Structural Modification ◽

X Ray Diffraction ◽

Ic50 Value ◽

Immunodeficiency Virus ◽

Antiviral Activities ◽

Hiv 1

Five new limonoids named thaigranatins A–E (1–5), containing a C1–O–C29 moiety, were isolated from seeds of the Thai Xylocarpus granatum, collected at the mangrove swamp of Trang Province, together with the known limonoid, granatumin L (6). The structures of these compounds were established by HR-ESIMS and extensive NMR spectroscopic data. The absolute configuration of 1 was unequivocally determined by single-crystal X-ray diffraction analysis, conducted with Cu Kα radiation; whereas that of 2 or 6 was established to be the same as that of 1 by the similarity of their electronic circular dichroism (ECD) spectra. In view of the marked antiviral activity of 6, its structure was modified via hydrolysis with alkaline KOH, esterification with diazomethane and various organic acids, and oximization with hydroxyamine. Finally, 18 derivatives, viz. 7–10, 8a–8i, 9a–9b, and 10a–10c, were obtained. In vitro antiviral activities of these derivatives against human immunodeficiency virus 1 (HIV-1) and influenza A virus (IAV) were evaluated. Most notably, 8i exhibited marked inhibitory activity against HIV-1 with an IC50 value of 15.98 ± 6.87 μM and a CC50 value greater than 100.0 μM; whereas 10b showed significant inhibitory activity against IAV with an IC50 value of 14.02 ± 3.54 μM and a CC50 value greater than 100.0 μM.

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Rapid Prescreening for Antiviral Agents against HIV-1 Based on Their Inhibitory Activity in Site-Directed Immunoassays. II. Porphyrins Reacting with the V3 Loop of gp120

Antiviral Chemistry and Chemotherapy ◽

10.1177/095632029200300108 ◽

1992 ◽

Vol 3 (1) ◽

pp. 55-63 ◽

Cited By ~ 23

Author(s):

A. R. Neurath ◽

N. Strick ◽

P. Haberfield ◽

S. Jiang

Keyword(s):

Antiviral Activity ◽

Inhibitory Activity ◽

Antiviral Agents ◽

V3 Loop ◽

Antiviral Compounds ◽

Porphyrin Derivatives ◽

Immunodeficiency Virus ◽

Glycoprotein Gp120 ◽

The Relationship ◽

Hiv 1

Recent observations that haernin inhibited the replication of the human immunodeficiency virus (HIV-1) and the reaction between the HIV-1 envelope glycoprotein gp120 and antibodies specific for the V3 hypervariable loop of this glycoprotein were an enticement to determine whether or not additional porphyrins had similar activities. Several porphyrin derivatives, particularly meso-tetra (4-carboxyphenyl) porphine, were more potent inhibitors of HIV-1 replication than haernin. They blocked the binding of homologous antibodies to synthetic peptides corresponding to V3 hypervariable loops of 21 distinct HIV-1 isolates, and inhibited the replication in lymphocytic (MT-2) and promonocyte (U937) cell lines of several HIV-1 isolates, tested (IIIB, RF, SF-2, and MN). Compounds with inhibitory activity had a tetrapyrrole ring and, carboxyl or sulphonate groups. However, antiviral activity depended on minor structural difference's between distinct derivatives endowed with these two features. Metalloporphyrins had a drastically reduced antiviral activity in comparison with the corresponding porphyrins. An understanding of the relationship between the structure of porphyrins and their antiviral effects, perceptible from the results presented, is expected to lead to the design of additional derivatives with more potent antiviral activity and to unravelling of molecular details involved in the association between the V3 loop of gp120 and antiviral compounds targeted to this loop.

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EGYVIR: An immunomodulatory herbal extract with potent antiviral activity against SARS-CoV-2

PLoS ONE ◽

10.1371/journal.pone.0241739 ◽

2020 ◽

Vol 15 (11) ◽

pp. e0241739

Author(s):

Wael H. Roshdy ◽

Helmy A. Rashed ◽

Ahmed Kandeil ◽

Ahmed Mostafa ◽

Yassmin Moatasim ◽

...

Keyword(s):

Antiviral Activity ◽

Nuclear Translocation ◽

Antiviral Agents ◽

In Vitro Study ◽

Antiviral Effect ◽

Black Pepper ◽

Infection Process ◽

Herbal Extract

Due to the challenges for developing vaccines in devastating pandemic situations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), developing and screening of novel antiviral agents are peremptorily demanded. Herein, we developed EGYVIR as a potent immunomodulatory herbal extract with promising antiviral activity against SARS-CoV-2. It constitutes of a combination of black pepper extract with curcumin extract. The antiviral effect of EGYVIR extract is attributed to the two key phases of the disease in severe cases. First, the inhibition of the nuclear translocation of NF-kβ p50, attenuating the SARS-CoV-2 infection-associated cytokine storm. Additionally, the EGYVIR extract has an in vitro virucidal effect for SARS-CoV-2. The in vitro study of EGYVIR extract against SARS-CoV-2 on Huh-7 cell lines, revealed the potential role of NF-kβ/TNFα/IL-6 during the infection process. EGYVIR antagonizes the NF-kβ pathway in-silico and in-vitro studies. Consequently, it has the potential to hinder the release of IL-6 and TNFα, decreasing the production of essential cytokines storm elements.

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The New Generation hDHODH Inhibitor MEDS433 Hinders the In Vitro Replication of SARS-CoV-2 and OtherHuman Coronaviruses

Microorganisms ◽

10.3390/microorganisms9081731 ◽

2021 ◽

Vol 9 (8) ◽

pp. 1731

Author(s):

Arianna Calistri ◽

Anna Luganini ◽

Barbara Mognetti ◽

Elizabeth Elder ◽

Giulia Sibille ◽

...

Keyword(s):

Antiviral Activity ◽

Broad Spectrum ◽

De Novo ◽

Antiviral Agents ◽

Embryonic Stem ◽

Potential Candidate ◽

In Vitro Replication ◽

Infected Cells ◽

New Generation

Although coronaviruses (CoVs) have long been predicted to cause zoonotic diseases and pandemics with high probability, the lack of effective anti-pan-CoVs drugs rapidly usable against the emerging SARS-CoV-2 actually prevented a promptly therapeutic intervention for COVID-19. Development of host-targeting antivirals could be an alternative strategy for the control of emerging CoVs infections, as they could be quickly repositioned from one pandemic event to another. To contribute to these pandemic preparedness efforts, here we report on the broad-spectrum CoVs antiviral activity of MEDS433, a new inhibitor of the human dihydroorotate dehydrogenase (hDHODH), a key cellular enzyme of the de novo pyrimidine biosynthesis pathway. MEDS433 inhibited the in vitro replication of hCoV-OC43 and hCoV-229E, as well as of SARS-CoV-2, at low nanomolar range. Notably, the anti-SARS-CoV-2 activity of MEDS433 against SARS-CoV-2 was also observed in kidney organoids generated from human embryonic stem cells. Then, the antiviral activity of MEDS433 was reversed by the addition of exogenous uridine or the product of hDHODH, the orotate, thus confirming hDHODH as the specific target of MEDS433 in hCoVs-infected cells. Taken together, these findings suggest MEDS433 as a potential candidate to develop novel drugs for COVID-19, as well as broad-spectrum antiviral agents exploitable for future CoVs threats.

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Acetate Kinase (AcK) is Essential for Microbial Growth and Betel-derived Compounds Potentially Target AcK, PhoP and MDR Proteins in M. tuberculosis, V. cholerae and Pathogenic E. coli: An in silico and in vitro Study

Current Topics in Medicinal Chemistry ◽

10.2174/1568026619666190121105851 ◽

2019 ◽

Vol 18 (31) ◽

pp. 2731-2740 ◽

Cited By ~ 3

Author(s):

Sandeep Tiwari ◽

Debmalya Barh ◽

M. Imchen ◽

Eswar Rao ◽

Ranjith K. Kumavath ◽

...

Keyword(s):

Broad Spectrum ◽

In Silico ◽

Pathogenic Bacteria ◽

In Vitro Study ◽

Docking Studies ◽

Acetate Kinase ◽

E Coli ◽

Pathogenic Escherichia Coli ◽

Novel Target

Background: Mycobacterium tuberculosis, Vibrio cholerae, and pathogenic Escherichia coli are global concerns for public health. The emergence of multi-drug resistant (MDR) strains of these pathogens is creating additional challenges in controlling infections caused by these deadly bacteria. Recently, we reported that Acetate kinase (AcK) could be a broad-spectrum novel target in several bacteria including these pathogens. Methods: Here, using in silico and in vitro approaches we show that (i) AcK is an essential protein in pathogenic bacteria; (ii) natural compounds Chlorogenic acid and Pinoresinol from Piper betel and Piperidine derivative compound 6-oxopiperidine-3-carboxylic acid inhibit the growth of pathogenic E. coli and M. tuberculosis by targeting AcK with equal or higher efficacy than the currently used antibiotics; (iii) molecular modeling and docking studies show interactions between inhibitors and AcK that correlate with the experimental results; (iv) these compounds are highly effective even on MDR strains of these pathogens; (v) further, the compounds may also target bacterial two-component system proteins that help bacteria in expressing the genes related to drug resistance and virulence; and (vi) finally, all the tested compounds are predicted to have drug-like properties. Results and Conclusion: Suggesting that, these Piper betel derived compounds may be further tested for developing a novel class of broad-spectrum drugs against various common and MDR pathogens.

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