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1.
Int J Mol Sci ; 23(4)2022 Feb 21.
Article in English | MEDLINE | ID: covidwho-1703931

ABSTRACT

The review presents the latest data on the role of selenium-containing agents in the regulation of diseases of the immune system. We mainly considered the contributions of selenium-containing compounds such as sodium selenite, methylseleninic acid, selenomethionine, and methylselenocysteine, as well as selenoproteins and selenium nanoparticles in the regulation of defense mechanisms against various viral infections, including coronavirus infection (COVID-19). A complete description of the available data for each of the above selenium compounds and the mechanisms underlying the regulation of immune processes with the active participation of these selenium agents, as well as their therapeutic and pharmacological potential, is presented. The main purpose of this review is to systematize the available information, supplemented by data obtained in our laboratory, on the important role of selenium compounds in all of these processes. In addition, the presented information makes it possible to understand the key differences in the mechanisms of action of these compounds, depending on their chemical and physical properties, which is important for obtaining a holistic picture and prospects for creating drugs based on them.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Selenium Compounds/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antiviral Agents/chemistry , Humans , Immune System/drug effects , Organoselenium Compounds/immunology , Organoselenium Compounds/pharmacokinetics , Organoselenium Compounds/pharmacology , Selenium Compounds/immunology , Selenocysteine/analogs & derivatives , Selenocysteine/immunology , Selenocysteine/pharmacology , Selenomethionine/pharmacokinetics , Selenomethionine/pharmacology , Sodium Selenite/pharmacology
2.
Molecules ; 26(19)2021 Sep 24.
Article in English | MEDLINE | ID: covidwho-1438673

ABSTRACT

We report the design and synthesis of a series of new 5-chloropyridinyl esters of salicylic acid, ibuprofen, indomethacin, and related aromatic carboxylic acids for evaluation against SARS-CoV-2 3CL protease enzyme. These ester derivatives were synthesized using EDC in the presence of DMAP to provide various esters in good to excellent yields. Compounds are stable and purified by silica gel chromatography and characterized using 1H-NMR, 13C-NMR, and mass spectral analysis. These synthetic derivatives were evaluated in our in vitro SARS-CoV-2 3CLpro inhibition assay using authentic SARS-CoV-2 3CLpro enzyme. Compounds were also evaluated in our in vitro antiviral assay using quantitative VeroE6 cell-based assay with RNAqPCR. A number of compounds exhibited potent SARS-CoV-2 3CLpro inhibitory activity and antiviral activity. Compound 9a was the most potent inhibitor, with an enzyme IC50 value of 160 nM. Compound 13b exhibited an enzyme IC50 value of 4.9 µM. However, it exhibited a potent antiviral EC50 value of 24 µM in VeroE6 cells. Remdesivir, an RdRp inhibitor, exhibited an antiviral EC50 value of 2.4 µM in the same assay. We assessed the mode of inhibition using mass spectral analysis which suggested the formation of a covalent bond with the enzyme. To obtain molecular insight, we have created a model of compound 9a bound to SARS-CoV-2 3CLpro in the active site.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , COVID-19/drug therapy , Coronavirus 3C Proteases/antagonists & inhibitors , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , SARS-CoV-2/drug effects , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Chlorocebus aethiops , Coronavirus 3C Proteases/metabolism , Esters/chemistry , Esters/pharmacology , Halogenation , Humans , Ibuprofen/analogs & derivatives , Ibuprofen/pharmacology , Indomethacin/analogs & derivatives , Indomethacin/pharmacology , Molecular Docking Simulation , Pyridines/chemistry , Pyridines/pharmacology , SARS-CoV-2/metabolism , Salicylic Acid/chemistry , Salicylic Acid/pharmacology , Vero Cells
3.
Bioorg Chem ; 116: 105346, 2021 11.
Article in English | MEDLINE | ID: covidwho-1401246

ABSTRACT

Starting from the antimalarial drugs chloroquine and hydroxychloroquine, we conducted a structural optimization on the side chain of chloroquine by introducing amino substituted longer chains thus leading to a series of novel aminochloroquine derivatives. Anti-infectious effects against SARS-Cov2 spike glycoprotein as well as immunosuppressive and anti-inflammatory activities of the new compounds were evaluated. Distinguished immunosuppressive activities on the responses of T cell, B cell and macrophages upon mitogen and pathogenic signaling were manifested. Compounds 9-11 displayed the most promising inhibitory effects both on cellular proliferation and on the production of multiple pro-inflammatory cytokines, including IL-17, IFN-γ, IL-6, IL-1ß and TNF-α, which might be insightful in the pursuit of treatment for immune disorders and inflammatory diseases.


Subject(s)
Amines/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antiviral Agents/pharmacology , Chloroquine/pharmacology , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Amines/chemistry , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , B-Lymphocytes/immunology , Cell Proliferation/drug effects , Chloroquine/chemical synthesis , Chloroquine/chemistry , Cytokines/metabolism , Dose-Response Relationship, Drug , Humans , Macrophages/drug effects , Macrophages/immunology , Microbial Sensitivity Tests , Molecular Structure , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Structure-Activity Relationship , T-Lymphocytes/drug effects , T-Lymphocytes/immunology
4.
Bioorg Chem ; 116: 105272, 2021 11.
Article in English | MEDLINE | ID: covidwho-1370451

ABSTRACT

Hypertension has been recognized as one of the most frequent comorbidities and risk factors for the seriousness and adverse consequences in COVID-19 patients. 3,4-dihydropyrimidin-2(1H) ones have attracted researchers to be synthesized via Beginilli reaction and evaluate their antihypertensive activities as bioisosteres of nifedipine a well-known calcium channel blocker. In this study, we report synthesis of some bioisosteres of pyrimidines as novel CCBs with potential ACE2 inhibitory effect as antihypertensive agents with protective effect against COVID-19 infection by suppression of ACE2 binding to SARS-CoV-2 Spike RBD. All compounds were evaluated for their antihypertensive and calcium channel blocking activities using nifedipine as a reference standard. Furthermore, they were screened for their ACE2 inhibition potential in addition to their anti-inflammatory effects on LPS-stimulated THP-1 cells. Most of the tested compounds exhibited significant antihypertensive activity, where compounds 7a, 8a and 9a exhibited the highest activity compared to nifedipine. Moreover, compounds 4a,b, 5a,b, 7a,b, 8a,c and 9a showed promising ACE2:SARS-CoV-2 Spike RBD inhibitory effect. Finally, compounds 5a, 7b and 9a exerted a promising anti-inflammatory effect by inhibition of CRP and IL-6 production. Ultimately, compound 9a may be a promising antihypertensive candidate with anti-inflammatory and potential efficacy against COVID-19 via ACE2 receptor inhibition.


Subject(s)
Angiotensin-Converting Enzyme Inhibitors/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antihypertensive Agents/pharmacology , Antiviral Agents/pharmacology , COVID-19/drug therapy , Calcium Channel Blockers/pharmacology , Angiotensin-Converting Enzyme Inhibitors/chemical synthesis , Angiotensin-Converting Enzyme Inhibitors/chemistry , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Antihypertensive Agents/chemical synthesis , Antihypertensive Agents/chemistry , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Calcium Channel Blockers/chemical synthesis , Calcium Channel Blockers/chemistry , Humans , SARS-CoV-2/drug effects
5.
Bioorg Chem ; 116: 105274, 2021 11.
Article in English | MEDLINE | ID: covidwho-1363884

ABSTRACT

Traditional Chinese herbal compound prescription in Xuanfei Baidu Tang (XBT) has obvious effects in the treatment of COVID-19. However, its effective compounds and targets for the treatment of COVID-19 remain unclear. Computer-Aided Drug Design is used to virtually screen out the anti-inflammatory or anti-viral compounds in XBT, and predict the potential targets by Discovery Studio 2020. Then, we searched for COVID-19 targets using Genecards databases and Protein Data Bank (PDB) databases and compared them to identify targets that were common to both. Finally, the target we screened out is: TP53 (Tumor Protein P53). This article also shows that XBT in the treatment of COVID-19 works in a multi-link and overall synergistic manner. Our results will help to design the new drugs for COVID-19.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antiviral Agents/pharmacology , COVID-19/drug therapy , Drugs, Chinese Herbal/pharmacology , SARS-CoV-2/drug effects , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Antiviral Agents/chemistry , Drug Evaluation, Preclinical , Drugs, Chinese Herbal/chemistry , Humans , Medicine, Chinese Traditional , Molecular Structure , SARS-CoV-2/metabolism , Tumor Suppressor Protein p53/antagonists & inhibitors , Tumor Suppressor Protein p53/metabolism
6.
Molecules ; 26(12)2021 Jun 21.
Article in English | MEDLINE | ID: covidwho-1282542

ABSTRACT

The discovery of drugs capable of inhibiting SARS-CoV-2 is a priority for human beings due to the severity of the global health pandemic caused by COVID-19. To this end, repurposing of FDA-approved drugs such as NSAIDs against COVID-19 can provide therapeutic alternatives that could be utilized as an effective safe treatment for COVID-19. The anti-inflammatory activity of NSAIDs is also advantageous in the treatment of COVID-19, as it was found that SARS-CoV-2 is responsible for provoking inflammatory cytokine storms resulting in lung damage. In this study, 40 FDA-approved NSAIDs were evaluated through molecular docking against the main protease of SARS-CoV-2. Among the tested compounds, sulfinpyrazone 2, indomethacin 3, and auranofin 4 were proposed as potential antagonists of COVID-19 main protease. Molecular dynamics simulations were also carried out for the most promising members of the screened NSAID candidates (2, 3, and 4) to unravel the dynamic properties of NSAIDs at the target receptor. The conducted quantum mechanical study revealed that the hybrid functional B3PW91 provides a good description of the spatial parameters of auranofin 4. Interestingly, a promising structure-activity relationship (SAR) was concluded from our study that could help in the future design of potential SARS-CoV-2 main protease inhibitors with expected anti-inflammatory effects as well. NSAIDs may be used by medicinal chemists as lead compounds for the development of potent SARS-CoV-2 (Mpro) inhibitors. In addition, some NSAIDs can be selectively designated for treatment of inflammation resulting from COVID-19.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , COVID-19/drug therapy , Drug Repositioning/methods , Anti-Inflammatory Agents, Non-Steroidal/metabolism , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Auranofin/chemistry , Auranofin/pharmacology , Binding Sites , COVID-19/complications , Computational Biology , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus 3C Proteases/chemistry , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/etiology , Databases, Chemical , Humans , Indomethacin/chemistry , Indomethacin/pharmacology , Ligands , Models, Molecular , Molecular Docking Simulation , Molecular Dynamics Simulation , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Protein Binding , SARS-CoV-2/chemistry , SARS-CoV-2/drug effects , Structure-Activity Relationship , Sulfinpyrazone/chemistry , Sulfinpyrazone/pharmacology , United States , United States Food and Drug Administration
7.
Eur Rev Med Pharmacol Sci ; 25(10): 3923-3932, 2021 May.
Article in English | MEDLINE | ID: covidwho-1264769

ABSTRACT

Angiotensin converting enzyme 2 (ACE2) has potentially conflicting roles in health and disease. COVID-19 coronavirus binds to human cells via ACE2 receptor, which is expressed on almost all body organs. Boosting the ACE2 receptor levels on heart and lung cells may provide more cellular enter to virus thereby worsening the infection. Therefore, among the drug targets, ACE2 is suggested as a vital target of COVID-19 therapy. This hypothesis is based on the protective role of the drugs acting on ACE2. Therefore, this review discusses the impact and challenges of using ACE2 as a target in the current therapy of COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Antiviral Agents/chemistry , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/chemistry , Adenosine Monophosphate/metabolism , Adenosine Monophosphate/therapeutic use , Alanine/analogs & derivatives , Alanine/chemistry , Alanine/metabolism , Alanine/therapeutic use , Angiotensin-Converting Enzyme 2/metabolism , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/metabolism , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Antiviral Agents/metabolism , Antiviral Agents/therapeutic use , Azithromycin/chemistry , Azithromycin/metabolism , Azithromycin/therapeutic use , COVID-19/drug therapy , COVID-19/virology , Humans , Hydroxychloroquine/chemistry , Hydroxychloroquine/metabolism , Hydroxychloroquine/therapeutic use , SARS-CoV-2/isolation & purification , Vitamin D/chemistry , Vitamin D/metabolism , Vitamin D/therapeutic use
8.
Molecules ; 26(7)2021 Mar 26.
Article in English | MEDLINE | ID: covidwho-1154457

ABSTRACT

The current COronaVIrus Disease 19 (COVID-19) pandemic caused by SARS-CoV-2 infection is enormously affecting the worldwide health and economy. In the wait for an effective global immunization, the development of a specific therapeutic protocol to treat COVID-19 patients is clearly necessary as a short-term solution of the problem. Drug repurposing and herbal medicine represent two of the most explored strategies for an anti-COVID-19 drug discovery. Clove (Syzygium aromaticum L.) is a well-known culinary spice that has been used for centuries in folk medicine in many disorders. Interestingly, traditional medicines have used clove since ancient times to treat respiratory ailments, whilst clove ingredients show antiviral and anti-inflammatory properties. Other interesting features are the clove antithrombotic, immunostimulatory, and antibacterial effects. Thus, in this review, we discuss the potential role of clove in the frame of anti-COVID-19 therapy, focusing on the antiviral, anti-inflammatory, and antithrombotic effects of clove and its molecular constituents described in the scientific literature.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antiviral Agents/pharmacology , COVID-19 , Fibrinolytic Agents/pharmacology , Syzygium/chemistry , Adjuvants, Immunologic/chemistry , Adjuvants, Immunologic/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Antiviral Agents/chemistry , COVID-19/drug therapy , COVID-19/prevention & control , Herbal Medicine/methods , Humans , Phytochemicals/chemistry , Phytochemicals/pharmacology , Plants, Medicinal/chemistry
9.
Bioorg Med Chem ; 32: 115973, 2021 02 15.
Article in English | MEDLINE | ID: covidwho-1064894

ABSTRACT

Amongst heterocyclic compounds, quinoline is an advantaged scaffold that appears as a significant assembly motif for the development of new drug entities. Quinoline and its derivatives tested with diverse biological activity constitute an important class of compounds for new drug development. Therefore, many scientific communities have developed these compounds as intent structure and evaluated their biological activities. The present, review provides brief natural sources of quinoline and including a new extent of quinoline-based marketed drugs. This review also confers information about the biological activities of quinoline derivatives such as antibacterial, antifungal, antimycobacterial, antiviral, anti-protozoal, antimalarial, anticancer, cardiovascular, CNS effects, antioxidant, anticonvulsant, analgesic, anti-inflammatory, anthelmintic and miscellaneous activities.


Subject(s)
Analgesics/pharmacology , Anti-Infective Agents/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antineoplastic Agents/pharmacology , Antioxidants/pharmacology , Antiprotozoal Agents/pharmacology , Analgesics/chemistry , Anti-Infective Agents/chemistry , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Antineoplastic Agents/chemistry , Antioxidants/chemistry , Antiprotozoal Agents/chemistry , Humans , Molecular Structure , Quinolines/chemistry , Quinolines/pharmacology
10.
Mar Drugs ; 19(1)2021 Jan 10.
Article in English | MEDLINE | ID: covidwho-1033055

ABSTRACT

Microalgae are at the start of the food chain, and many are known producers of a significant amount of lipids with essential fatty acids. However, the bioactivity of microalgal lipids for anti-inflammatory and antithrombotic activities have rarely been investigated. Therefore, for a sustainable source of the above bioactive lipids, the present study was undertaken. The total lipids of microalga Chlorococcum sp., isolated from the Irish coast, were fractionated into neutral-, glyco-, and phospho-lipids, and were tested in vitro for their anti-inflammatory and antithrombotic activities. All tested lipid fractions showed strong anti-platelet-activating factor (PAF) and antithrombin activities in human platelets (half maximal inhibitory concentration (IC50) values ranging ~25-200 µg of lipid) with the highest activities in glyco- and phospho-lipid fractions. The structural analysis of the bioactive lipid fraction-2 revealed the presence of specific sulfoquinovosyl diacylglycerols (SQDG) bioactive molecules and the HexCer-t36:2 (t18:1/18:1 and 18:2/18:0) cerebrosides with a phytosphingosine (4-hydrosphinganine) base, while fraction-3 contained bioactive phosphatidylcholine (PC) and phosphatidylethanolamine (PE) molecules. These novel bioactive lipids of Chlorococcum sp. with putative health benefits may indicate that marine microalgae can be a sustainable alternative source for bioactive lipids production for food supplements and nutraceutical applications. However, further studies are required towards the commercial technology pathways development and biosafety analysis for the use of the microalga.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Fibrinolytic Agents/chemistry , Fibrinolytic Agents/pharmacology , Lipids/chemistry , Lipids/pharmacology , Microalgae/chemistry , Antithrombins/pharmacology , Blood Platelets/drug effects , Fatty Acids/chemistry , Fatty Acids/pharmacology , Humans , Platelet Activating Factor/antagonists & inhibitors , Platelet Aggregation/drug effects , Water Microbiology
11.
Biomolecules ; 10(11)2020 11 02.
Article in English | MEDLINE | ID: covidwho-921178

ABSTRACT

Plants have been used as drugs to treat human disease for centuries. Ursonic acid (UNA) is a naturally occurring pentacyclic triterpenoid extracted from certain medicinal herbs such as Ziziphus jujuba. Since the pharmacological effects and associated mechanisms of UNA are not well-known, in this work, we attempt to introduce the therapeutic potential of UNA with a comparison to ursolic acid (ULA), a well-known secondary metabolite, for beneficial effects. UNA has a keto group at the C-3 position, which may provide a critical difference for the varied biological activities between UNA and ULA. Several studies previously showed that UNA exerts pharmaceutical effects similar to, or stronger than, ULA, with UNA significantly decreasing the survival and proliferation of various types of cancer cells. UNA has potential to exert inhibitory effects in parasitic protozoa that cause several tropical diseases. UNA also exerts other potential effects, including antihyperglycemic, anti-inflammatory, antiviral, and antioxidant activities. Of note, a recent study highlighted the suppressive potential of UNA against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Molecular modifications of UNA may enhance bioavailability, which is crucial for in vivo and clinical studies. In conclusion, UNA has promising potential to be developed in anticancer and antiprotozoan pharmaceuticals. In-depth investigations may increase the possibility of UNA being developed as a novel reagent for chemotherapy.


Subject(s)
Antiviral Agents/pharmacology , Triterpenes/pharmacology , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antineoplastic Agents, Phytogenic/pharmacology , Antioxidants/chemistry , Antioxidants/pharmacology , Antiprotozoal Agents/chemistry , Antiprotozoal Agents/pharmacology , Antiviral Agents/chemistry , Betacoronavirus/drug effects , Betacoronavirus/physiology , Humans , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Plants/chemistry , SARS-CoV-2 , Triterpenes/chemistry , Triterpenes/metabolism
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