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1.
Molecules ; 27(1)2021 Dec 28.
Article in English | MEDLINE | ID: covidwho-1580565

ABSTRACT

Baricitinib (BTB) is an orally administered Janus kinase inhibitor, therapeutically used for the treatment of rheumatoid arthritis. Recently it has also been approved for the treatment of COVID-19 infection. In this study, four different BTB-loaded lipids (stearin)-polymer (Poly(d,l-lactide-co-glycolide)) hybrid nanoparticles (B-PLN1 to B-PLN4) were prepared by the single-step nanoprecipitation method. Next, they were characterised in terms of physicochemical properties such as particle size, zeta potential (ζP), polydispersity index (PDI), entrapment efficiency (EE) and drug loading (DL). Based on preliminary evaluation, the B-PLN4 was regarded as the optimised formulation with particle size (272 ± 7.6 nm), PDI (0.225), ζP (-36.5 ± 3.1 mV), %EE (71.6 ± 1.5%) and %DL (2.87 ± 0.42%). This formulation (B-PLN4) was further assessed concerning morphology, in vitro release, and in vivo pharmacokinetic studies in rats. The in vitro release profile exhibited a sustained release pattern well-fitted by the Korsmeyer-Peppas kinetic model (R2 = 0.879). The in vivo pharmacokinetic data showed an enhancement (2.92 times more) in bioavailability in comparison to the normal suspension of pure BTB. These data concluded that the formulated lipid-polymer hybrid nanoparticles could be a promising drug delivery option to enhance the bioavailability of BTB. Overall, this study provides a scientific basis for future studies on the entrapment efficiency of lipid-polymer hybrid systems as promising carriers for overcoming pharmacokinetic limitations.


Subject(s)
Azetidines/pharmacokinetics , Drug Carriers/chemistry , Drug Liberation , Liposomes/chemistry , Nanoparticles/chemistry , Polymers/chemistry , Purines/pharmacokinetics , Pyrazoles/pharmacokinetics , Sulfonamides/pharmacokinetics , Administration, Oral , Animals , Azetidines/administration & dosage , Azetidines/chemistry , Biological Availability , Male , Purines/administration & dosage , Purines/chemistry , Pyrazoles/administration & dosage , Pyrazoles/chemistry , Rats , Rats, Wistar , Sulfonamides/administration & dosage , Sulfonamides/chemistry
2.
PLoS One ; 16(10): e0258292, 2021.
Article in English | MEDLINE | ID: covidwho-1480450

ABSTRACT

Chagas disease is a neglected illness caused by Trypanosoma cruzi and its treatment is done only with two drugs, nifurtimox and benznidazole. However, both drugs are ineffective in the chronic phase, in addition to causing serious side effects. This context of therapeutic limitation justifies the continuous research for alternative drugs. Here, we study the in vitro trypanocidal effects of the non-steroidal anti-inflammatory drug nimesulide, a molecule that has in its chemical structure a toxicophoric nitroaromatic group (NO2). The set of results obtained in this work highlights the potential for repurposing nimesulide in the treatment of this disease that affects millions of people around the world.


Subject(s)
Chagas Disease/drug therapy , Chagas Disease/parasitology , Drug Repositioning , Sulfonamides/therapeutic use , Trypanosoma cruzi/physiology , Animals , Cell Death/drug effects , Cell Survival/drug effects , Life Cycle Stages/drug effects , Mice, Inbred BALB C , Parasites/drug effects , Sulfonamides/chemistry , Sulfonamides/pharmacology , Trypanosoma cruzi/drug effects , Trypanosoma cruzi/growth & development , Trypanosoma cruzi/ultrastructure
3.
Bioorg Chem ; 114: 105153, 2021 09.
Article in English | MEDLINE | ID: covidwho-1324044

ABSTRACT

A series of novel substituted phenyl 1, 3-thiazolidin-4-one sulfonyl derivatives 5 (a-t) were synthesized and screened for their in-vitro anti-microbial and anti-viral activity. The result of the anti-microbial assay demonstrated compounds 5d, 5f, 5g, 5h, 5i, 5j showed prominent inhibitory activity against all the tested Gram-positive and Gram-negative bacterial strains, while compounds 5g, 5j, 5o, 5p, 5q showed significant activity against the entire set of fungal strains as compared to standard drug Ampicillin and Clotrimazole, respectively. The antimicrobial study revealed that compounds having electron-withdrawing groups showed significant antimicrobial potency. The most active antibacterial compound 5j showed potent inhibition of S. aureus DNA Gyrase enzyme as a possible mechanism of action for antimicrobial activity. Moreover, the antiviral testing of selected compounds showed considerable activity against Herpes simplex virus-1(KOS), Herpes simplex virus-2 (G), Herpes simplex virus-1(TK- KOS ACVr), Vaccinia virus, Human Coronavirus (229E), Reovirus-1, Sindbis virus, Coxsackie virus B4, Yellow Fever virus and Influenza A, B virus. Compounds 5h exhibited low anti-viral activity against HIV-1(strain IIIB) and HIV-2 (strain ROD). The study clearly outlined that synthesized compounds endowed with good antimicrobial property together with considerable antiviral activity.


Subject(s)
Phenols/chemical synthesis , Sulfonamides/chemical synthesis , Toluene/analogs & derivatives , Animals , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Bacteria/classification , Bacteria/drug effects , Cell Line , Chlorocebus aethiops , Humans , Phenols/chemistry , Phenols/pharmacology , Sulfonamides/chemistry , Sulfonamides/pharmacology , Toluene/chemical synthesis , Toluene/chemistry , Toluene/pharmacology , Vero Cells , Viruses/classification , Viruses/drug effects
4.
Biomolecules ; 11(7)2021 07 16.
Article in English | MEDLINE | ID: covidwho-1323103

ABSTRACT

Cyclooxygenase-2 (COX-2) is an important enzyme involved in prostaglandins biosynthesis from arachidonic acid. COX-2 is frequently overexpressed in human cancers and plays a major tumor promoting function. Accordingly, many efforts have been devoted to efficiently target the catalytic site of this enzyme in cancer cells, by using COX-2 specific inhibitors such as celecoxib. However, despite their potent anti-tumor properties, the myriad of detrimental effects associated to the chronic inhibition of COX-2 in healthy tissues, has considerably limited their use in clinic. In addition, increasing evidence indicate that these anti-cancerous properties are not strictly dependent on the inhibition of the catalytic site. These findings have led to the development of non-active COX-2 inhibitors analogues aiming at preserving the antitumor effects of COX-2 inhibitors without their side effects. Among them, two celecoxib derivatives, 2,5-Dimethyl-Celecoxib and OSU-03012, have been developed and suggested for the treatment of viral (e.g., recently SARS-CoV-2), inflammatory, metabolic diseases and cancers. These molecules display stronger anti-tumor properties than celecoxib and thus may represent promising anti-cancer molecules. In this review, we discuss the impact of these two analogues on cancerous processes but also their potential for cancer treatment alone or in combination with existing approaches.


Subject(s)
Antineoplastic Agents/therapeutic use , Celecoxib/therapeutic use , Cyclooxygenase 2 Inhibitors/therapeutic use , Neoplasms/drug therapy , Pyrazoles/therapeutic use , Sulfonamides/therapeutic use , Animals , Antineoplastic Agents/adverse effects , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Celecoxib/adverse effects , Celecoxib/analogs & derivatives , Celecoxib/pharmacology , Cell Cycle/drug effects , Cyclooxygenase 2 Inhibitors/adverse effects , Cyclooxygenase 2 Inhibitors/chemistry , Cyclooxygenase 2 Inhibitors/pharmacology , Humans , Pyrazoles/adverse effects , Pyrazoles/chemistry , Pyrazoles/pharmacology , Sulfonamides/adverse effects , Sulfonamides/chemistry , Sulfonamides/pharmacology
5.
Sci Rep ; 11(1): 6248, 2021 03 18.
Article in English | MEDLINE | ID: covidwho-1142451

ABSTRACT

The outbreak of a novel febrile respiratory disease called COVID-19, caused by a newfound coronavirus SARS-CoV-2, has brought a worldwide attention. Prioritizing approved drugs is critical for quick clinical trials against COVID-19. In this study, we first manually curated three Virus-Drug Association (VDA) datasets. By incorporating VDAs with the similarity between drugs and that between viruses, we constructed a heterogeneous Virus-Drug network. A novel Random Walk with Restart method (VDA-RWR) was then developed to identify possible VDAs related to SARS-CoV-2. We compared VDA-RWR with three state-of-the-art association prediction models based on fivefold cross-validations (CVs) on viruses, drugs and virus-drug associations on three datasets. VDA-RWR obtained the best AUCs for the three fivefold CVs, significantly outperforming other methods. We found two small molecules coming together on the three datasets, that is, remdesivir and ribavirin. These two chemical agents have higher molecular binding energies of - 7.0 kcal/mol and - 6.59 kcal/mol with the domain bound structure of the human receptor angiotensin converting enzyme 2 (ACE2) and the SARS-CoV-2 spike protein, respectively. Interestingly, for the first time, experimental results suggested that navitoclax could be potentially applied to stop SARS-CoV-2 and remains to further validation.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Angiotensin-Converting Enzyme 2/chemistry , Antiviral Agents/chemistry , Ribavirin/chemistry , Spike Glycoprotein, Coronavirus/chemistry , Adenosine Monophosphate/chemistry , Alanine/chemistry , Aniline Compounds/chemistry , Drug Evaluation, Preclinical , Genome, Viral , Molecular Docking Simulation , SARS-CoV-2/genetics , Sulfonamides/chemistry
6.
Biosci Rep ; 40(6)2020 06 26.
Article in English | MEDLINE | ID: covidwho-1099357

ABSTRACT

Due to the lack of efficient therapeutic options and clinical trial limitations, the FDA-approved drugs can be a good choice to handle Coronavirus disease (COVID-19). Many reports have enough evidence for the use of FDA-approved drugs which have inhibitory potential against target proteins of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Here, we utilized a structure-based drug design approach to find possible drug candidates from the existing pool of FDA-approved drugs and checked their effectiveness against the SARS-CoV-2. We performed virtual screening of the FDA-approved drugs against the main protease (Mpro) of SARS-CoV-2, an essential enzyme, and a potential drug target. Using well-defined computational methods, we identified Glecaprevir and Maraviroc (MVC) as the best inhibitors of SARS-CoV-2 Mpro. Both drugs bind to the substrate-binding pocket of SARS-CoV-2 Mpro and form a significant number of non-covalent interactions. Glecaprevir and MVC bind to the conserved residues of substrate-binding pocket of SARS-CoV-2 Mpro. This work provides sufficient evidence for the use of Glecaprevir and MVC for the therapeutic management of COVID-19 after experimental validation and clinical manifestations.


Subject(s)
Betacoronavirus/enzymology , Maraviroc/pharmacology , Protease Inhibitors/pharmacology , Quinoxalines/pharmacology , Sulfonamides/pharmacology , Aminoisobutyric Acids , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Computer Simulation , Cyclopropanes , Drug Evaluation, Preclinical/methods , Lactams, Macrocyclic , Leucine/analogs & derivatives , Maraviroc/chemistry , Maraviroc/metabolism , Molecular Structure , Proline/analogs & derivatives , Protease Inhibitors/chemistry , Protease Inhibitors/metabolism , Quinoxalines/chemistry , Quinoxalines/metabolism , SARS-CoV-2 , Sulfonamides/chemistry , Sulfonamides/metabolism
7.
Mini Rev Med Chem ; 21(6): 704-723, 2021.
Article in English | MEDLINE | ID: covidwho-922755

ABSTRACT

The current pandemic of COVID-19 caused by SARS-Cov-2 has posed a severe threat to the whole world with its highly infectious, progressive nature with up to 10% mortality rates. The severity of the situation faced by the whole world and the lack of efficient therapeutics to treat this viral disease have led the WHO to depend on the drug-repurposing approach to tackle this major global health problem. This review aims at highlighting the various synthetic approaches employed for the synthesis of these FDA approved drugs that have been presently used for COVID-19 treatment. Additionally, a brief overview of several therapeutic strategies is also presented. This review will encourage the scientific community across the globe to come up with better and efficient synthetic protocols and also novel chemical entities along with this core with more potent activity.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Drug Repositioning/methods , SARS-CoV-2/drug effects , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Antiviral Agents/therapeutic use , Azetidines/chemical synthesis , Azetidines/chemistry , Azetidines/pharmacology , Azetidines/therapeutic use , Chemistry Techniques, Synthetic/methods , Humans , Nitriles , Purines/chemical synthesis , Purines/chemistry , Purines/pharmacology , Purines/therapeutic use , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyrazoles/pharmacology , Pyrazoles/therapeutic use , Pyrimidines , SARS-CoV-2/physiology , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , Sulfonamides/pharmacology , Sulfonamides/therapeutic use , Virus Internalization/drug effects
8.
Bioorg Med Chem Lett ; 31: 127667, 2021 01 01.
Article in English | MEDLINE | ID: covidwho-907172

ABSTRACT

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 , COVID-19/drug therapy , 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
9.
Comb Chem High Throughput Screen ; 24(5): 716-728, 2021.
Article in English | MEDLINE | ID: covidwho-721423

ABSTRACT

AIMS: To predict potential drugs for COVID-19 by using molecular docking for virtual screening of drugs approved for other clinical applications. BACKGROUND: SARS-CoV-2 is the betacoronavirus responsible for the COVID-19 pandemic. It was listed as a potential global health threat by the WHO due to high mortality, high basic reproduction number, and lack of clinically approved drugs and vaccines. The genome of the virus responsible for COVID-19 has been sequenced. In addition, the three-dimensional structure of the main protease has been determined experimentally. OBJECTIVE: To identify potential drugs that can be repurposed for treatment of COVID-19 by using molecular docking based virtual screening of all approved drugs. METHODS: A list of drugs approved for clinical use was obtained from the SuperDRUG2 database. The structure of the target in the apo form, as well as structures of several target-ligand complexes, were obtained from RCSB PDB. The structure of SARS-CoV-2 Mpro determined from X-ray diffraction data was used as the target. Data regarding drugs in clinical trials for COVID-19 was obtained from clinicaltrials.org. Input for molecular docking based virtual screening was prepared by using Obabel and customized python, bash, and awk scripts. Molecular docking calculations were carried out with Vina and SMINA, and the docked conformations were analyzed and visualized with PLIP, Pymol, and Rasmol. RESULTS: Among the drugs that are being tested in clinical trials for COVID-19, Danoprevir and Darunavir were predicted to have the highest binding affinity for the Main protease (Mpro) target of SARS-CoV-2. Saquinavir and Beclabuvir were identified as the best novel candidates for COVID-19 therapy by using Virtual Screening of drugs approved for other clinical indications. CONCLUSION: Protease inhibitors approved for treatment of other viral diseases have the potential to be repurposed for treatment of COVID-19.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , COVID-19/virology , Drug Evaluation, Preclinical , Molecular Docking Simulation , SARS-CoV-2/drug effects , Antiviral Agents/chemistry , Benzazepines/chemistry , Benzazepines/pharmacology , Cyclopropanes/chemistry , Cyclopropanes/pharmacology , Darunavir/chemistry , Darunavir/pharmacology , Drug Repositioning , High-Throughput Screening Assays , Humans , Indoles/chemistry , Indoles/pharmacology , Isoindoles/chemistry , Isoindoles/pharmacology , Lactams, Macrocyclic/chemistry , Lactams, Macrocyclic/pharmacology , Proline/analogs & derivatives , Proline/chemistry , Proline/pharmacology , Saquinavir/chemistry , Saquinavir/pharmacology , Sulfonamides/chemistry , Sulfonamides/pharmacology
10.
Virus Res ; 286: 198068, 2020 09.
Article in English | MEDLINE | ID: covidwho-603573

ABSTRACT

The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to a renewed interest in studying the role of the spike S glycoprotein in regulating coronavirus infections in the natural host. Taking advantage of the cryo-electron microscopy structure of SARS-CoV-2 S trimer in the prefusion conformation, we performed a virtual screening simulation with the aim to identify novel molecules that could be used as fusion inhibitors. The spike glycoprotein structure has been completed using modeling techniques and its inner cavity, needful for the postfusion transition of the trimer, has been scanned for the identification of strongly interacting available drugs. Finally, the stability of the protein-drug top complexes has been tested using classical molecular dynamics simulations. The free energy of interaction of the molecules to the spike protein has been evaluated through the MM/GBSA method and per-residue decomposition analysis. Results have been critically discussed considering previous scientific knowledge concerning the selected compounds and sequence alignments have been carried out to evaluate the spike glycoprotein similarity among the betacoronavirus family members. Finally, a cocktail of drugs that may be used as SARS-CoV-2 fusion inhibitors has been suggested.


Subject(s)
Antiviral Agents/chemistry , Betacoronavirus/chemistry , Heterocyclic Compounds, 4 or More Rings/chemistry , Indoles/chemistry , Perylene/analogs & derivatives , Spike Glycoprotein, Coronavirus/chemistry , Sulfonamides/chemistry , Anthracenes , Antiviral Agents/pharmacology , Betacoronavirus/pathogenicity , Binding Sites , COVID-19 , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Gene Expression , Heterocyclic Compounds, 4 or More Rings/pharmacology , High-Throughput Screening Assays , Humans , Indoles/pharmacology , Isoindoles , Molecular Docking Simulation , Molecular Dynamics Simulation , Pandemics , Perylene/chemistry , Perylene/pharmacology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , Protein Multimerization , SARS-CoV-2 , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacology , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Sulfonamides/pharmacology , Thermodynamics , User-Computer Interface , Virus Internalization/drug effects
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