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2.
Acta Biomed ; 93(2): e2022156, 2022 05 11.
Article in English | MEDLINE | ID: covidwho-1848005

ABSTRACT

Background and aim Recurrent wheezing is often triggered by viral respiratory infections. The aims of our study were: i) to evaluate whether the addition of a nutraceutical (Leucodif®), could improve the efficacy of montelukast or inhaled steroids (ICS) compared to the single treatment; ii) to verify whether a treatment is more effective than another. Our study was biased by the COVID-19 pandemic, which resulted in a lockdown of almost two months in Italy. Methods The multicenter, open-label study enrolled 84 children aged 2-6 years diagnosed with recurrent wheezing and randomized them into four treatment arms for three months: ICS treatment; ii) montelukast; iii) montelukast + Leucodif; iv) ICS + Leucodif. Children were assessed at baseline and after one, two, and three months of treatment using the TRACK score for both the caregiver and the physician. Results Out of the 84 patients, 18 patients received ICS therapy, 22 patients ICS + Leucodif, 24 patients montelukast, and 20 patients montelukast + Leucodif. All four treatments resulted in a significant reduction in symptoms with no differences among the various groups. Conclusions Our study demonstrates that montelukast therapy appears to be equally effective as ICS therapy and that the addition of the nutraceutical Leucodif does not appear to improve the treatment outcome. However, in our opinion our study was strongly influenced and biased by the lockdown due to the COVID-19 pandemic, which inherently resulted in reduced exposure to the viruses that commonly cause respiratory infections in children.


Subject(s)
Anti-Asthmatic Agents , Asthma , COVID-19 , Acetates , Administration, Inhalation , Anti-Asthmatic Agents/adverse effects , Asthma/drug therapy , Child , Communicable Disease Control , Cyclopropanes , Dietary Supplements , Humans , Pandemics , Quinolines , Respiratory Sounds , Steroids/therapeutic use , Sulfides
3.
Thorac Cancer ; 13(10): 1463-1470, 2022 05.
Article in English | MEDLINE | ID: covidwho-1846156

ABSTRACT

BACKGROUND: The aim of this prospective, pilot, single-arm phase II trial was to evaluate the safety and efficacy of anlotinib combined with etoposide and platinum-based regimens in the first-line treatment of extensive-stage small cell lung cancer (ES-SCLC). METHODS: This phase II study was conducted at Fudan University Shanghai Cancer Center between December 2018 and December 2020. All patients received standard chemotherapy (etoposide plus cisplatin/carboplatin) consisting of four courses and anlotinib at 12 mg once per day for 2 weeks followed by a one-week rest. Anlotinib administration was continued until disease progression, intolerable adverse events (AEs) or patient withdrawal from the study. The primary outcome measure was progression-free survival (PFS). The secondary outcome measures were overall survival (OS), objective control rate (ORR), disease control rate (DCR) and AEs. RESULTS: Thirty-seven patients were included in this study, and 30 patients were eligible for efficacy analysis. ORR and DCR were 90.0% and 96.7%, respectively. The estimated PFS and OS were 6.0 months (95% CI: 1.1-11.9 months) and 14.0 months (95% CI: 8.6-19.4 months), respectively. No unexpected adverse effects were reported. Hypertension (20/37, 54.1%), anemia (16/37, 43.2%), alopecia (15/37, 40.5%), elevated transaminases (9/37, 24.3%) and alkaline phosphatase (9/37, 24.3%) were the most commonly reported AEs. Thirteen patients (35.1%) reported grade 3-5 AEs. No treatment-related deaths occurred during this study. CONCLUSION: The addition of anlotinib to standard etoposide/platinum chemotherapy achieved encouraging PFS and OS in previously untreated ES-SCLC patients, with an acceptable tolerability profile and no new safety signals observed.


Subject(s)
Lung Neoplasms , Small Cell Lung Carcinoma , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carboplatin , China , Etoposide , Humans , Indoles , Platinum/pharmacology , Platinum/therapeutic use , Prospective Studies , Quinolines
4.
Viruses ; 14(5)2022 04 21.
Article in English | MEDLINE | ID: covidwho-1822446

ABSTRACT

Coronaviruses (CoVs) consist of a large group of RNA viruses causing various diseases in humans and in lots of animals. Human coronavirus (HCoV) OC43, the prototype of beta-coronavirus discovered in the 1960s, has been circulating in humans for long time, and infection with other emerging strains of beta-coronavirus (SARS-CoV, SARS-CoV-2, and MERS-CoV) can lead to severe illness and death. In this study, we found that montelukast, a leukotriene receptor antagonist, potently inhibited the infection of HCoV-OC43 in distinct cells in a dose- and time- dependent manner. Additionally, the results showed that montelukast induced release of HCoV-OC43 genomic RNA by disrupting the integrity of the viral lipid membrane, and irreversibly inhibited viral infection. Considering the similarity among HCoV-OC43, MERS-CoV, and SARS-CoV-2, it suggests that montelukast may be a potential candidate for the treatment of human beta-coronavirus infection.


Subject(s)
COVID-19 , Coronavirus OC43, Human , Middle East Respiratory Syndrome Coronavirus , Acetates/pharmacology , Animals , COVID-19/drug therapy , Cyclopropanes , Quinolines , SARS-CoV-2 , Sulfides
5.
Clin Pharmacol Ther ; 111(6): 1324-1333, 2022 Jun.
Article in English | MEDLINE | ID: covidwho-1802136

ABSTRACT

Cystic fibrosis transmembrane conductance regulator (CFTR) modulating therapies, including elexacaftor-tezacaftor-ivacaftor, are primarily eliminated through cytochrome P450 (CYP) 3A-mediated metabolism. This creates a therapeutic challenge to the treatment of coronavirus disease 2019 (COVID-19) with nirmatrelvir-ritonavir in people with cystic fibrosis (CF) due to the potential for significant drug-drug interactions (DDIs). However, the population with CF is more at risk of serious illness following COVID-19 infection and hence it is important to manage the DDI risk and provide treatment options. CYP3A-mediated DDI of elexacaftor-tezacaftor-ivacaftor was evaluated using a physiologically-based pharmacokinetic modeling approach. Modeling was performed incorporating physiological information and drug-dependent parameters of elexacaftor-tezacaftor-ivacaftor to predict the effect of ritonavir (the CYP3A inhibiting component of the combination) on the pharmacokinetics of elexacaftor-tezacaftor-ivacaftor. The elexacaftor-tezacaftor-ivacaftor models were verified using independent clinical pharmacokinetic and DDI data of elexacaftor-tezacaftor-ivacaftor with a range of CYP3A modulators. When ritonavir was administered on Days 1 through 5, the predicted area under the curve (AUC) ratio of ivacaftor (the most sensitive CYP3A substrate) on Day 6 was 9.31, indicating that its metabolism was strongly inhibited. Based on the predicted DDI, the dose of elexacaftor-tezacaftor-ivacaftor should be reduced when coadministered with nirmatrelvir-ritonavir to elexacaftor 200 mg-tezacaftor 100 mg-ivacaftor 150 mg on Days 1 and 5, with delayed resumption of full-dose elexacaftor-tezacaftor-ivacaftor on Day 9, considering the residual inhibitory effect of ritonavir as a mechanism-based inhibitor. The simulation predicts a regimen of elexacaftor-tezacaftor-ivacaftor administered concomitantly with nirmatrelvir-ritonavir in people with CF that will likely decrease the impact of the drug interaction.


Subject(s)
COVID-19 , Cystic Fibrosis , Aminophenols/pharmacology , Benzodioxoles/pharmacology , COVID-19/drug therapy , Chloride Channel Agonists/therapeutic use , Cystic Fibrosis/drug therapy , Cystic Fibrosis Transmembrane Conductance Regulator , Cytochrome P-450 CYP3A/metabolism , Drug Combinations , Drug Interactions , Humans , Indoles/pharmacology , Lactams/pharmacokinetics , Leucine/pharmacokinetics , Mutation , Nitriles/pharmacokinetics , Proline/pharmacokinetics , Pyrazoles/pharmacology , Pyridines/pharmacology , Pyrrolidines , Quinolines/pharmacology , Quinolones , Ritonavir/pharmacokinetics
6.
Sci Rep ; 12(1): 6501, 2022 04 20.
Article in English | MEDLINE | ID: covidwho-1799560

ABSTRACT

TaqMan probe-based commercial real-time (RT) PCR kits are expensive but most frequently used in COVID-19 diagnosis. The unprecedented scale of SARS-CoV-2 infections needs to meet the challenge of testing more persons at a reasonable cost. This study developed a simple and cost-effective alternative diagnostic method based on melting curve analysis of SYBR green multiplex assay targeting two virus-specific genes along with a host-specific internal control. A total of 180 randomly selected samples portioning into two subsets based on crude and high-quality RNA extraction were used to compare this assay with a nationwide available commercial kit (Sansure Biotech Inc., (Hunan, China)), so that we could analyze the variation and validity of this in-house developed method. Our customized-designed primers can specifically detect the viral RNA likewise Sansure. We separately optimized SYBR Green RT-PCR reaction of N, E, S, and RdRp genes based on singleplex melting curve analysis at the initial stage. After several rounds of optimization on multiplex assays of different primer combinations, the optimized method finally targeted N and E genes of the SARS-CoV-2 virus, together with the ß-actin gene of the host as an internal control. Comparing with the Sansure commercial kit, our proposed assay provided up to 97% specificity and 93% sensitivity. The cost of each sample processing ranged between ~2 and ~6 USD depending on the purification level of extracted RNA template. Overall, this one-step and one-tube method can revolutionize the COVID-19 diagnosis in low-income countries.


Subject(s)
COVID-19 , Benzothiazoles , COVID-19/diagnosis , COVID-19 Testing , Cost-Benefit Analysis , Diamines , Humans , Quinolines , RNA, Viral/genetics , Real-Time Polymerase Chain Reaction/methods , Reverse Transcriptase Polymerase Chain Reaction , SARS-CoV-2/genetics , Sensitivity and Specificity
7.
J Photochem Photobiol B ; 231: 112447, 2022 Jun.
Article in English | MEDLINE | ID: covidwho-1796437

ABSTRACT

Cuspareine as an antiviral alkaloid can be used in the treatment of COVID-19. In this study, we introduced the ionic liquids (ILs) concluded cuspareinium as a cation with CH3COO-, CF3COO-, and PF6 as anions. The optimized geometry, thermodynamic parameters, and reactivity descriptors were calculated with density functional theory (DFT) approach and time-dependent density functional theory (TD-DFT) using B3LYP/6-311G. In addition, the UV and IR spectra of the introduced ILs were investigated. Based on DFT calculation, the designed IL CH3COO- can be to the most suitable anions due to most solubility in the water. DFT studies displayed that all the introduced ILs have more polarity than pristine cuspareine and CH3COO--cuspareine is the most polarity due to high dipole moment. Also, the thermo- chemical data of the designed ionic liquids revealed that PF6-cuspareine is distinguished to be stable. A molecular docking study of the designed ILs with 6 LU7 protease was performed to display interactions and binding energy. Results of molecular docking displayed that CH3COO- ion liquid has the highest binding energy (- 7.20 kcal/mol) and Ala7, and Lys 5 residues are involved in an interaction. DFT and molecular docking studies of cuspareine as alkaloid based on ionic liquids can be helpful to for more pharmaceutical and biological researches of cuspareine as an antiviral agent against COVID-19.


Subject(s)
Alkaloids , COVID-19 , Ionic Liquids , Alkaloids/pharmacology , Anions/chemistry , Antiviral Agents/pharmacology , COVID-19/drug therapy , Humans , Ionic Liquids/chemistry , Molecular Docking Simulation , Quinolines
8.
J Med Virol ; 94(5): 1950-1958, 2022 05.
Article in English | MEDLINE | ID: covidwho-1777576

ABSTRACT

The inflammatory/anti-inflammatory balance has an important role in the clinical course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (coronavirus disease [COVID-19]) infection, which has affected over 200 million people since it first appeared in China in December 2019. This study aimed to determine the effectiveness of montelukast, which has known anti-inflammatory and bronchodilatory effects, in these patients. The prospective randomized controlled study included 180 patients who were hospitalized in the infectious diseases department of our hospital between May and July 2021 and were diagnosed with the delta variant of SARS-CoV-2 by real-time polymerase chain reaction of nasopharyngeal swabs. The patients were divided into three groups and received only standard treatment according to national guidelines (Group 1) or standard treatment plus 10 mg/day montelukast (Group 2) or 20 mg/day montelukast (Group 3). Laboratory parameters and pulmonary function tests (PFTs) at admission and on Day 5 of treatment were compared. Comparison of laboratory parameters on Day 5 showed that Groups 2 and 3 had significantly lower levels of lactate dehydrogenase, fibrinogen, D-dimer, C-reactive protein, and procalcitonin compared with Group 1 (p = 0.04, 0.002, 0.05, 0.03, and 0.04, respectively). In the comparison between Groups 2 and 3, only fibrinogen was significantly lower in Group 3 (p = 0.02). PFT results did not differ between the groups at admission, while on Day 5, only Group 3 showed significant improvements in forced expiratory volume in 1 s, forced vital capacity, and peak expiratory flow 25-75 compared with admission (p = 0.001 for all). Montelukast may be beneficial in COVID-19 patients to maintain the inflammatory/anti-inflammatory balance, prevent respiratory failure through its bronchodilator activity, and reduce mortality.


Subject(s)
COVID-19 , Acetates , COVID-19/drug therapy , Cyclopropanes , Humans , Prospective Studies , Quinolines , SARS-CoV-2 , Sulfides
9.
Molecules ; 27(6)2022 Mar 09.
Article in English | MEDLINE | ID: covidwho-1732134

ABSTRACT

In the search for new anti-HIV-1 agents, two forms of phenylamino-phenoxy-quinoline derivatives have been synthesized, namely, 2-phenylamino-4-phenoxy-quinoline and 6-phenylamino-4-phenoxy-quinoline. In this study, the binding interactions of phenylamino-phenoxy-quinoline derivatives and six commercially available drugs (hydroxychloroquine, ritonavir, remdesivir, S-217622, N3, and PF-07321332) with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro) were investigated using molecular docking and the ONIOM method. The molecular docking showed the hydrogen bonding and hydrophobic interactions of all the compounds in the pocket of SARS-CoV-2 main protease (Mpro), which plays an important role for the division and proliferation of the virus into the cell. The binding free energy values between the ligands and Mpro ranged from -7.06 to -10.61 kcal/mol. The molecular docking and ONIOM results suggested that 4-(2',6'-dimethyl-4'-cyanophenoxy)-2-(4″-cyanophenyl)-aminoquinoline and 4-(4'-cyanophenoxy)-2-(4″-cyanophenyl)-aminoquinoline have low binding energy values and appropriate molecular properties; moreover, both compounds could bind to Mpro via hydrogen bonding and Pi-Pi stacking interactions with amino acid residues, namely, HIS41, GLU166, and GLN192. These amino acids are related to the proteolytic cleavage process of the catalytic triad mechanisms. Therefore, this study provides important information for further studies on synthetic quinoline derivatives as antiviral candidates in the treatment of SARS-CoV-2.


Subject(s)
COVID-19 , Quinolines , COVID-19/drug therapy , Cysteine Endopeptidases/chemistry , Humans , Lactams , Leucine , Molecular Docking Simulation , Nitriles , Peptide Hydrolases , Proline , Quinolines/pharmacology , SARS-CoV-2 , Viral Proteins/metabolism
10.
Appl Microbiol Biotechnol ; 106(5-6): 2207-2218, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1712228

ABSTRACT

The pandemic of coronavirus disease 2019 (COVID-19) continues to threaten public health. For developing countries where vaccines are still in shortage, cheaper alternative molecular methods for SARS-CoV-2 identification can be crucial to prevent the next wave. Therefore, 14 primer sets recommended by the World Health Organization (WHO) was evaluated on testing both clinical patient and environmental samples with the gold standard diagnosis method, TaqMan-based RT-qPCR, and a cheaper alternative method, SYBR Green-based RT-qPCR. Using suitable primer sets, such as ORF1ab, 2019_nCoV_N1 and 2019_nCoV_N3, the performance of the SYBR Green approach was comparable or better than the TaqMan approach, even when considering the newly dominating or emerging variants, including Delta, Eta, Kappa, Lambda, Mu, and Omicron. ORF1ab and 2019_nCoV_N3 were the best combination for sensitive and reliable SARS-CoV-2 molecular diagnostics due to their high sensitivity, specificity, and broad accessibility. KEY POINTS: • With suitable primer sets, the SYBR Green method performs better than the TaqMan one. • With suitable primer sets, both methods should still detect the new variants well. • ORF1ab and 2019_nCoV_N3 were the best combination for SARS-CoV-2 detection.


Subject(s)
COVID-19 , SARS-CoV-2 , Benzothiazoles , COVID-19/diagnosis , Diamines , Humans , Quinolines , RNA, Viral/analysis , Real-Time Polymerase Chain Reaction/methods , SARS-CoV-2/genetics , Sensitivity and Specificity
11.
ChemMedChem ; 17(9): e202200005, 2022 05 04.
Article in English | MEDLINE | ID: covidwho-1705786

ABSTRACT

The newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cause life-threatening diseases in millions of people worldwide, in particular, in patients with cancer, and there is an urgent need for antiviral agents against this infection. While in vitro activities of artemisinins against SARS-CoV-2 and cancer have recently been demonstrated, no study of artemisinin and/or synthetic peroxide-based hybrid compounds active against both cancer and SARS-CoV-2 has been reported yet. However, the hybrid drug's properties (e. g., activity and/or selectivity) can be improved compared to its parent compounds and effective new agents can be obtained by modification/hybridization of existing drugs or bioactive natural products. In this study, a series of new artesunic acid and synthetic peroxide based new hybrids were synthesized and analyzed in vitro for the first time for their inhibitory activity against SARS-CoV-2 and leukemia cell lines. Several artesunic acid-derived hybrids exerted a similar or stronger potency against K562 leukemia cells (81-83 % inhibition values) than the reference drug doxorubicin (78 % inhibition value) and they were also more efficient than their parent compounds artesunic acid (49.2 % inhibition value) and quinoline derivative (5.5 % inhibition value). Interestingly, the same artesunic acid-quinoline hybrids also show inhibitory activity against SARS-CoV-2 in vitro (EC50 13-19 µm) and no cytotoxic effects on Vero E6 cells (CC50 up to 110 µM). These results provide a valuable basis for design of further artemisinin-derived hybrids to treat both cancer and SARS-CoV-2 infections.


Subject(s)
Artemisinins , COVID-19 , Leukemia , Neoplasms , Quinolines , Animals , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Artemisinins/pharmacology , COVID-19/drug therapy , Chlorocebus aethiops , Humans , Leukemia/drug therapy , Neoplasms/drug therapy , Peroxides , Quinolines/therapeutic use , SARS-CoV-2 , Vero Cells
12.
Trials ; 23(1): 19, 2022 Jan 06.
Article in English | MEDLINE | ID: covidwho-1677532

ABSTRACT

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic continues to affect the globe. After 18 months of the SARS-CoV-2 emergence, clinicians have clearly defined a subgroup of patients with lasting, disabling symptoms. While big strides have been made in understanding the acute phase of SARS-CoV-2 infection, the pathophysiology of long COVID is still largely unknown, and evidence-based, effective treatments for this condition remain unavailable. OBJECTIVES: To evaluate the efficacy of 10 mg oral montelukast every 24 h versus placebo in improving quality of life associated with mild to moderate respiratory symptoms in patients with long COVID as measured with the COPD Assessment Test (CAT) questionnaire. The secondary objectives will evaluate the effect of montelukast versus placebo on improving exercise capacity, COVID-19 symptoms (asthenia, headache, mental confusion or brain fog, ageusia, and anosmia), oxygen desaturation during exertion, functional status, and mortality. METHODS AND ANALYSIS: Phase III, randomized, double-blind clinical trial. We will include 18- to 80-year-old patients with SARS-CoV-2 infection and mild to moderate respiratory symptoms lasting more than 4 weeks. Participants will be randomly allocated in a 1:1 ratio to the intervention (experimental treatment with 10 mg/day montelukast) or the control group (placebo group), during a 28-day treatment. Follow-up will finish 56 days after the start of treatment. The primary outcome will be health-related quality of life associated with respiratory symptoms according to the COPD Assessment Test 4 weeks after starting the treatment. The following are the secondary outcomes: (a) exercise capacity and oxygen saturation (1-min sit-to-stand test); (b) Post-COVID-19 Functional Status Scale; (c) other symptoms: asthenia, headache, mental confusion (brain fog), ageusia, and anosmia (Likert scale); (d) use of healthcare resources; (e) mortality; (f) sick leave duration in days; and (g) side effects of montelukast. ETHICS AND DISSEMINATION: This study has been approved by the Clinical Research Ethics Committee of the IDIAPJGol (reference number 21/091-C). The trial results will be published in open access, peer-reviewed journals and explained in webinars to increase awareness and understanding about long COVID among primary health professionals. TRIAL REGISTRATION: ClinicalTrials.gov NCT04695704 . Registered on January 5, 2021. EudraCT number 2021-000605-24. Prospectively registered.


Subject(s)
COVID-19 , Acetates , COVID-19/complications , Cyclopropanes , Double-Blind Method , Humans , Quality of Life , Quinolines , Randomized Controlled Trials as Topic , SARS-CoV-2 , Sulfides , Treatment Outcome
13.
Chemistry ; 28(4): e202200039, 2022 Jan 19.
Article in English | MEDLINE | ID: covidwho-1633218

ABSTRACT

Invited for the cover of this issue are Manfred Marschall, Svetlana B. Tsogoeva and co-workers at Friedrich-Alexander University of Erlangen-Nürnberg. The image depicts a new anti-SARS-CoV-2 compound in front of SARS-CoV-2 viruses. Read the full text of the article at 10.1002/chem.202103861.


Subject(s)
COVID-19 , Quinolines , Cell Culture Techniques , Humans , SARS-CoV-2
14.
Int Immunopharmacol ; 103: 108412, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1568781

ABSTRACT

Levocetirizine, a third-generation antihistamine, and montelukast, a leukotriene receptor antagonist, exhibit remarkable synergistic anti-inflammatory activity across a spectrum of signaling proteins, cell adhesion molecules, and leukocytes. By targeting cellular protein activity, they are uniquely positioned to treat the symptoms of COVID-19. Clinical data to date with an associated six-month follow-up, suggests the combination therapy may prevent the progression of the disease from mild to moderate to severe, as well as prevent/treat many of the aspects of 'Long COVID,' thereby cost effectively reducing both morbidity and mortality. To investigate patient outcomes, 53 consecutive COVID-19 test (+) cases (ages 3-90) from a well-established, single-center practice in Boston, Massachusetts, between March - November 2020, were treated with levocetirizine and montelukast in addition to then existing protocols [2]. The data set was retrospectively reviewed. Thirty-four cases were considered mild (64%), 17 moderate (32%), and 2 (4%) severe. Several patients presented with significant comorbidities (obesity: n = 22, 41%; diabetes: n = 10, 19%; hypertension: n = 24, 45%). Among the cohort there were no exclusions, no intubations, and no deaths. The pilot study in Massachusetts encompassed the first COVID-19 wave which peaked on April 23, 2020 as well as the ascending portion of the second wave in the fall. During this period the average weekly COVID-19 case mortality rate (confirmed deaths/confirmed cases) varied considerably between 1 and 7.5% [37]. FDA has approved a multicenter, randomized, placebo-controlled, Phase 2 clinical trial design, replete with electronic diaries and laboratory metrics to explore scientific questions not addressed herein.


Subject(s)
Acetates/therapeutic use , COVID-19/drug therapy , Cetirizine/therapeutic use , Cyclopropanes/therapeutic use , Histamine H1 Antagonists, Non-Sedating/therapeutic use , Leukotriene Antagonists/therapeutic use , Quinolines/therapeutic use , SARS-CoV-2/drug effects , Sulfides/therapeutic use , Adolescent , Adult , Aged , Aged, 80 and over , Child , Child, Preschool , Female , Humans , Male , Middle Aged , Retrospective Studies , Treatment Outcome , Young Adult
15.
Chemistry ; 28(4): e202103861, 2022 Jan 19.
Article in English | MEDLINE | ID: covidwho-1549185

ABSTRACT

The presently ongoing pandemic of human SARS-CoV-2 infections (COVID-19) presents an enormous challenge in surveillance, vaccine and antiviral drug development. Here we report the synthesis of new bioactive quinoline-morpholine hybrid compounds and their virological evaluation, which proves pronounced cell culture-based inhibitory profile against SARS-CoV-2. Thus, selected quinoline compounds may suggest specific hit-to-lead development.


Subject(s)
COVID-19 , Quinolines , Antiviral Agents/pharmacology , Cell Culture Techniques , Humans , Pandemics , Quinolines/pharmacology , SARS-CoV-2
16.
Mol Ther ; 30(2): 963-974, 2022 02 02.
Article in English | MEDLINE | ID: covidwho-1525991

ABSTRACT

Small molecule inhibitors have previously been investigated in different studies as possible therapeutics in the treatment of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). In the current drug repurposing study, we identified the leukotriene (D4) receptor antagonist montelukast as a novel agent that simultaneously targets two important drug targets of SARS-CoV-2. We initially demonstrated the dual inhibition profile of montelukast through multiscale molecular modeling studies. Next, we characterized its effect on both targets by different in vitro experiments including the enzyme (main protease) inhibition-based assay, surface plasmon resonance (SPR) spectroscopy, pseudovirus neutralization on HEK293T/hACE2+TMPRSS2, and virus neutralization assay using xCELLigence MP real-time cell analyzer. Our integrated in silico and in vitro results confirmed the dual potential effect of montelukast both on the main protease enzyme inhibition and virus entry into the host cell (spike/ACE2). The virus neutralization assay results showed that SARS-CoV-2 virus activity was delayed with montelukast for 20 h on the infected cells. The rapid use of new small molecules in the pandemic is very important today. Montelukast, whose pharmacokinetic and pharmacodynamic properties are very well characterized and has been widely used in the treatment of asthma since 1998, should urgently be completed in clinical phase studies and, if its effect is proved in clinical phase studies, it should be used against coronavirus disease 2019 (COVID-19).


Subject(s)
Acetates/pharmacology , Angiotensin-Converting Enzyme 2/metabolism , Cyclopropanes/pharmacology , Quinolines/pharmacology , SARS-CoV-2/physiology , Serine Endopeptidases/metabolism , Sulfides/pharmacology , A549 Cells , Acetates/chemistry , Angiotensin-Converting Enzyme 2/chemistry , Animals , Cell Survival/drug effects , Chlorocebus aethiops , Cyclopropanes/chemistry , Drug Repositioning , HEK293 Cells , Humans , Models, Molecular , Molecular Docking Simulation , Molecular Structure , Neutralization Tests , Protein Conformation , Quinolines/chemistry , SARS-CoV-2/drug effects , Serine Endopeptidases/chemistry , Sulfides/chemistry , Vero Cells , Virus Internalization/drug effects
17.
Anticancer Drugs ; 32(10): 1116-1117, 2021 11 01.
Article in English | MEDLINE | ID: covidwho-1475864

ABSTRACT

During the coronavirus disease 2019 (COVID-19) pandemic, clinicians are required to manage patient care for pre-existing conditions. Currently, there are no clear indications regarding the management of lenvatinib-treated patients for radioiodine-refractory thyroid cancer and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. A 74-year-old male patient was treated with lenvatinib since March 2019, with disease recurrence in the thyroid bed and bilateral multiple lung metastases. The patient partially responded to treatment, with reduction in lung metastases. In September 2019, the patient tested positive for SARS-CoV-2 and isolated at home. Initially asymptomatic, the patient developed mild symptoms. Lenvatinib treatment continued with daily monitoring of vital signs. After telemedicine consultation of patient's clinical condition, severity of symptoms was low. He tested negative for SARS-CoV-2 21 days after testing positive. The patient received the full course of lenvatinib treatment. This is the first reported case of a lenvatinib-treated patient who developed COVID-19 and could continue treatment. Despite concerns over COVID-19, clinicians should not overlook treatment of pre-existing diseases or discontinue treatment, particularly for cancer. Clinicians should evaluate a patient's history and clinical presentation, monitoring the patient to reduce the development of complications in high-risk settings, avoiding treatment discontinuation.


Subject(s)
COVID-19/complications , Lung Neoplasms/drug therapy , Phenylurea Compounds/therapeutic use , Quinolines/therapeutic use , Thyroid Neoplasms/drug therapy , Aged , Humans , Lung Neoplasms/secondary , Male , Thyroid Neoplasms/pathology
18.
Mol Biol Rep ; 48(11): 7243-7249, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1453812

ABSTRACT

BACKGROUND: The new SARS-CoV-2 variant VOC (202012/01), identified recently in the United Kingdom (UK), exhibits a higher transmissibility rate compared to other variants, and a reproductive number 0.4 higher. In the UK, scientists were able to identify the increase of this new variant through the rise of false negative results for the spike (S) target using a three-target RT-PCR assay (TaqPath kit). METHODS: To control and study the current coronavirus pandemic, it is important to develop a rapid and low-cost molecular test to identify the aforementioned variant. In this work, we designed primer sets specific to the VOC (202012/01) to be used by SYBR Green-based RT-PCR. These primers were specifically designed to confirm the deletion mutations Δ69/Δ70 in the spike and the Δ106/Δ107/Δ108 in the NSP6 gene. We studied 20 samples from positive patients, detected by using the Applied Biosystems TaqPath RT-PCR COVID-19 kit (Thermo Fisher Scientific, Waltham, USA) that included the ORF1ab, S, and N gene targets. 16 samples displayed an S-negative profile (negative for S target and positive for N and ORF1ab targets) and four samples with S, N and ORF1ab positive profile. RESULTS: Our results emphasized that all S-negative samples harbored the mutations Δ69/Δ70 and Δ106/Δ107/Δ108. This protocol could be used as a second test to confirm the diagnosis in patients who were already positive to COVID-19 but showed false negative results for S-gene. CONCLUSIONS: This technique may allow to identify patients carrying the VOC (202012/01) or a closely related variant, in case of shortage in sequencing.


Subject(s)
Benzothiazoles , COVID-19/virology , Diamines , Fluorescent Dyes , Quinolines , Real-Time Polymerase Chain Reaction/methods , SARS-CoV-2/isolation & purification , COVID-19/diagnosis , Costs and Cost Analysis , DNA Primers , Genome, Viral , Humans , Mutation , Real-Time Polymerase Chain Reaction/economics , SARS-CoV-2/genetics , Sensitivity and Specificity , Spike Glycoprotein, Coronavirus/genetics , Time Factors
20.
Eur J Med Chem ; 215: 113220, 2021 Apr 05.
Article in English | MEDLINE | ID: covidwho-1385485

ABSTRACT

In current scenario, various heterocycles have come up exhibiting crucial role in various medicinal agents which are valuable for mankind. Out of diverse range of heterocycle, quinoline scaffold have been proved to play an important role in broad range of biological activities. Several drug molecules bearing a quinoline molecule with useful anticancer, antibacterial activities etc have been marketed such as chloroquine, saquinavir etc. Owing to their broad spectrum biological role, various synthetic strategies such as Skraup reaction, Combes reaction etc. has been developed by the researchers all over the world. But still the synthetic methods are associated with various limitations as formation of side products, use of expensive metal catalysts. Thus, several efforts to develop an efficient and cost effective synthetic protocol are still carried out till date. Moreover, quinoline scaffold displays remarkable antiviral activity. Therefore, in this review we have made an attempt to describe recent synthetic protocols developed by various research groups along with giving a complete explanation about the role of quinoline derivatives as antiviral agent. Quinoline derivatives were found potent against various strains of viruses like zika virus, enterovirus, herpes virus, human immunodeficiency virus, ebola virus, hepatitis C virus, SARS virus and MERS virus etc.


Subject(s)
Antiviral Agents/therapeutic use , Quinolines/therapeutic use , Virus Diseases/drug therapy , Viruses/drug effects , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Cell Line, Tumor , Humans , Quinolines/chemical synthesis , Quinolines/pharmacology
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