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Molecules ; 27(2)2022 Jan 13.
Article in English | MEDLINE | ID: covidwho-1624914


A novel series of 1-aryl-N-[4-phenyl-5-(arylazo)thiazol-2-yl)methanimines has been synthesized via the condensation of 2-amino-4-phenyl-5-arylazothiazole with various aromatic aldehydes. The synthesized imines were characterized by spectroscopic techniques, namely 1H and 13C-NMR, FTIR, MS, and Elemental Analysis. A molecular comparative docking study for 3a-f was calculated, with reference to two approved drugs, Molnupiravir and Remdesivir, using 7BQY (Mpro; PDB code 7BQY; resolution: 1.7 A°) under identical conditions. The binding scores against 7BQY were in the range of -7.7 to -8.7 kcal/mol for 3a-f. The high scores of the compounds indicated an enhanced binding affinity of the molecules to the receptor. This is due to the hydrophobic interactions and multi-hydrogen bonds between 3a-f ligands and the receptor's active amino acid residues. The main aim of using in silco molecular docking was to rank 3a-f with respect to the approved drugs, Molnupiravir and Remdesivir, using free energy methods as greener pastures. A further interesting comparison presented the laydown of the ligands before and after molecular docking. These results and other supporting statistical analyses suggested that ligands 3a-f deserve further investigation in the context of potential therapeutic agents for COVID-19. Free-cost, PASS, SwissADME, and Way2drug were used in this research paper to determine the possible biological activities and cytotoxicity of 3a-f.

Antiviral Agents/chemistry , COVID-19/drug therapy , Imines/chemistry , Thiazoles/chemistry , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/chemistry , Alanine/analogs & derivatives , Alanine/chemistry , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacokinetics , Antiviral Agents/toxicity , Binding Sites , Computer Simulation , Coronavirus 3C Proteases/chemistry , Cytidine/analogs & derivatives , Cytidine/chemistry , Hydroxylamines/chemistry , Imines/chemical synthesis , Imines/pharmacokinetics , Imines/toxicity , Molecular Docking Simulation , SARS-CoV-2/drug effects , Thiazoles/chemical synthesis , Thiazoles/pharmacokinetics , Thiazoles/toxicity
Clin Pharmacol Ther ; 111(3): 585-594, 2022 03.
Article in English | MEDLINE | ID: covidwho-1482119


Repurposing approved drugs may rapidly establish effective interventions during a public health crisis. This has yielded immunomodulatory treatments for severe coronavirus disease 2019 (COVID-19), but repurposed antivirals have not been successful to date because of redundancy of the target in vivo or suboptimal exposures at studied doses. Nitazoxanide is a US Food and Drug Administration (FDA) approved antiparasitic medicine, that physiologically-based pharmacokinetic (PBPK) modeling has indicated may provide antiviral concentrations across the dosing interval, when repurposed at higher than approved doses. Within the AGILE trial platform (NCT04746183) an open label, adaptive, phase I trial in healthy adult participants was undertaken with high-dose nitazoxanide. Participants received 1,500 mg nitazoxanide orally twice-daily with food for 7 days. Primary outcomes were safety, tolerability, optimum dose, and schedule. Intensive pharmacokinetic (PK) sampling was undertaken day 1 and 5 with minimum concentration (Cmin ) sampling on days 3 and 7. Fourteen healthy participants were enrolled between February 18 and May 11, 2021. All 14 doses were completed by 10 of 14 participants. Nitazoxanide was safe and with no significant adverse events. Moderate gastrointestinal disturbance (loose stools or diarrhea) occurred in 8 participants (57.1%), with urine and sclera discoloration in 12 (85.7%) and 9 (64.3%) participants, respectively, without clinically significant bilirubin elevation. This was self-limiting and resolved upon drug discontinuation. PBPK predictions were confirmed on day 1 but with underprediction at day 5. Median Cmin was above the in vitro target concentration on the first dose and maintained throughout. Nitazoxanide administered at 1,500 mg b.i.d. with food was safe with acceptable tolerability a phase Ib/IIa study is now being initiated in patients with COVID-19.

Antiviral Agents/administration & dosage , Nitro Compounds/administration & dosage , Nitro Compounds/adverse effects , Nitro Compounds/pharmacokinetics , Thiazoles/administration & dosage , Thiazoles/adverse effects , Thiazoles/pharmacokinetics , Adult , Antiviral Agents/adverse effects , Antiviral Agents/pharmacokinetics , COVID-19/drug therapy , Drug Repositioning , Female , Healthy Volunteers , Humans , Male , Middle Aged , Young Adult
Br J Clin Pharmacol ; 87(4): 2078-2088, 2021 04.
Article in English | MEDLINE | ID: covidwho-883246


BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been declared a global pandemic and urgent treatment and prevention strategies are needed. Nitazoxanide, an anthelmintic drug, has been shown to exhibit in vitro activity against SARS-CoV-2. The present study used physiologically based pharmacokinetic (PBPK) modelling to inform optimal doses of nitazoxanide capable of maintaining plasma and lung tizoxanide exposures above the reported SARS-CoV-2 EC90 . METHODS: A whole-body PBPK model was validated against available pharmacokinetic data for healthy individuals receiving single and multiple doses between 500 and 4000 mg with and without food. The validated model was used to predict doses expected to maintain tizoxanide plasma and lung concentrations above the EC90 in >90% of the simulated population. PopDes was used to estimate an optimal sparse sampling strategy for future clinical trials. RESULTS: The PBPK model was successfully validated against the reported human pharmacokinetics. The model predicted optimal doses of 1200 mg QID, 1600 mg TID and 2900 mg BID in the fasted state and 700 mg QID, 900 mg TID and 1400 mg BID when given with food. For BID regimens an optimal sparse sampling strategy of 0.25, 1, 3 and 12 hours post dose was estimated. CONCLUSION: The PBPK model predicted tizoxanide concentrations within doses of nitazoxanide already given to humans previously. The reported dosing strategies provide a rational basis for design of clinical trials with nitazoxanide for the treatment or prevention of SARS-CoV-2 infection. A concordant higher dose of nitazoxanide is now planned for investigation in the seamless phase I/IIa AGILE trial.

Antiviral Agents/administration & dosage , COVID-19/drug therapy , COVID-19/prevention & control , Drug Repositioning , Models, Biological , Nitro Compounds/administration & dosage , Thiazoles/administration & dosage , Adult , Antiviral Agents/blood , Antiviral Agents/pharmacokinetics , COVID-19/blood , Computer Simulation , Drug Dosage Calculations , Female , Humans , Lung/metabolism , Male , Middle Aged , Nitro Compounds/blood , Nitro Compounds/pharmacokinetics , Reproducibility of Results , Thiazoles/blood , Thiazoles/pharmacokinetics , Tissue Distribution , Young Adult