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Anal Bioanal Chem ; 413(23): 5811-5820, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1321733


Remdesivir is a nucleotide analog prodrug that has received much attention since the outbreak of the COVID-19 pandemic in December 2019. GS-441524 (Nuc) is the active metabolite of remdesivir and plays a pivotal role in the clinical treatment of COVID-19. Here, a robust HPLC-MS/MS method was developed to determine Nuc concentrations in rat plasma samples after a one-step protein precipitation process. Chromatographic separation was accomplished on Waters XBrige C18 column (50 × 2.1 mm, 3.5 µm) under gradient elution conditions. Multiple reaction monitoring transitions in electrospray positive ion mode were m/z 292.2 → 163.2 for Nuc and 237.1 → 194.1 for the internal standard (carbamazepine). The quantitative analysis method was fully validated in line with the United States Food and Drug Administration guidelines. The linearity, accuracy and precision, matrix effect, recovery, and stability results met the requirements of the guidelines. Uncertainty of measurement and incurred sample reanalysis were analyzed to further ensure the robustness and reproducibility of the method. This optimized method was successfully applied in a rat pharmacokinetics study of remdesivir (intravenously administration, 5 mg kg-1). The method can act as a basis for further pharmacokinetic and clinical efficacy investigations in patients with COVID-19. Graphical abstract.

Adenosine Monophosphate/analogs & derivatives , Adenosine/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/blood , Chromatography, High Pressure Liquid/methods , Tandem Mass Spectrometry/methods , Adenosine/blood , Adenosine/pharmacokinetics , Adenosine/standards , Adenosine Monophosphate/blood , Adenosine Monophosphate/pharmacokinetics , Adenosine Monophosphate/standards , Alanine/blood , Alanine/pharmacokinetics , Alanine/standards , Animals , Antiviral Agents/pharmacokinetics , Antiviral Agents/standards , Limit of Detection , Male , Quality Control , Rats , Rats, Sprague-Dawley , Reference Standards , Reproducibility of Results
Eur J Med Chem ; 223: 113622, 2021 Nov 05.
Article in English | MEDLINE | ID: covidwho-1263253


The emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the global pandemic coronavirus disease (COVID-19), but no specific antiviral drug has been proven effective for controlling this pandemic to date. In this study, several 2-((indol-3-yl)thio)-N-benzyl-acetamides were identified as SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) inhibitors. After a two-round optimization, a new series of 2-((indol-3-yl)thio)-N-benzyl-acetamides was designed, synthesized, and evaluated for SARS-CoV-2 RdRp inhibitory effect. Compounds 6b2, 6b5, 6c9, 6d2, and 6d5 were identified as potent inhibitors with IC50 values of 3.35 ± 0.21 µM, 4.55 ± 0.2 µM, 1.65 ± 0.05 µM, 3.76 ± 0.79 µM, and 1.11 ± 0.05 µM, respectively; the IC50 of remdesivir (control) was measured as 1.19 ± 0.36 µM. All of the compounds inhibited RNA synthesis by SARS-CoV-2 RdRp. The most potent compound 6d5, which showed a stronger inhibitory activity against the human coronavirus HCoV-OC43 than remdesivir, is a promising candidate for further investigation.

Acetamides/chemical synthesis , Antiviral Agents/chemical synthesis , COVID-19/drug therapy , Enzyme Inhibitors/chemical synthesis , RNA, Viral/antagonists & inhibitors , RNA-Dependent RNA Polymerase/antagonists & inhibitors , SARS-CoV-2/drug effects , Acetamides/pharmacology , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Adenosine Monophosphate/standards , Alanine/analogs & derivatives , Alanine/pharmacology , Alanine/standards , Antiviral Agents/pharmacology , Drug Evaluation, Preclinical , Enzyme Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Molecular Docking Simulation , Molecular Structure , Protein Binding , SARS-CoV-2/genetics , Structure-Activity Relationship