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Favipiravir is a wide-spectrum antiviral generic drug that has received large attention during the recent COVID-19 pandemic. While there are synthetic strategies for favipiravir synthesis, economical procedures could contribute to industrial scale synthesis and availability. Accordingly, our efforts focused on an economic and scalable procedure for favipiravir synthesis via the 3,6-dichloropyrazine-2-carbonitrile intermediate obtained from 3-aminopyrazine-2-carboxylic acid. The process afforded favipiravir with 43% yield (from 3,6-dichloropyrazine-2-carbonitrile, by fluorination, hydroxylation, and nitrile hydrolysis reactions) and greater than 99% purity without a chromatographic purification step., Supplementary Information: The online version contains supplementary material available at 10.1007/s11696-022-02595-1., (© Institute of Chemistry, Slovak Academy of Sciences 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

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)., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)