New Pyrazine Conjugates: Synthesis, Computational Studies, and Antiviral Properties against SARS‐CoV‐2

• Published in: ChemMedChem 2021-11, Vol.16 (22), p.3418-3427
• Main Authors: Seliem, Israa A., Girgis, Adel S., Moatasim, Yassmin, Kandeil, Ahmed, Mostafa, Ahmed, Ali, Mohamed A., Bekheit, Mohamed S., Panda, Siva S.
• Format: Article
• Language: English
• Subjects: 1,2,3-Triazole; Amides - pharmacology; Animals; Antiviral activity; Antiviral Agents - chemical synthesis; Antiviral Agents - metabolism; Antiviral Agents - pharmacology; Antiviral Agents - toxicity; Benzothiazole; Benzotriazole; Chemical synthesis; Chlorocebus aethiops; Computational studies; Computer applications; Conjugates; Coronavirus RNA-Dependent RNA Polymerase - metabolism; Coronaviruses; Cytotoxicity; Microbial Sensitivity Tests; Molecular Docking Simulation; Molecular Structure; Pyrazine; Pyrazines - chemical synthesis; Pyrazines - metabolism; Pyrazines - pharmacology; Pyrazines - toxicity; Quantitative Structure-Activity Relationship; SARS-CoV-2; SARS-CoV-2 - drug effects; Selectivity; Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Toxicity; Vero Cells; Viral diseases; Viruses
• ISSN: 1860-7179; 1860-7187; 1860-7187
• DOI: 10.1002/cmdc.202100476

Currently, limited therapeutic options are available for severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2). We have developed a set of pyrazine‐based small molecules. A series of pyrazine conjugates was synthesized by microwave‐assisted click chemistry and benzotriazole chemistry. All the synthesized conjugates were screened against the SAR‐CoV‐2 virus and their cytotoxicity was determined. Computational studies were carried out to validate the biological data. Some of the pyrazine‐triazole conjugates (5 d–g) and (S)‐N‐(1‐(benzo[d]thiazol‐2‐yl)‐2‐phenylethyl)pyrazine‐2‐carboxamide 12 i show significant potency against SARS‐CoV‐2 among the synthesized conjugates. The selectivity index (SI) of potent conjugates indicates significant efficacy compared to the reference drug (Favipiravir). Antiviral drug development for SARS‐CoV‐2: The design and microwave‐assisted synthesis of pyrazine conjugates are reported. Some of the newly synthesized conjugates show better antiviral activity and selectivity indexes than those of the reference drug. All the lead compounds exhibited low cytotoxicity. Thus, these conjugates could lead to the development of potential drug candidates for SARS‐CoV‐2.