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<p>4-Aminotetrahydroquinazoline <i>N</i>-oxides form a prominent chemotype of orthoflavivirus reproduction inhibitors, attractive for the search of lead compounds for development as direct-action antiviral agents. Here we explored the relationship between the structure and antiviral activity within an extended series of adamantyl-containing 4-aminotetrahydroquinazolines, synthesized via S<sub>N</sub>Ar reactions of 4-chlorotetrahydroquinazolines with adamantyl-containing amines. Most of the obtained compounds inhibited the reproduction of tick-borne encephalitis, yellow fever, and West Nile viruses in phenotypic assays with micromolar EC<sub>50</sub>s. The most favorable substituents at 4-amino group were 2-adamant-(1/2)-ylethyls, while the position 2 of heterocyclic core served as a toxicity switch, 2-chlorotetrahydroquinazolines being much less toxic than other analogues. Time-of-addition experiments for hit compounds against West Nile virus revealed a possibility for multi-factorial mechanism of action in the 4-aminotetrahydroquinazoline series.</p><p></p>

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SAR exploration for 4-aminotetrahydroquinazolines with adamantyl moiety against orthoflaviviruses

  • 期刊论文

  • 发表日期：

    2026年3月25日

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  • Sergey V. Kositov,
  • Evgeny V. Khvatov,
  • Victoria I. Uvarova,
  • Kseniya N. Sedenkova,
  • Alexander S. Goryashchenko,
  • Maria K. Kaleda,
  • Aleksandra V. Peisikova,
  • Yuri K. Grishin,
  • Boris P. Gladkikh,
  • Gennady M. Butov,
  • Dmitry I. Osolodkin,
  • Aydar A. Ishmukhametov,
  • Elena B. Averina

摘要

4-Aminotetrahydroquinazoline N-oxides form a prominent chemotype of orthoflavivirus reproduction inhibitors, attractive for the search of lead compounds for development as direct-action antiviral agents. Here we explored the relationship between the structure and antiviral activity within an extended series of adamantyl-containing 4-aminotetrahydroquinazolines, synthesized via SNAr reactions of 4-chlorotetrahydroquinazolines with adamantyl-containing amines. Most of the obtained compounds inhibited the reproduction of tick-borne encephalitis, yellow fever, and West Nile viruses in phenotypic assays with micromolar EC50s. The most favorable substituents at 4-amino group were 2-adamant-(1/2)-ylethyls, while the position 2 of heterocyclic core served as a toxicity switch, 2-chlorotetrahydroquinazolines being much less toxic than other analogues. Time-of-addition experiments for hit compounds against West Nile virus revealed a possibility for multi-factorial mechanism of action in the 4-aminotetrahydroquinazoline series.