Facile access to potent antiviral quinazoline heterocycles with fluorescence properties via merging metal-free domino reactions

Felix E. Held, Anton A. Guryev, Tony Fröhlich, Frank Hampel, Axel Kahnt, Corina Hutterer, Mirjam Steingruber, Hanife Bahsi, Clemens von Bojničić-Kninski, Daniela S. Mattes, Tobias C. Foertsch, Alexander Nesterov-Mueller, Manfred Marschall and Svetlana B. Tsogoeva ()
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Felix E. Held: Organic Chemistry Chair I and Interdisciplinary Center for Molecular Materials, Friedrich-Alexander University of Erlangen-Nürnberg
Anton A. Guryev: Organic Chemistry Chair I and Interdisciplinary Center for Molecular Materials, Friedrich-Alexander University of Erlangen-Nürnberg
Tony Fröhlich: Organic Chemistry Chair I and Interdisciplinary Center for Molecular Materials, Friedrich-Alexander University of Erlangen-Nürnberg
Frank Hampel: Organic Chemistry Chair I and Interdisciplinary Center for Molecular Materials, Friedrich-Alexander University of Erlangen-Nürnberg
Axel Kahnt: Physical Chemistry Chair I, Friedrich-Alexander University of Erlangen-Nürnberg
Corina Hutterer: Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-Nürnberg
Mirjam Steingruber: Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-Nürnberg
Hanife Bahsi: Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-Nürnberg
Clemens von Bojničić-Kninski: Karlsruhe Institute of Technology, Institute of Microstructure Technology
Daniela S. Mattes: Karlsruhe Institute of Technology, Institute of Microstructure Technology
Tobias C. Foertsch: Karlsruhe Institute of Technology, Institute of Microstructure Technology
Alexander Nesterov-Mueller: Karlsruhe Institute of Technology, Institute of Microstructure Technology
Manfred Marschall: Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-Nürnberg
Svetlana B. Tsogoeva: Organic Chemistry Chair I and Interdisciplinary Center for Molecular Materials, Friedrich-Alexander University of Erlangen-Nürnberg

Nature Communications, 2017, vol. 8, issue 1, 1-9

Abstract: Abstract Most of the known approved drugs comprise functionalized heterocyclic compounds as subunits. Among them, non-fluorescent quinazolines with four different substitution patterns are found in a variety of clinically used pharmaceuticals, while 4,5,7,8-substituted quinazolines and those displaying their own specific fluorescence, favourable for cellular uptake visualization, have not been described so far. Here we report the development of a one-pot synthetic strategy to access these 4,5,7,8-substituted quinazolines, which are fluorescent and feature strong antiviral properties (EC50 down to 0.6±0.1 μM) against human cytomegalovirus (HCMV). Merging multistep domino processes in one-pot under fully metal-free conditions leads to sustainable, maximum efficient and high-yielding organic synthesis. Furthermore, generation of artesunic acid–quinazoline hybrids and their application against HCMV (EC50 down to 0.1±0.0 μM) is demonstrated. Fluorescence of new antiviral hybrids and quinazolines has potential applications in molecular imaging in drug development and mechanistic studies, avoiding requirement of linkage to external fluorescent markers.

Date: 2017
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DOI: 10.1038/ncomms15071

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