5 years ago

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

Facile access to potent antiviral quinazoline heterocycles with fluorescence properties via merging metal-free domino reactions
Tony Fröhlich, Mirjam Steingruber, Felix E. Held, Alexander Nesterov-Mueller, Svetlana B. Tsogoeva, Tobias C. Foertsch, Manfred Marschall, Corina Hutterer, Hanife Bahsi, Anton A. Guryev, Axel Kahnt, Daniela S. Mattes, Frank Hampel, Clemens von Bojničić-Kninski
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.

Publisher URL: http://www.nature.com/articles/ncomms15071

DOI: 10.1038/ncomms15071

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