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Open AccessArticle

Naphthoquinones as Covalent Reversible Inhibitors of Cysteine Proteases—Studies on Inhibition Mechanism and Kinetics

1
Department of Chemistry, Organic Chemistry Section, Johannes Gutenberg-Universität, Duesbergweg 10-14, 55128 Mainz, Germany
2
Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg-Universität, Staudingerweg 5, 55128 Mainz, Germany
3
Department of Chemistry, Biochemistry Section, Johannes Gutenberg-Universität, Johann-Joachim Becherweg 30, 55128 Mainz, Germany
4
Institute of Immunology, University Medical Center, Johannes Gutenberg-Universität Mainz, Langenbeckstr. 1, 55131 Mainz, Germany
5
Institute of Physical and Theoretical Chemistry, Universität Würzburg, Emil-Fischer-Straße 42, 97074 Würzburg, Germany
6
Centre for Biomolecular Magnetic Resonance (BMRZ), Goethe-University Frankfurt, 60323 Frankfurt, Germany
*
Authors to whom correspondence should be addressed.
Molecules 2020, 25(9), 2064; https://doi.org/10.3390/molecules25092064
Received: 31 March 2020 / Revised: 16 April 2020 / Accepted: 21 April 2020 / Published: 28 April 2020
(This article belongs to the Special Issue Covalent Inhibitors in Drug Discovery and Chemical Biology)
The facile synthesis and detailed investigation of a class of highly potent protease inhibitors based on 1,4-naphthoquinones with a dipeptidic recognition motif (HN-l-Phe-l-Leu-OR) in the 2-position and an electron-withdrawing group (EWG) in the 3-position is presented. One of the compound representatives, namely the acid with EWG = CN and with R = H proved to be a highly potent rhodesain inhibitor with nanomolar affinity. The respective benzyl ester (R = Bn) was found to be hydrolyzed by the target enzyme itself yielding the free acid. Detailed kinetic and mass spectrometry studies revealed a reversible covalent binding mode. Theoretical calculations with different density functionals (DFT) as well as wavefunction-based approaches were performed to elucidate the mode of action. View Full-Text
Keywords: protease; rhodesain; covalent reversible inhibition; 1,4-naphthoquinone; nucleophilic addition; prodrug protease; rhodesain; covalent reversible inhibition; 1,4-naphthoquinone; nucleophilic addition; prodrug
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MDPI and ACS Style

Klein, P.; Barthels, F.; Johe, P.; Wagner, A.; Tenzer, S.; Distler, U.; Le, T.A.; Schmid, P.; Engel, V.; Engels, B.; Hellmich, U.A.; Opatz, T.; Schirmeister, T. Naphthoquinones as Covalent Reversible Inhibitors of Cysteine Proteases—Studies on Inhibition Mechanism and Kinetics. Molecules 2020, 25, 2064.

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