Experimental and Computational Investigation of the Oxime Bond Stereochemistry in c-Jun N-terminal Kinase 3 Inhibitors 11 H-Indeno[1,2- b]quinoxalin-11-one Oxime and Tryptanthrin-6-oxime

Vladislava V Matveevskaya; Dmitry I Pavlov; Anastasia R Kovrizhina; Taisiya S Sukhikh; Evgeniy H Sadykov; Pavel V Dorovatovskii; Vladimir A Lazarenko; Andrei I Khlebnikov; Andrei S Potapov

doi:10.3390/pharmaceutics15071802

Experimental and Computational Investigation of the Oxime Bond Stereochemistry in c-Jun N-terminal Kinase 3 Inhibitors 11 H-Indeno[1,2- b]quinoxalin-11-one Oxime and Tryptanthrin-6-oxime

Pharmaceutics. 2023 Jun 23;15(7):1802. doi: 10.3390/pharmaceutics15071802.

Authors

Vladislava V Matveevskaya¹, Dmitry I Pavlov¹, Anastasia R Kovrizhina², Taisiya S Sukhikh¹, Evgeniy H Sadykov¹, Pavel V Dorovatovskii³, Vladimir A Lazarenko³, Andrei I Khlebnikov², Andrei S Potapov¹

Affiliations

¹ Nikolaev Institute of Inorganic Chemistry, Siberian Branch of the Russian Academy of Sciences, 3 Lavrentiev Ave., 630090 Novosibirsk, Russia.
² Kizhner Research Center, National Research Tomsk Polytechnic University, 30 Lenin Ave., 634050 Tomsk, Russia.
³ National Research Centre "Kurchatov Institute", Kurchatov Square 1, 123182 Moscow, Russia.

Abstract

11H-Indeno[1,2-b]quinoxalin-11-one oxime (IQ-1) and tryptanthrin-6-oxime are potent c-Jun N-terminal kinase 3 (JNK-3) inhibitors demonstrating neuroprotective, anti-inflammatory and anti-arthritic activity. However, the stereochemical configuration of the oxime carbon-nitrogen double bond (E- or Z-) in these compounds was so far unknown. In this contribution, we report the results of the determination of the double bond configuration in the solid state by single crystal X-ray diffraction and in solution by 1D and 2D NMR techniques and DFT calculations. It was found that both in the solid state and in solution, IQ-1 adopts the E-configuration stabilized by intermolecular hydrogen bonds, in contrast to previously assumed Z-configuration that could be stabilized only by an intramolecular hydrogen bond.

Keywords: crystal structure; kinase inhibitor; nuclear magnetic resonance; oxime; rotation barrier.

Abstract

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