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Evaluation of Michael-type Acceptor Reactivity of 5-Benzylidenebarbiturates, 5-benzylidenerhodanines, and Related Heterocycles Using NMR

Emilija Arsovska, Jurij Trontelj, Nace Zidar, Tihomir Tomašić, Lucija Peterlin Mašič, Danijel Kikelj, Janez Plavec, Anamarija Zega


Despite existing experimental and computational tools to assess the risk, the non-specific chemical modification of protein thiol groups remains a significant source of false-positive hits, particularly in academic drug discovery. Herein, we describe the application of a simple NMR method in a systematic study on the reactivity of 5-benzylidenebarbiturates, 5-benzylidenerhodanines, and their related oxo-heterocycles, which have been associated with numerous biological activities and have recently gained a reputation as unselective promiscuous binders. Using this method, we confirmed the reactivity of 5-benzylidenebarbiturates, which are known to easily form Michael adducts with nucleophiles. In contrast, 5-benzylidene five-membered oxo-heterocycles revealed almost insignificant reactivity. We can conclude that the distinct binding profile of the most controversial compounds, 5-benzylidenerhodanines, is not necessarily related to their unspecific Michael acceptor reactivity.


Drug discovery; False positives; Michael acceptors; 5-benzylidene heterocycles; NMR spectroscopy

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