4-Iminooxazolidin-2-one as a Bioisostere of the Cyanohydrin Moiety: Inhibitors of Enterovirus 71 3C Protease

Abstract

A recently reported potent inhibitor of enterovirus 71 3C protease, (R)-1, was found to have stability and potential toxicity issues due to the presence of a cyanohydrin moiety. Modifying the labile cyanohydrin moiety, by serendipity, led to the discovery of 4-iminooxazolidin-2-onebased inhibitors 4e and 4g with potent inhibitory activity and significantly improved stability. In vivo pharmacokinetic studies of 4e also demonstrated high plasma exposure and moderate half-life. These compounds have shown potential of becoming anti-EV71 drug candidates.

Antivirals and vaccines for Enterovirus A71

“…Cyanohyfdrin (R)-1 is another potent inhibitor of EV-A71 3C pro but was unstable and showed potential toxicity. Modifying the labile cyanohydrin moiety led to the discovery of the 4-iminooxazolidin-2-one-based inhibitors 4e and 4 g with potent inhibitory activity and significantly improved stability [36]. One small-molecule inhibitor, DC07090, inhibited EV-A71 replication with an EC 50 value of 22.09 ± 1.07 μM by targeting 3C protease [37].…”

BF3·OEt2-Catalyzed Synthesis of anti-β-(N-Arylamino)-α-hydroxynitriles by Regio- and Diastereospecific Ring Opening of 3-Aryloxirane-2-carbonitriles with Anilines

“…Cyanohydrins are versatile building blocks in synthetic organic chemistry in which the two functional groups hydroxyl and cyano group connect to the same carbon nucleus, making them not only possessing the ability to participate in monofunctional group conversion reactions, 1 but also bifunctional group conversion reactions. [2][3][4] Furthermore, cyanohydrins are also proven to be biological active molecules 3,5,6 and have certain biological applications. 7 Traditional methods for the synthesis of cyanohydrins and their O-protected derivatives involved the addition of highly toxic cyanide to aldehydes or ketones.…”

“…As a result, the development of novel, safe, and practical methods for construction of cyanohydrins still is an issue to deeply investigate. -Aminocyanohydrins, derivatives of cyanohydrins, are also proven to be biologically active compounds 3,5 and have prevalent applications in the synthesis of -amino-hydroxycarboxylic acid derivatives 11 and heterocyclic compounds. 2,3 However, there are few investigations on the synthesis of -aminocyanohydrins, all of which involve the addition of highly toxic cyanide sources to the corresponding N-protected -aminoaldehydes (Scheme 1a).…”

“…-Aminocyanohydrins, derivatives of cyanohydrins, are also proven to be biologically active compounds 3,5 and have prevalent applications in the synthesis of -amino-hydroxycarboxylic acid derivatives 11 and heterocyclic compounds. 2,3 However, there are few investigations on the synthesis of -aminocyanohydrins, all of which involve the addition of highly toxic cyanide sources to the corresponding N-protected -aminoaldehydes (Scheme 1a). 5,11,12 More recently, we reported a new method for the synthesis of 2-arylindoles from vicinal 3-aryloxirane-2-carbonitriles and anilines, and showed that -(N-arylamino)cyanohydrins are important intermediates (Scheme 1b).…”

“…5,11,12 More recently, we reported a new method for the synthesis of 2-arylindoles from vicinal 3-aryloxirane-2-carbonitriles and anilines, and showed that -(N-arylamino)cyanohydrins are important intermediates (Scheme 1b). 2 Inspired by our previous work, 2 a microwave-assisted BF 3 •OEt 2 -catalyzed synthesis of anti--(N-arylamino)--hydroxynitriles through regio-and diastereospecific ring opening of ox-…”