- Structure-Activity Relationships of Benzamides and Isoindolines Designed as SARS-CoV Protease Inhibitors Effective against SARS-CoV-2
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Inhibition of coronavirus (CoV)-encoded papain-like cysteine proteases (PLpro) represents an attractive strategy to treat infections by these important human pathogens. Herein we report on structure-activity relationships (SAR) of the noncovalent active-site directed inhibitor (R)-5-amino-2-methyl-N-(1-(naphthalen-1-yl)ethyl) benzamide (2 b), which is known to bind into the S3 and S4 pockets of the SARS-CoV PLpro. Moreover, we report the discovery of isoindolines as a new class of potent PLpro inhibitors. The studies also provide a deeper understanding of the binding modes of this inhibitor class. Importantly, the inhibitors were also confirmed to inhibit SARS-CoV-2 replication in cell culture suggesting that, due to the high structural similarities of the target proteases, inhibitors identified against SARS-CoV PLpro are valuable starting points for the development of new pan-coronaviral inhibitors.
- Welker, Armin,Kersten, Christian,Müller, Christin,Madhugiri, Ramakanth,Zimmer, Collin,Müller, Patrick,Zimmermann, Robert,Hammerschmidt, Stefan,Maus, Hannah,Ziebuhr, John,Sotriffer, Christoph,Schirmeister, Tanja
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supporting information
p. 340 - 354
(2020/10/19)
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- Site-Specific C(sp3)–H Aminations of Imidates and Amidines Enabled by Covalently Tethered Distonic Radical Anions
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The utilization of N-centered radicals to synthesize nitrogen-containing compounds has attracted considerable attention recently, due to their powerful reactivities and the concomitant construction of C?N bonds. However, the generation and control of N-centered radicals remain particularly challenging. We report a tethering strategy using SOMO-HOMO-converted distonic radical anions for the site-specific aminations of imidates and amidines with aid of the non-covalent interaction. This reaction features a remarkably broad substrate scope and also enables the late-stage functionalization of bioactive molecules. Furthermore, the reaction mechanism is thoroughly investigated through kinetic studies, Raman spectroscopy, electron paramagnetic resonance spectroscopy, and density functional theory calculations, revealing that the aminations likely involve direct homolytic cleavage of N?H bonds and subsequently controllable 1,5 or 1,6 hydrogen atom transfer.
- Fang, Yuanding,Fu, Kang,Shi, Lei,Zhao, Rong,Zhou, Jia
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p. 20682 - 20690
(2020/09/07)
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- Highly efficient asymmetric access to 1-azaspiro[4.4]nonane skeleton
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Vinylogous Mukaiyama aldol type reaction of chiral non-racemic silyloxypyrroles followed by acidic treatment affords an efficient asymmetric access to 1-azaspiro[4.4]nonanes in high diastereoisomeric excess (up to 79%).
- Planas, Lo?c,Pérard-Viret, Jo?lle,Royer, Jacques,Selkti, Mohamed,Thomas, Alain
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p. 1629 - 1632
(2007/10/03)
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- Improved Chiral Derivatizing Agents for the Chromatographic Resolution of Racemic Primary Amines
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Several 4- and/or 5-aryl-substituted 2-oxazolidones have been prepared and studied as chiral derivatizing agents (CDA) for the chromatographic resolution of chiral primary amines via diastereomeric allophanates.The diastereomeric allophanates derived from either racemic primary amines and cis-4,5-diphenyl-2-oxazolidone-3-carbamyl chloride or racemic isocyanates and cis-4,5-diphenyl-2-oxazolidone show sufficient NMR chemical shift differences and chromatographic separability that this heterocyclic system should prove to be a very useful CDA for the chromatographic resolution and determination of the absolute configuration of a variety of chiral primary amines.The diastereomeric allophanates are readily hydrolyzed to return both chiral components of the allophanates in excellent yield.Both solution and adsorbed conformations of these allophanates are discussed in reference to the determination of the absolute configuration of the allophanates (and hence of the chiral primary amine) from the senses of NMR nonequivalence between and chromatographic elution order of the diastereomers.
- Pirkle, William H.,Simmons, Kirk A.
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p. 2520 - 2527
(2007/10/02)
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