SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is the etiological agent responsible for the global COVID-19 (coronavirus disease 2019) outbreak. The main protease of SARS-CoV-2, Mpro, is a key enzyme that plays a pivotal role in mediating viral replication and transcription. We designed and synthesized two lead compounds (11a and 11b) targeting Mpro. Both exhibited excellent inhibitory activity and potent anti–SARS-CoV-2 infection activity. The x-ray crystal structures of SARS-CoV-2 Mpro in complex with 11a or 11b, both determined at a resolution of 1.5 angstroms, showed that the aldehyde groups of 11a and 11b are covalently bound to cysteine 145 of Mpro. Both compounds showed good pharmacokinetic properties in vivo, and 11a also exhibited low toxicity, which suggests that these compounds are promising drug candidates.
A catalytic system‐controlled divergent reaction strategy was here reported to construct four types of intriguing spiroheterocyclic skeletons from simple and readily available starting materials via a precise chemical bond activation/[n+1] annulation cascade. The tetraazaspiroheterocyclic and trizazspiroheterocyclic scaffolds could be independently constructed by a selective N−N bond activation/[n+1] annulation cascade, a C(sp2)‐H activation/[4+1] annulation and a novel tandem C(sp2)‐H/C(sp3)−H bond activation/[4+1] annulation strategy, along with a broad scope of substrates, moderate to excellent yields and valuable transformations. More importantly, in these transformations, we are the first time to capture a N−N bond activation and a C(sp3)−H bond activation of pyrazolidinones under different catalytic system.
SARS-CoV-2 is the etiological agent responsible for the COVID-19 outbreak in Wuhan. Specific antiviral drug are urgently needed to treat COVID-19 infections. The main protease (M pro ) of SARS-CoV-2 is a key CoV enzyme that plays a pivotal role in mediating viral replication and transcription, which makes it an attractive drug target.In an effort to rapidly discover lead compounds targeting M pro , two compounds (11a and 11b) were designed and synthesized, both of which exhibited excellent inhibitory activity with an IC 50 value of 0.05 μ M and 0.04 μ M respectively. Significantly, both compounds exhibited potent anti-SARS-CoV-2 infection activity in a cell-based assay with an EC 50 value of 0.42 μ M and 0.33 μ M, respectively. The X-ray crystal structures of SARS-CoV-2 M pro in complex with 11a and 11b were determined at 1.5 Å resolution, respectively. The crystal structures showed that 11a and 11b are covalent inhibitors, the aldehyde groups of which are bound covalently to Cys145 of M pro . Both compounds showed good PK properties in vivo, and 11a also exhibited low toxicity which is promising drug leads with clinical potential that merits further studies.
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