Discovery of Di- and Trihaloacetamides as Covalent SARS-CoV-2 Main Protease Inhibitors with High Target Specificity.

The main protease (M) is a validated antiviral drug target of SARS-CoV-2. A number of M inhibitors have now advanced to animal model study and human clinical trials. However, one issue yet to be addressed is the target selectivity over host proteases such as cathepsin L.

Rational Design of Hybrid SARS-CoV-2 Main Protease Inhibitors Guided by the Superimposed Cocrystal Structures with the Peptidomimetic Inhibitors GC-376, Telaprevir, and Boceprevir.

SARS-CoV-2 main protease (M) is a cysteine protease that mediates the cleavage of viral polyproteins and is a validated antiviral drug target. M is highly conserved among all seven human coronaviruses, with certain M inhibitors having broad-spectrum antiviral activity. In this study, we designed two hybrid inhibitors and based on the superimposed X-ray crystal structures of SARS-CoV-2 M with GC-376, telaprevir, and boceprevir.

Discovery of SARS-CoV-2 Papain-like Protease Inhibitors through a Combination of High-Throughput Screening and a FlipGFP-Based Reporter Assay.

The papain-like protease (PL) of SARS-CoV-2 is a validated antiviral drug target. Through a fluorescence resonance energy transfer-based high-throughput screening and subsequent lead optimization, we identified several PL inhibitors including and with improved enzymatic inhibition and antiviral activity compared to , which was reported as a SARS-CoV PL inhibitor. Significantly, we developed a cell-based FlipGFP assay that can be applied to predict the cellular antiviral activity of PL inhibitors in the BSL-2 setting.

Discovery of SARS-CoV-2 papain-like protease inhibitors through a combination of high-throughput screening and FlipGFP-based reporter assay.

The papain-like protease (PL ) of SARS-CoV-2 is a validated antiviral drug target. PL is involved in the cleavage of viral polyproteins and antagonizing host innate immune response through its deubiquitinating and deISG15ylating activities, rendering it a high profile antiviral drug target. Through a FRET-based high-throughput screening, several hits were identified as PL inhibitors with IC values at the single-digit micromolar range.

Chiral phosphoric acid-catalyzed asymmetric dearomatization reactions.

We summarize in this review the recent development of chiral phosphoric acid (CPA)-catalyzed asymmetric dearomatization reactions. A wide array of electron-rich arenes (indoles, phenols, naphthols, benzothiophenes, benzofurans, etc.) and electron-poor arenes (pyridines, quinolines, isoquinolines, etc.

Potent HIV-1 Protease Inhibitors Containing Carboxylic and Boronic Acids: Effect on Enzyme Inhibition and Antiviral Activity and Protein-Ligand X-ray Structural Studies.

We report the synthesis and biological evaluation of phenylcarboxylic acid and phenylboronic acid containing HIV-1 protease inhibitors and their functional effect on enzyme inhibition and antiviral activity in MT-2 cell lines. Inhibitors bearing bis-THF ligand as P2 ligand and phenylcarboxylic acids and carboxamide as the P2' ligands, showed very potent HIV-1 protease inhibitory activity. However, carboxylic acid containing inhibitors showed very poor antiviral activity relative to carboxamide-derived inhibitors which showed good antiviral IC value.

Chiral phosphoric acid catalyzed aminative dearomatization of α-naphthols/Michael addition sequence.

Asymmetric dearomatization reactions have recently emerged as a powerful tool for the rapid build-up of the molecular complexity. Chiral three-dimensional polycyclic molecules bearing contiguous stereogenic centers can be synthesized from readily available planar aromatic feedstocks. Here we report that an intermolecular asymmetric dearomatization reaction of α-naphthols bearing a tethered nucleophile at the C4 position of the naphthol ring is achieved by a chiral phosphoric acid.

Manipulation of Spiroindolenine Intermediates for Enantioselective Synthesis of 3-(Indol-3-yl)-Pyrrolidines.

By manipulating the reactivity of spiroindolenine species, a sequential Michael/retro-Mannich/Mannich reaction of ω-indol-3-yl α,β-unsaturated ketones was developed. In the presence of 10 mol % of a chiral phosphoric acid as the catalyst, a series of 3-(indol-3-yl)-pyrrolidines were synthesized in high yields (up to 91 %) with excellent stereoselectivities (up to 92 % ee, >19:1 d.r.

Catalytic Asymmetric Dearomatization of Indolyl Dihydropyridines through an Enamine Isomerization/Spirocyclization/Transfer Hydrogenation Sequence.

A highly efficient synthesis of enantioenriched spiroindolines by catalytic asymmetric dearomatization of indolyl dihydropyridines through a chiral phosphoric acid catalyzed enamine isomerization/spirocyclization/transfer hydrogenation sequence has been developed. This reaction proceeds under mild reaction conditions, affording novel spiroindolines in good yields (up to 88 %) with excellent enantioselectivity (up to 97 % ee). DFT calculations provide insights into the reaction mechanism as well as the origin of stereochemistry.

Facile access to 2,2-disubstituted indolin-3-ones via a cascade Fischer indolization/Claisen rearrangement reaction.

An efficient approach for the synthesis of 2,2-disubstituted indolin-3-ones is described. From readily accessible aryl hydrazines and allyloxyketones, 2,2-disubstituted indolin-3-ones could be obtained in good to excellent yields under mild reaction conditions via a cascade Fischer indolization/Claisen rearrangement process. This protocol provides a facile entry to 2,2-disubstituted indolin-3-ones, which have been applied in the construction of the benzofuroindoline framework related to Phalarine.

Construction of Chiral Tetrahydro-β-Carbolines: Asymmetric Pictet-Spengler Reaction of Indolyl Dihydropyridines.

A highly efficient synthesis of the enantioenriched tetrahydro-β-carbolines was developed by using a chiral phosphoric acid catalyzed Pictet-Spengler reaction of indolyl dihydropyridines. The reaction proceeds under mild reaction conditions to afford the desired chiral tetrahydro-β-carbolines in good to excellent yields (up to 96 %) and high enantioselectivities (up to 99 % ee). With this method, a formal synthesis of tangutorine and a total synthesis of deplancheine were achieved in a highly efficient manner.

Chiral Phosphoric Acid Catalyzed Intramolecular Dearomative Michael Addition of Indoles to Enones.

An enantioselective intramolecular dearomative Michael addition of indolyl enones is presented. In the presence of catalytic amount of chiral phosphoric acid, various enantioenriched spiro-indolenines bearing a quaternary stereogenic center were obtained with good yields and enantioselectivity (up to 97% ee) under mild reaction conditions.

Enantioselective Bromo-oxycyclization of Silanol.

Relying on the nucleophilicity of silanol for building up silicon-incorporated scaffold with an enantiopure tetrasubstituted carbon center remains elusive. In this report, asymmetric bromo-oxycyclization of olefinic silanol by using chiral anionic phase-transfer catalyst is described. This protocol provided a facile entry to a wide arrangement of enantiopure benzoxasilole in moderate to excellent enantioselectivities depending on the unique reactivity of bromine/N-benzyl-DABCO complex.

Total Synthesis of (-)-Conolutinine.

The first enantioselective synthesis of (-)-conolutinine was achieved in 10 steps. The synthesis featured a catalytic asymmetric bromocyclization of tryptamine to forge the tricycle intermediate. Hydration of an alkene catalyzed by Co(acac)2 was also employed as a key step to diastereoselectively introduce the tertiary alcohol moiety.

Synthesis of naked amino-pyrroloindoline via direct aminocyclization of tryptamine.

The first direct access to unprotected amino-pyrroloindoline via aminocyclization of tryptamine and tryptophan has been described. A variety of structurally diverse amino-pyrroloindolines are furnished by the use of O-(2,4-dinitrophenyl)hydroxylamine (DPH) as the nitrogen source in the presence of catalytic Rh2(esp)2.