Identification of novel and potent inhibitors of SARS-CoV-2 main protease from DNA-encoded chemical libraries.

In vitro screening of large compound libraries with automated high-throughput screening is expensive and time-consuming and requires dedicated infrastructures. Conversely, the selection of DNA-encoded chemical libraries (DECLs) can be rapidly performed with routine equipment available in most laboratories. In this study, we identified novel inhibitors of SARS-CoV-2 main protease (Mpro) through the affinity-based selection of the DELopen library (open access for academics), containing 4.2 billion compounds. The identified inhibitors were peptide-like compounds containing an N-terminal electrophilic group able to form a covalent bond with the nucleophilic Cys145 of Mpro, as confirmed by x-ray crystallography. This DECL selection campaign enabled the discovery of the unoptimized compound SLL11 (IC50 = 30 nM), proving that the rapid exploration of large chemical spaces enabled by DECL technology allows for the direct identification of potent inhibitors avoiding several rounds of iterative medicinal chemistry. As demonstrated further by x-ray crystallography, SLL11 was found to adopt a highly unique U-shaped binding conformation, which allows the N-terminal electrophilic group to loop back to the S1' subsite while the C-terminal amino acid sits in the S1 subsite. MP1, a close analog of SLL11, showed antiviral activity against SARS-CoV-2 in the low micromolar range when tested in Caco-2 and Calu-3 (EC50 = 2.3 µM) cell lines. As peptide-like compounds can suffer from low cell permeability and metabolic stability, the cyclization of the compounds will be explored in the future to improve their antiviral activity.

Base-catalysed 18F-labelling of trifluoromethyl ketones. Application to the synthesis of 18F-labelled neutrophil elastase inhibitors.

A new method for the fluorine-18 labelling of trifluoromethyl ketones has been developed. This method is based on the conversion of a-COCF3 functional group to a difluoro enol silyl ether followed by halogenation and fluorine-18 labelling. The utility of this new method was demonstrated by the synthesis of fluorine-18 labelled neutrophil elastase inhibitors, which are potentially useful for detection of inflammatory disorders.

A Study of an 8-Aminoquinoline-Directed C(sp2)-H Arylation Reaction on the Route to Chiral Cyclobutane Keto Acids from Myrtenal.

This work outlines a synthetic route that can be used to access chiral cyclobutane keto acids with two stereocenters in five steps from the inexpensive terpene myrtenal. Furthermore, the developed route includes an 8-aminoquinoline-directed C(sp2)-H arylation as one of its key steps, which allows a wide range of aryl and heteroaryl groups to be incorporated into the bicyclic myrtenal scaffold prior to the ozonolysis-based ring-opening step that furnishes the target cyclobutane keto acids. This synthetic route is expected to find many applications connected to the synthesis of natural product-like compounds and small molecule libraries.

Synthesis of Elaborate Benzofuran-2-carboxamide Derivatives through a Combination of 8-Aminoquinoline Directed C-H Arylation and Transamidation Chemistry.

Herein, we present a short and highly modular synthetic route that involves 8-aminoquinoline directed C-H arylation and transamidation chemistry, and which enables access to a wide range of elaborate benzofuran-2-carboxamides. For the directed C-H arylation reactions, Pd catalysis was used to install a wide range of aryl and heteroaryl substituents at the C3 position of the benzofuran scaffold in high efficiency. Directing group cleavage and further diversification of the C3-arylated benzofuran products were then achieved in a single synthetic operation through the utilization of a one-pot, two-step transamidation procedure, which proceeded via the intermediate N-acyl-Boc-carbamates. Given the high efficiency and modularity of this synthetic strategy, it constitutes a very attractive method for generating structurally diverse collections of benzofuran derivatives for small molecule screening campaigns.

A Two-Step Procedure for the Overall Transamidation of 8-Aminoquinoline Amides Proceeding via the Intermediate N-Acyl-Boc-Carbamates.

Herein a two-step strategy for achieving overall transamidation of 8-aminoquinoline amides has been explored. In this protocol, the 8-aminoquinoline amides were first treated with Boc2O and DMAP to form the corresponding N-acyl-Boc-carbamates, which were found to be sufficiently reactive to undergo subsequent aminolysis with different amines in the absence of any additional reagents or catalysts. To demonstrate the utility of this approach, it was applied on a number of 8-aminoquinoline amides from the recent C-H functionalization literature, enabling access to a range of elaborate amide derivatives in good to high yields.