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Mac1 is a conserved macrodomain enzyme in the non-structural protein 3 (Nsp3) of SARS-CoV-2 and is part of the viral replication machinery. Due to its mode of action, Mac1 can be considered a target for small-molecule inhibitors that could ultimately enable new therapeutics to be developed to treat COVID-19. This study reports the structure-guided design, synthesis and Mac1 inhibition profiling of 25 analogues derived from a previously characterised hit identified through crystallographic fragment screening. In particular, the heteroaryl group and scaffold ( cis - and trans -cyclopentane and cyclopentene) were varied. The cis -cyclopentanes and cyclopentenes with a range of heteroaryl groups were readily synthesised. This stage was expedited since the initial fragment hits were from previously developed 3-D fragments that were synthetically enabled for rapid follow-up studies. Two new approaches to trans- cyclopentanes were developed using previously developed methodology: MacMillan's Ir/Ni-mediated photoredox cross-coupling of alcohols and Barluenga-Valdés’ metal-free cross-coupling of sulfonyl hydrazones and boronic acids. This demonstrated the potential of these methodologies for use in medicinal chemistry. X-ray crystal structures of 19 compounds bound to Mac1 were determined to guide the design and to rationalise the observed structure-activity relationships. Thereby, a new family of Mac1 inhibitors incorporating a benzothiazole or amino benzothiazole substituent was discovered and characterised. The optimisation studies culminated with the development of readily synthesised cyclopentene amino benzothiazoles, which had IC ₅₀ values of 6-8 microM and ligand efficiency values up to 0.40.