Structure Activity of β-Amidomethyl Vinyl Sulfones as Covalent Inhibitors of nsP2 Cysteine Protease with Antialphavirus Activity.

Despite their widespread impact on human health, there are no approved drugs for combating alphavirus infections. The heterocyclic β-aminomethyl vinyl sulfone RA-0002034 () is a potent irreversible covalent inhibitor of the alphavirus nsP2 cysteine protease with broad-spectrum antiviral activity. Analogs of that varied each of the three regions of the molecule were synthesized to establish structure-activity relationships for the inhibition of (CHIKV) nsP2 protease and viral replication. The vinyl sulfone covalent warhead was highly sensitive to modifications. However, alterations to the core five-membered heterocycle and aryl substituent were well tolerated. The 5-(2,5-dimethoxyphenyl)pyrazole () and 4-cyanopyrazole () analogs exhibited / ratios >9000 M s. 3-Arylisoxazole () was identified as an isosteric replacement for the five-membered heterocycle, which circumvented the intramolecular cyclization of pyrazole-based inhibitors like . A ligand-based model of the enzyme active site was developed to aid the design of nsP2 protease inhibitors as potential therapeutics against alphaviruses.