Structure Activity of β-Amidomethyl Vinyl Sulfones as Covalent Inhibitors of <i>Chikungunya</i> nsP2 Cysteine Protease with Antialphavirus Activity

Abstract

Despite their widespread impact on human health, there are no approved drugs for combating alphavirus infections. The heterocyclic β-aminomethyl vinyl sulfone RA-0002034 (<b>1a</b>) is a potent irreversible covalent inhibitor of the alphavirus nsP2 cysteine protease with broad-spectrum antiviral activity. Analogs of <b>1a</b> that varied each of the three regions of the molecule were synthesized to establish structure-activity relationships for the inhibition of <i>Chikungunya</i> (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 (<b>1o</b>) and 4-cyanopyrazole (<b>8d</b>) analogs exhibited <i>k</i>_inact/<i>K</i>_i ratios >9000 M^-1 s^-1. 3-Arylisoxazole (<b>10</b>) was identified as an isosteric replacement for the five-membered heterocycle, which circumvented the intramolecular cyclization of pyrazole-based inhibitors like <b>1a</b>. A ligand-based model of the enzyme active site was developed to aid the design of nsP2 protease inhibitors as potential therapeutics against alphaviruses.