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

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作   者：

Ghoshal, Anirban;  Asressu, Kesatebrhan Haile;  Hossain, Mohammad Anwar;  Brown, Peter J.;  Nandakumar, Meganathan;  Vala, Anand;  Merten, Eric M.;  Sears, John D.;  Law, Isabella;  Burdick, Jane E.;  Morales, Noah L.;  Perveen, Sumera;  Pearce, Kenneth H.;  Popov, Konstantin I.;  Moorman, Nathaniel J.;  Heise, Mark T.;  Willson, Timothy M.; 

作者机构：

Piramal Discovery Solut;  Univ Toronto;  Univ N Carolina; 

期刊名称：

Journal of Medicinal Chemistry

i s s n：

0022-2623

年卷期：

2024 年 67 卷 18 期

页   码：

16505-16532

页   码：

摘   要：

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