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Design, synthesis, and biological evaluation of monopyrrolinone-based HIV-1 protease inhibitors possessing augmented P2′ side chains

2005; Elsevier BV; Volume: 16; Issue: 4 Linguagem: Inglês

10.1016/j.bmcl.2005.11.011

1464-3405

Amos B. Smith, Adam K. Charnley, Hironori Harada, Jason J. Beiger, Louis‐David Cantin, Craig S. Kenesky, Ralph Hirschmann, Sanjeev Munshi, David B. Olsen, Mark W. Stahlhut, William A. Schleif, Lawrence C. Kuo,

Click Chemistry and Applications

A series of monopyrrolinone-based HIV-1 protease inhibitors possessing rationally designed P2' side chains have been synthesized and evaluated for activity against wild-type HIV-1 protease. The most potent inhibitor displays subnanomolar potency in vitro for the wild-type HIV-1 protease. Additionally, the monopyrrolinone inhibitors retain potency in cellular assays against clinically significant mutant forms of the virus. X-ray structures of these inhibitors bound in the wild-type enzyme reveal important insights into the observed biological activity.