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. 2005 May 19;48(10):3576-85.
doi: 10.1021/jm050019i.

Structure-based design: synthesis and biological evaluation of a series of novel cycloamide-derived HIV-1 protease inhibitors

Arun K Ghosh  1 , Lisa M Swanson, Hanna Cho, Sofiya Leshchenko, Khaja Azhar Hussain, Stephanie Kay, D Eric Walters, Yasuhiro Koh, Hiroaki Mitsuya
Affiliations

Structure-based design: synthesis and biological evaluation of a series of novel cycloamide-derived HIV-1 protease inhibitors

Arun K Ghosh et al. J Med Chem. .

Abstract

The structure-based design and synthesis of a series of novel nonpeptide HIV protease inhibitors are described. The inhibitors were designed based upon the X-ray crystal structure of inhibitor 1 (UIC-94017)-bound HIV-1 protease. The inhibitors incorporated 3-hydroxysalicyclic acid-derived acyclic and cyclic P2 ligand into the (R)-(hydroxyethylamino)sulfonamide isostere. The inhibitors contain only two chiral centers and are readily synthesized in optically active form utilizing Sharpless asymmetric epoxidation, regioselective epoxide opening, and ring-closing olefin metathesis using Grubbs' catalyst as the key steps. We have synthesized 13-15-membered cycloamides and evaluated their HIV-1 protease enzyme inhibitory and antiviral activities in MT-2 cells. Interestingly, all cycloamide-derived inhibitors are noticeably more potent than the corresponding acyclic compounds. The ring size and substituent effects were investigated. It turned out that the 14-membered saturated ring is preferred by the S(1)-S(2) active sites of HIV-1 protease. Macrocycle 26 showed excellent enzyme inhibitory potency with a K(i) value of 0.7 nM and an antiviral IC(50) value of 0.3 microM. In view of their structural simplicity and preliminary interesting results, further optimization of these inhibitors is underway.

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