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Comparative Study
. 2010 Feb 1;20(3):1241-6.
doi: 10.1016/j.bmcl.2009.11.123. Epub 2009 Dec 5.

Synthesis and biological evaluation of novel allophenylnorstatine-based HIV-1 protease inhibitors incorporating high affinity P2-ligands

Arun K Ghosh  1 , Sandra Gemma, Elena Simoni, Abigail Baldridge, D Eric Walters, Kazuhiko Ide, Yasushi Tojo, Yasuhiro Koh, Masayuki Amano, Hiroaki Mitsuya
Affiliations
Comparative Study

Synthesis and biological evaluation of novel allophenylnorstatine-based HIV-1 protease inhibitors incorporating high affinity P2-ligands

Arun K Ghosh et al. Bioorg Med Chem Lett. .

Abstract

A series of stereochemically defined cyclic ethers as P2-ligands were incorporated in an allophenylnorstatine-based isostere to provide a new series of HIV-1 protease inhibitors. Inhibitors 3b and 3c, containing conformationally constrained cyclic ethers, displayed impressive enzymatic and antiviral properties and represent promising lead compounds for further optimization.

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Figures

Figure 1
Figure 1
Structures of inhibitors1, 2, and 3b
Figure 2
Figure 2
Structure of inhibitor 3b, modeled into the active site of HIV-1 protease, superimposed on the X-ray crystal structure of KNI-764. Inhibitor 3b carbons are shown in green and KNI-764 carbons are shown in magenta.
Scheme 1
Scheme 1
Reagents and conditions: (a) H2, Pd/C, Boc2O, EtOAc; (b) Ac2O, Pyr, DMAP; (c) LiCO3, AcOH, DMF; (d) 2- methoxypropene, CSA, DCM; (e) K2CO3, MeOH; (f) RuCl3, NaIO4, CCl4-MeCN-H2O (2:2:3); g) N-methylmorpholine, iBuOCOCl, 8a, THF.
Scheme 2
Scheme 2
(a) 1 M HCl, MeOH; (b) 11a, Et3N, CH2Cl2; (c) 11b,c Et3N, CH2Cl2; or, 11d,e, DIPEA, THF.
Scheme 3
Scheme 3
Reagents and conditions: (a) 8a, Li(ClO4), Et2O; (b) CF3CO2H, CH2Cl2; (c) 11a or, 11b, Et3N, CH2Cl2; (d) N-methylmorpholine, iso-butylchloroformate, 8b–d, THF; (e) CF3CO2H, CH2Cl2, then 11b, Et3N, CH2Cl2.
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