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. 2008 Oct 21;6(20):3703-13.
doi: 10.1039/b809178a. Epub 2008 Aug 11.

Potent HIV-1 protease inhibitors incorporating meso-bicyclic urethanes as P2-ligands: structure-based design, synthesis, biological evaluation and protein-ligand X-ray studies

Arun K Ghosh  1 , Sandra Gemma, Jun Takayama, Abigail Baldridge, Sofiya Leshchenko-Yashchuk, Heather B Miller, Yuan-Fang Wang, Andrey Y Kovalevsky, Yashiro Koh, Irene T Weber, Hiroaki Mitsuya
Affiliations

Potent HIV-1 protease inhibitors incorporating meso-bicyclic urethanes as P2-ligands: structure-based design, synthesis, biological evaluation and protein-ligand X-ray studies

Arun K Ghosh et al. Org Biomol Chem. .

Abstract

Recently, we designed a series of novel HIV-1 protease inhibitors incorporating a stereochemically defined bicyclic fused cyclopentyl (Cp-THF) urethane as the high affinity P2-ligand. Inhibitor with this P2-ligand has shown very impressive potency against multi-drug-resistant clinical isolates. Based upon the -bound HIV-1 protease X-ray structure, we have now designed and synthesized a number of meso-bicyclic ligands which can conceivably interact similarly to the Cp-THF ligand. The design of meso-ligands is quite attractive as they do not contain any stereocenters. Inhibitors incorporating urethanes of bicyclic-1,3-dioxolane and bicyclic-1,4-dioxane have shown potent enzyme inhibitory and antiviral activities. Inhibitor (K(i) = 0.11 nM; IC(50) = 3.8 nM) displayed very potent antiviral activity in this series. While inhibitor showed comparable enzyme inhibitory activity (K(i) = 0.18 nM) its antiviral activity (IC(50) = 170 nM) was significantly weaker than inhibitor . Inhibitor maintained an antiviral potency against a series of multi-drug resistant clinical isolates comparable to amprenavir. A protein-ligand X-ray structure of -bound HIV-1 protease revealed a number of key hydrogen bonding interactions at the S2-subsite. We have created an active model of inhibitor based upon this X-ray structure.

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Figures

Fig. 1
Fig. 1
Structure of inhibitors 1–3.
Fig. 2
Fig. 2
Stereoview of the X-ray structure of inhibitor 3 bound to the active site of wild-type HIV-1 protease.
Fig. 3
Fig. 3
A stereoview of an active model of inhibitor 2 (green) with the X-ray structure of inhibitor 3 (magenta)-bound HIV-1 protease.
Scheme 1
Scheme 1
Synthesis of alcohols 9–12.
Scheme 2
Scheme 2
Synthesis of alcohols 15 and 16.
Scheme 3
Scheme 3
Synthesis of activated alcohols 17–22.
Scheme 4
Scheme 4
Synthesis of inhibitors 2,3 and 26–30.
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