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. 2011 Mar 31;2(6):461-5.
doi: 10.1021/ml2000356. eCollection 2011 Jun 9.

Disubstituted Bis-THF Moieties as New P2 Ligands in Nonpeptidal HIV-1 Protease Inhibitors

Konrad Hohlfeld  1 , Cyrille Tomassi  1 , Jörg Kurt Wegner  2 , Bart Kesteleyn  2 , Bruno Linclau  1
Affiliations

Disubstituted Bis-THF Moieties as New P2 Ligands in Nonpeptidal HIV-1 Protease Inhibitors

Konrad Hohlfeld et al. ACS Med Chem Lett. .

Abstract

A series of darunavir analogues featuring a substituted bis-THF ring as P2 ligand have been synthesized and evaluated. High affinity protease inhibitors (PIs) with an interesting activity on wild-type HIV and a panel of multi-PI resistant HIV-1 mutants containing clinically observed, primary mutations were identified using a cell-based assay. A number of PIs have been synthesized that show equivalent and greater activity for HIV-1 mutant strains as compared to wild-type HIV-1. The activity on the purified enzyme was confirmed for a selection of analogues.

Keywords: HIV protease; bis-THF bis-diol; darunavir; inhibitors.

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Figures

Figure 1
Figure 1
Structure of DRV (1) and PIs 2−5.
Scheme 1
Scheme 1. Retrosynthetic Analysis of Inhibitors 3 and 5
Scheme 2
Scheme 2. Synthesis of Building Blocks 6b−j
Reagents and conditions: (a) NaH, DMF/THF; R-X, TBAI. (b) DMSO, Ac2O, AcOH. (c) (i) F−C6H4−NO2, KHMDS, THF; (ii) cyclohexene, Pd(OH)2, EtOH; (iii) tBuONO, BF3·OEt2, CH2Cl2; Cu powder, EtOH. (d) NaHMDS, THF; PMBCl, TBAI. (e) TBAF, THF. (f) DDQ, CH2Cl2/H2O. (g) H2, Pd/C, EtOH.
Scheme 3
Scheme 3. Synthesis of Inhibitors 1 and 2
Reagents and conditions: (a) Et3N, CH2Cl2. (b) Compound 7a or 7b, Et3N, CH2Cl2. (c) TBAF, THF (only for analogues b).
Figure 2
Figure 2
Three-dimensional depiction of possible binding modes of 3a (A) and 3h (B).
See this image and copyright information in PMC

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