Impact of the central hydroxyl groups on the activity of symmetrical HIV-1protease inhibitors derived from L-mannaric acid

Citation
J. Wachtmeister et al., Impact of the central hydroxyl groups on the activity of symmetrical HIV-1protease inhibitors derived from L-mannaric acid, TETRAHEDRON, 56(20), 2000, pp. 3219-3225
Citations number
29
Categorie Soggetti
Chemistry & Analysis","Organic Chemistry/Polymer Science
Journal title
TETRAHEDRON
ISSN journal
00404020 → ACNP
Volume
56
Issue
20
Year of publication
2000
Pages
3219 - 3225
Database
ISI
SICI code
0040-4020(20000512)56:20<3219:IOTCHG>2.0.ZU;2-A
Abstract
The influence of the central hydroxyl groups on the anti-viral activity of symmetrical HIV-1 protease inhibitors derived from L-mannaric acid has been examined. L-Iditol was synthesized and used as a chiral precursor for the synthesis of the corresponding inhibitor with inverted configuration at C-3 and C-4. Key intermediates were 3,4-O-isopropylidene-L-iditol and the acti vated L-idaric acid succinimidyl ester. The configurations of the central h ydroxyl groups required for optimal inhibition of the HIV-1 protease were d etermined to be the C-3R and C-4R, i.e. the L-manno-configuration. Three Ct -symmetric inhibitors were converted to their thiocarbonates and reduced to provide the corresponding hydroxyethyl transition-state mimics. Deletion o f the C-4 hydroxyl group in these inhibitors gave no further improvement in the anti-viral activity. (C) 2000 Published by Elsevier Science Ltd.