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
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.