High-speed synthesis of potent C2-symmetric HIV-1 protease inhibitors by in-situ aminocarbonylations.
Two novel series of C2-symmetric HIV-1 protease inhibitors were synthesized by microwave-promoted, palladium-catalyzed aminocarbonylations of the o-iodo- and m-bromobenzyloxy P1/P1' substituted core structures. Molybdenum hexacarbonyl was used as a convenient solid source of carbon monoxide in these transformations. After the initial high-speed library generation, biological testing identified highly active HIV-1 protease inhibitors. Selected ortho- and meta-decorated inhibitors were subsequently resynthesized on a larger scale and retested for their affinity toward HIV-1 protease, showing micromolar to low nanomolar inhibition. The discovery of highly active inhibitors containing large phenyl amide ortho substituents in the P1/P1' positions indicates that larger groups than previously believed are tolerated in this part of the S1/S1' pocket.
Wannberg
Johan
J
Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala University, BMC, Box 574, SE-751 23 Uppsala, Sweden.
Kaiser
Nils-Fredrik K
NF
Vrang
Lotta
L
Samuelsson
Bertil
B
Larhed
Mats
M
Hallberg
Anders
A
D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D015195:Drug Design; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry*; D015394:Molecular Structure
D017320:HIV Protease Inhibitors