title: High-speed synthesis of potent C2-symmetric HIV-1 protease inhibitors by in-situ aminocarbonylations.
abstract: 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.
authors: Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala University, BMC, Box 574, SE-751 23 Uppsala, Sweden.
authors: Johan
authors: J
authors: Wannberg
authors: Nils-Fredrik K
authors: NF
authors: Kaiser
authors: Lotta
authors: L
authors: Vrang
authors: Bertil
authors: B
authors: Samuelsson
authors: Mats
authors: M
authors: Larhed
authors: Anders
authors: A
authors: Hallberg
mesh_terms: D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D015195:Drug Design; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry*; D015394:Molecular Structure
chemical_list: D017320:HIV Protease Inhibitors