62723-81-3Relevant articles and documents
Structure-based design and synthesis of substituted 2-butanols as nonpeptidic inhibitors of HIV protease: Secondary amide series
Reich, Siegfried H.,Melnick, Michael,Pino, Mark J.,Fuhry, Mary Ann M.,Trippe, Anthony J.,Appelt, Krzysztof,Davies II, Jay F.,Wu, Bor-Wen,Musick, Linda
, p. 2781 - 2794 (2007/10/03)
The design, synthesis, and crystallographic analysis of protein- inhibitor complexes is described for a novel series of nonpeptidic HIV protease (HIV Pr) inhibitors. Beginning with a cocrystal structure of a Phe- Pro peptidomimetic bound to the HIV Pr, design was initiated that resulted in the substituted 2-butanol compound 8 as the lead compound (K(i) = 24.5 μM, racemic mixture). Modifications on the initial compound were then made on the basis of its cocrystal structure with HIV Pr and inhibition data, resulting in compounds with enhanced potency against the enzyme (compound 18, K(i) = 0.48 μM). These inhibitors were found to bind to the enzyme essentially as predicted on the basis of the original design hypothesis. Stereospecific synthesis of individual enantiomers confirmed the prediction of a binding preference for the S alcohol stereochemistry. Modest antiviral activity was demonstrated for several of the more potent HIV Pr inhibitors in a HIV-1 infected CEM-SS cell line.
Efficient Intramolecular General Acid Catalysis of Enol Ether Hydrolysis. Hydrogen-bonding Stabilisation of the Transition State for Proton Transfer to Carbon
Kirby, Anthony J.,Williams, Nicholas H.
, p. 643 - 648 (2007/10/02)
The intrinsically low efficiency of intramolecular general acid-base catalysis is enhanced when the proton transfer generates a strong intramolecular hydrogen bond.This principle is shown to apply to proton transfer to carbon: the carboxy groups of methyl vinyl ethers 3E and 3Z derived from 2-carboxyphenylacetaldehyde act as general acids to catalyse the hydrolysis of the neighbouring enol ether groups with effective molarities (EM) of about 300 and 2000 M, respectively.The solvent deuterium isotope effects confirm that the usual mechanism for enol ether hydrolysis is operative.In this system the oxocarbocation intermediate is trapped by the neighbouring carboxylate group to give the acylal 6, rather than the formal product of hydrolysis.
