Elsevier, Bioorganic and Medicinal Chemistry, 11(14), p. 3835-3847
DOI: 10.1016/j.bmc.2006.01.031
Full text: Unavailable
The donor–acceptor interaction between a tertiary amine and an aldehyde, first observed among a select class of alkaloïds, was deliberately established in a peptidomimetic (1a–c) to mimic features of the two principal transition states of peptide hydrolysis. Compounds 1a–c show preferential adoption in methanol and water of a ‘folded’ conformation displaying the interaction. Proportions of the folded form in MeOH range from 45% to 70% and can reach 84% in buffer. Significantly, three tendencies for the folded/unfolded equilibrium are observed: increasing solubility and polarity of the medium and decreasing temperature results in a higher extent of folding. In the absence of any parameter set available for this weak bond, no modeling studies were conducted to aid in the design of 1a–c. The successful straightforward synthesis of 1 and its folding and inhibition results with HIV-1 peptidase using FRET technology encourage studies to further preorganize candidate molecules and to screen the structure space by modeling and parallel combinatorial chemistry.