Molecular modeling, synthesis, and structures of N-methylated 3,5-linked pyrrolin-4-ones toward the creation of a privileged nonpeptide scaffold

The molecular modeling, synthesis, and elucidations of the solid state and solution structures of N-methylated 3,5-linked bispyrrolin-4-ones are descr ibed. Prior investigations established that the 3,5-linked pyrrolin-4-one b ased scaffold can be incorporated into mimics of beta-sheet/beta-strands an d into potent, orally bioavailable inhibitors of the HIV-1 protease. To ext end the utility of this scaffold beyond that of the initially designed mimi cs of beta-sheet/beta-strands, we have now explored the structure of N-meth ylated pyrrolinones. Molecular modeling indicated that N-methylated bispyrr olinones could adopt three low-energy backbone conformations (ca. 165 degre es, 289 degrees, and 320 degrees). Upon their successful synthesis, structu ral elucidation both in the solid state and in solution revealed the existe nce of two of the three predicted backbone conformers (ca. 165 degrees and 289 degrees). Two structures were particularly noteworthy and completely un expected. Mono-N-methyl bispyrrolinone (+)-1 self assembled in the solid st ate to form a novel helix, while the acetylene-linked dimer of(+)-1, design ed to potentiate the observed helical array, instead associated via an inte rmolecular hydrogen bond in parallel columns. These serendipitous observati ons led us to speculate that the pyrrolinone moiety may in fact represent a privileged nonpeptide scaffold, able to mimic not only the extended beta-s heet/beta-strand conformation as initially targeted, but also diverse confo rmations including those analogous to beta-turns and helices. These seeming ly unlimited conformations greatly expand the scope of this scaffold for th e development of low-molecular weight ligands for biologically important ma cromolecules. (C) 1999 Elsevier Science Ltd. All rights reserved.