Cyclopentane-1,3-diones are known to be relatively strong acids with pKa values typically in the range of carboxylic acids. To explore the potential of the cyclopentane-1,3-dione unit as an isosteric replacement of the carboxylic acid moiety, the physical chemical properties of representative mono- and di-substituted cyclopentane-1,3-diones were examined and compared with similar derivatives bearing carboxylic acid or tetrazole residues. The ability of cyclopentane-1,3-diones to form salts with amidines was evaluated by NMR and mass spectrometry. The structure of the dione�amidine complex was also estimated by molecular modeling. These studies reveal that cyclopentane-1,3-diones, in the enol-ketone tautomeric forms, can generate 1:1 complexes with amidines, suggesting that these fragments can substitute for the carboxylic acid functional group in the formation of salt-bridges (J. Med. Chem. 2011, 54, 6969�83). Examples of the use of the cyclopentane-1,3-dione isostere in drug-design will be presented.

Evaluation of cyclopentane-1,3-dione as isostere of the carboxylic acid functional group

243rd National Meeting (2012)

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