Reactivity of imidazolidin-4-one derivatives of primaquine: implications for prodrug design

Chambel, Paula; Capela, Rita; Lopes, Francisca; Iley, Jim; Morais, Jose; Gouveia, Luıs; Gomes, Jose R. B.; Gomes, Paula and Moreira, Rui (2006). Reactivity of imidazolidin-4-one derivatives of primaquine: implications for prodrug design. Tetrahedron, 62(42) pp. 9883–9891.



In contrast to peptide-based imidazolidin-4-ones, those synthesized from N-(alpha-aminoacyl) derivatives of the antimalarial drug, primaquine and ketones are unexpectedly stable in pH 7.4 at 37 C. The kinetics of hydrolysis of primaquine-based imidazolidin-4-ones were investigated in the pH range 0.3–13.5 at 60 C. The hydrolysis to the parent alpha-aminoacylprimaquine is characterized by sigmoidal shaped pH–rate profiles, reflecting the spontaneous decomposition of both unionized and protonated (at N-1) forms of the imidazolidin-4-one. The kinetically determined pKa values are ca. 3.6–4.0, i.e. 4 pKa units lower than those of amino acid amides, thus implying that hydrolysis of imidazolidin-4-ones at pH 7.4 involves the unionized form. Reactivity of this form decreases with the steric crowding of the amino acid alpha-substituent. In contrast, the rate constant for the spontaneous decomposition of the unionized form increases sharply for
imidazolidin-4-ones derived from cyclic ketones, an observation that can be explained by the I-strain (internal strain) effect. These results are consistent with a mechanism of hydrolysis involving an SN1-type unimolecular cleavage of the imidazolidin-4-one C2–N3 bond with departure of an amide-leaving group. The mechanism for the decomposition of the protonated imidazolidin-4-one is likely to involve an amide-carbonyl oxygen protonated species, followed by the C2–N3 bond scission, as supported by computational studies. The results herein presented suggest that imidazolidin-4-ones derived from simple N-alkyl alpha-aminoamides are too stable and therefore may be useful as slow drug release prodrugs.

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  • Item ORO ID
  • 5961
  • Item Type
  • Journal Item
  • ISSN
  • 0040-4020
  • Extra Information
  • Some of the symbols may not have transferred correctly into this bibliographic record and/or abstract.
  • Keywords
  • Imidazolidin-4-ones; Prodrugs; Primaquine; Kinetics; Substituent effects; mechanism of hydrolysis
  • Academic Unit or School
  • Other Departments > Other Departments
    Other Departments
  • Depositing User
  • James Iley