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

• Type: Article in International Scientific Journal
• Date: 2006

Authors

Paula Chambel (Author) Other; Rita Capela (Author) Other; Francisca Lopes (Author) Other; Jim Iley (Author) Other; Jose Morais (Author) Other; Luis Gouveia (Author) Other; Jose R B Gomes (Author) Other; Paula Gomes (Author) FCUP; Rui Moreira (Author) Other

Journal

Title: Tetrahedron

Vol. 62

Pages: 9883-9891

ISSN: 0040-4020

Publisher: Elsevier

Indexing

ISI Web of Knowledge - 27 Citations

Scopus - 27 Citations

Scientific classification

FOS: Natural sciences > Chemical sciences

Other information

Authenticus ID: P-004-GK1

DOI: 10.1016/j.tet.2006.08.026

Abstract (EN): 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 degrees C. The kinetics of hydrolysis of primaquine-based imidazolidin-4-ones were investigated in the pH range 0.3-13.5 at 60 degrees 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 pK(a) 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 S(N)1-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.

Language: English

Type (Professor's evaluation): Scientific