Reactivity of imidazolidin-4-one derivatives of primaquine: implications for prodrug design |
| |
Authors: | Paula Chambel Rita Capela Jim Iley Luís Gouveia Paula Gomes |
| |
Institution: | a Centro de Estudos de Ciências Farmacêuticas, Faculdade de Farmácia da Universidade de Lisboa, Av. Forças Armadas, P-1649-019 Lisboa, Portugal b UCTM, Faculdade de Farmácia da Universidade de Lisboa, Av. Forças Armadas, P-1649-019 Lisboa, Portugal c Department of Chemistry, The Open University, Milton Keynes, MK7 6AA, United Kingdom d Centro de Investigação em Química da Universidade do Porto, Departamento de Química da Faculdade de Ciências do Porto, Rua do Campo Alegre 687, P-4169-007 Porto, Portugal |
| |
Abstract: | In contrast to peptide-based imidazolidin-4-ones, those synthesized from N-(α-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 α-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 α-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 α-aminoamides are too stable and therefore, may be useful as slow drug release prodrugs. |
| |
Keywords: | Imidazolidin-4-ones Prodrugs Primaquine Kinetics Substituent effects Mechanism of hydrolysis |
本文献已被 ScienceDirect 等数据库收录! |
|