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

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• 作者：Paula Chambel ; Rita Capela ; Francisca Lopes ; Jim Iley ; José ; Morais ; Luí ; s Gouveia ; José ; R.B. Gomes ; Paula Gomes and Rui Moreira
• 关键词：Imidazolidin-4-ones ; Prodrugs ; Primaquine ; Kinetics ; Substituent effects ; Mechanism of hydrolysis
• 刊名：Tetrahedron
• 出版年：2006
• 出版时间：16 October 2006
• 年：2006
• 卷：62
• 期：42
• 页码：9883-9891
• 全文大小：439 K

文摘

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 pK_a values are ca. 3.6–4.0, i.e., 4 pK_a 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 S_N1-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.