Metabolism of primaquine by liver homogenate fractions

Constantino, Luís; Paixão, Paulo; Moreira, Rui; Portela, M.J.; Rosário, Virgílio Estólio do; Iley, Jim

doi:10.1016/s0940-2993(99)80010-4

Cited by 83 publications

(37 citation statements)

References 9 publications

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“…Alternatively, alcohol dehydrogenase may convert PQ to PQ alcohol (7) [96,138]. Carboxyprimaquine (6) is the main metabolite of PQ and was identified in mice, monkeys and humans [139][140][141][142][143][144][145]. PQ is rapidly converted into 6 and the peak levels are reached within 3-12 h post-dose, attaining 1427 AE 307 ng/mL, 10-fold higher than those of the parent drug.…”

Section: Carboxyprimaquinementioning

confidence: 99%

Primaquine revisited six decades after its discovery

Vale¹,

Moreira²,

Gomes³

2009

European Journal of Medicinal Chemistry

321

308

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Section: Carboxyprimaquinementioning

confidence: 99%

Primaquine revisited six decades after its discovery

Vale¹,

Moreira²,

Gomes³

2009

European Journal of Medicinal Chemistry

321

308

View full text Add to dashboard Cite

“…However, primaquine presents a short plasma half-life (ca. 6 h) [6,7], as a result of its rapid oxidative deamination to the inactive metabolite carboxyprimaquine 2 (Scheme 1) [8][9][10][11][12]. Blood toxicity, in particular the ability of primaquine to induce oxidation of oxyhemoglobin to methemoglobin, has been also a source of concern [13].…”

Section: Introductionmentioning

confidence: 99%

Primaquine dipeptide derivatives bearing an imidazolidin-4-one moiety at the N-terminus as potential antimalarial prodrugs

Vale

Nogueira

Rosário

et al. 2009

European Journal of Medicinal Chemistry

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a b s t r a c tPrimaquine dipeptide derivatives bearing an imidazolidin-4-one moiety at the N-terminus were synthesized and evaluated as potential transmission-blocking antimalarial prodrugs. All compounds were hydrolyzed to the parent dipeptide derivative of primaquine in neutral and basic solutions, with half lives ranging from 0.7 to 31 h at 37 C, depending on the nature of the substituents present in the imidazolidin-4-one moiety and in the C-terminal amino acid directly coupled to primaquine. The antimalarial activity was studied for selected compounds using a model consisting of Plasmodium berghei, BalbC mice and Anopheles stephensi mosquitoes. The imidazolidin-4-one derived from Ala-Ala-primaquine and acetone reduced the transmission of the infection to mosquitoes more efficiently than primaquine as shown by the significant decrease in the number of oocysts in the midguts of the mosquitoes at 10 and 50 mmol/kg when compared to the control.

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“…10 We have recently synthesized the imidazolidin-4-ones 4 as potential pro-prodrugs of the antimalarial primaquine, 5 (PQ). 11,12 Compounds 4 were designed with the aim of reducing the metabolic inactivation pathway of primaquine that involves oxidative deamination at the primary amino group, [13][14][15][16] as well as to reduce the blood toxicity induced by primaquine, particularly its ability to induce oxidation of oxyhemoglobin to methemoglobin. 17 The proposed activation pathway of imidazolin-4-ones 4 implies the spontaneous hydrolysis to the corresponding amino acid derivatives 6, which in turn can be enzymatically hydrolyzed to the parent drug by parasitic aminopeptidases.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2006

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Abstract-In contrast to peptide-based imidazolidin-4-ones, those synthesized from N-(a-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 a-aminoacylprimaquine is characterized by sigmoidalshaped 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 a-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 a-aminoamides are too stable and therefore, may be useful as slow drug release prodrugs.

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Metabolism of primaquine by liver homogenate fractions

Cited by 83 publications

References 9 publications

Primaquine revisited six decades after its discovery

Primaquine revisited six decades after its discovery

Primaquine dipeptide derivatives bearing an imidazolidin-4-one moiety at the N-terminus as potential antimalarial prodrugs

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

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