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

Abstract

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.

PRIMACENES: novel non-cytotoxic primaquine-ferrocene conjugates with anti-Pneumocystis carinii activity

“…The relevance of such a group has been proposed earlier 33 and confirmed by our previous studies with PQ peptide and peptidomimetic (imidazoquine) derivatives. [23][24][25][26][27][28][29][30][31] To check this hypothesis, we are now working on the synthesis and in vitro evaluation of second-generation primacenes bearing basic amino groups.…”

Anti-tumoral activity of imidazoquines, a new class of antimalarials derived from primaquine

“…At the light of the above findings and of our former promising results with imidazoquines, derivatives of the 8-aminoquinoline antimalarial primaquine, 1, as a new class of antimalarials not susceptible to oxidative deamination, [12][13][14][15][16][17][18][19] we decided to investigate their activity as anti-proliferative agents against the human tumoral cell lines HT-29 (human colon adenocarcinoma), Caco-2 (human epithelial colo-rectal adenocarcinoma), and MCF-7 (breast cancer). The study was focused on imidazoquines 2-4, but also included the parent drug (1), its N-acetyl (5) and two N-dipeptidyl (6 and 7) derivatives, as well as other three quinolines (8-10) for comparison and establishment of preliminary SAR.…”

“…The study was focused on imidazoquines 2-4, but also included the parent drug (1), its N-acetyl (5) and two N-dipeptidyl (6 and 7) derivatives, as well as other three quinolines (8-10) for comparison and establishment of preliminary SAR. Primaquine (1) and quinolines 8-10 were commercially available from Sigma-Aldrich, whereas primaquine derivatives (2-7) were prepared in good yields and with correct spectral data, by previously reported methods [12][13][14][15][16][17][18][19] described in Supplementary data. Cytotoxicity assays were performed according to the procedure adopted by the National Cancer Institute (NCI, USA), 20,21 as detailed in Supplementary data, where inhibition curves obtained for all compounds against all three cell lines are also given.…”

“…Though primaquine (1) and its N-alanylprolyl derivative (7) were better than imidazoquine 3a against MCF-7 cells, the latter has the advantage of being both resistant against proteases (that promptly degrade the peptide moiety of 7) and oxidative deamination (the main metabolic process behind premature deactivation and low oral bioavailability of primaquine). [12][13][14][15][16][17][18][19]29 Known algorithms 22,23 were used to calculate parameters relevant to predict drug oral bioavailability, like log P or log S and to estimate the overall drug score of the test compounds (Table 1). Data show that imidazoquine 3a has not only the highest drug score of the set, but is also considerably soluble (120 mg/L) and has a log P value that falls within the optimal interval for gastric absorption (2 ± 1).…”

Synthesis, crystal structure and biological activity screening of novel N-(α-bromoacyl)-α-amino esters containing valyl moiety

“…[6][7][8][9] Dipeptides represent attractive pro-moieties for generating dipeptide prodrugs also of other drugs containing hydroxyl-, [10][11][12] thiol- 4 and amino groups. [13][14][15] Variation of the dipeptide carrier structure allows fine adjustment of the lipophilicity, prodrug stability and pharmacological activity.…”