Anti-Pneumocystis carinii and antiplasmodial activities of primaquine-derived imidazolidin-4-ones

Abstract

Abstract-A series of primaquine-derived imidazolidin-4-ones were screened for their in vitro activity against Pneumocystis carinii and Plasmodium falciparum W2 strain. Most compounds were active against P. carinii above 10 lg/mL and displayed slight to marked activity. The imidazolidin-4-ones most active against P. carinii were also those most active antiplasmodial agents, in the lM range. One of the tested imidazolidin-4-ones was slightly more active than the parent primaquine and may represent a lead compound for the development of novel anti-P. carinii 8-aminoquinolines with increased stability and resistance to metabolic inactivation.

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

“…The synthetic approaches for the preparation of imidazolidin-4-ones involve the reaction of the peptide with an aldehyde or ketone followed by intramolecular cyclization. Recently, we prepared imidazolidin-4-ones, 3 (Scheme 1), as potential peptidase-stable prodrugs of amino acid derivatives of primaquine [23][24][25]. Compounds 3 displayed gametocytocidal activity against Plasmodium berghei comparable to that of primaquine, as well as antiplasmodial activity against Plasmodium falciparum, but presented low aqueous solubility and, unexpectedly, high stability in pH 7.4 buffer (half lives for hydrolysis typically higher than 12 h), i.e.…”

Imidazolidin-4-one peptidomimetic derivatives of primaquine: Synthesis and antimalarial activity

“…11,12 Recently, we prepared imidazolidin-4-ones, 3, as potential peptidase-stable prodrugs of amino acid derivatives of primaquine. [13][14][15] Compounds 3 displayed gametocytocidal activity against Plasmodium berghei comparable to that of primaquine, as well as activity against P. falciparum asexual stages, while presenting high stability in pH 7.4 buffer (half-lives for hydrolysis typically higher than 12 h). 14, 16 We now set out to incorporate the imidazolidin-4-one moiety into dipeptide derivatives of primaquine, for example, 5 (Scheme 1), both to (i) introduce a terminal basic amino group reported as relevant for activity, 17 and (ii) effectively suppress hydrolysis of the imidazolidin-4-one due to acylation of the N 1 nitrogen atom.…”

“…The same separation problem had already been observed for precursor compounds 3 and dipeptide derivatives of primaquine. 10,[13][14][15][16]18 Imidazolidin-4-ones 5a-g were evaluated against the chloroquine-resistant P. falciparum strain W2, and IC 50 values obtained are given in Table 1, together with those previously determined 15 for the parent drug, 1, and also for precursors 3a and 3b. IC 50 values for 5 range from 5.5 to 12 lM, with one compound (5g) displaying activity close to that of primaquine, 1 (3.3 lM).…”

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.…”