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

Abstract

a b s t r a c tThe growth inhibitory activity of imidazoquines, antimalarial imidazolidin-4-ones derived from primaquine, on human cancer cell lines HT-29, Caco-2, and MCF-7 has been evaluated. Primaquine, N-dipeptidyl-primaquine derivatives, and other quinolines have been included in the study for comparison purposes. Primaquine and some of its derivatives were significantly active against the MCF-7 human breast cancer cell line, so these compounds might represent useful leads targeted at the development of novel specific agents against breast cancer. Conversely, all compounds were generally inactive against HT-29, with only one of the imidazoquines having IC 50 below 50 lM. Activities against the Caco-2 cell line were modest and did not follow any defined trend.

Novel 1-acyl-4-substituted semicarbazide derivatives of primaquine − synthesis, cytostatic, antiviral and antioxidative studies

“…This phenomenon was already noted in the authors' previous work with urea derivatives of PQ 20 . Some other authors reported selectivity of quinidine, PQ, N-dipeptidylprimaquines and imidazolin-4-one PQ derivatives towards MCF-7 cell line as well 16,29 . Selective growth inhibitory activity towards breast cancer cells could be explained by selective induction of cytochrome P450 (CYP-1) enzymes specifically in the MCF-7 line, known as CYP-1 inducible cell line 30 .…”

“…Mahajan et aldescribed 7-chloroquinolyl thioureas as potential antimalarial and anticancer agents 15 . Several research groups found dual antimalarial and anticancer activity of both quinoline and trioxane derivatives as well [16][17][18] . Based on these findings, we have synthesized a series of compounds containing the antimalarial drug primaquine (PQ) substituted by an N-4-cycloalkyl, aryl,…”

Comparative Analysis of In Vitro Rat Liver Metabolism of the Antimalarial Primaquine and a Derived Imidazoquine

“…The present study provided proof-of-concept regarding the expected high enzymatic stability of primaquine-derived imidazolidin-4-ones, imidazoquines (9), formerly developed in our group as potential alternatives to the parent antimalarial with improved oral bioavailability [29][30][31][32][33][53][54][55]. Relevant experimental evidence on the remarkably low propensity of imidazoquines to undergo metabolic conversions, mediated by rat liver enzymes, was obtained.…”

“…All compounds were active in vitro on P.berghei-infected hepatocytes and most of them were also active against P. carinii [32]. To test these hypotheses, we have profiled, by means of mass spectrometry techniques, the metabolic behaviour of PQ and one of its most active and "drug-like" derivatives, 9.2 [32,33], in combined rat liver cytosolic and microsomal protein fractions. This suggests that they will probably have a significantly higher oral bioavailability than PQ, which would allow usage of lower doses and, hence, lead to decreased levels of toxic PQ-derived metabolites [32].…”

Attenuation of Colchicine Toxicity in Drug-resistant Cancer Cells by Co-treatment with Anti-malarial Drugs

“…We found that COLresistant KBV20C cells can be sensitized at COL concentrations 4-fold higher than that required for parent sensitive KB cells, suggesting that P-gp activity is saturated at high COL concentrations. The cancer-sensitizing ability of anti-malarial drugs has been demonstrated in various cancer models (13)(14)(15)(16)(17), suggesting that anti-malarial drugs have potential as chemotherapeutic agents. CHL, MEF and PRI treatment may increase the toxicity of other chemotherapeutics through their P-gp inhibitory activity (18,19), which increases their clinical potential.…”