quercetin and Malaria

Chemically modified versions of bioactive substances, are particularly useful in overcoming barriers associated with drug formulation, drug delivery and poor pharmacokinetic properties. In this study, a series of fourteen (E)-methyl 2-(7-chloroquinolin-4-ylthio)-3-(4-hydroxyphenyl) acrylate (2-15) were prepared by using a one step synthesis from 1 previously described by us as potential antimalarial and antitumor agent. Molecules were evaluated as inhibitors of β-hematin formation, where most of them showed a significant inhibition value (% > 70). The best inhibitors were tested in vivo as potential antimalarials in mice infected with P. berghei ANKA, chloroquine susceptible strain. Three of them (5, 6, and 15) displayed antimalarial activity comparable to that of chloroquine. Also, molecules were evaluated for their cytotoxic activity against two human cancer cell lines (Jurkat E6.1 and HL60) and primary culture of human lymphocytes. Most of the synthesized compounds, except for analogs 2-6, 8, and 10-12, displayed cytotoxicity against cancer cell lines without affecting normal cells. The potency of the compounds was 15 ≫ 1, and 14 > 7, 9, and 13. Flow cytometry analysis demonstrated an increase in apoptotic cell death after 24 h. The compounds may affect tumor cell autophagy and consequently increase cell apoptosis.

Topics: Acrylates; Animals; Antimalarials; Antineoplastic Agents; Apoptosis; Cells, Cultured; Chloroquine; Hemin; HL-60 Cells; Humans; Jurkat Cells; Malaria; Mice; Plasmodium berghei; Stereoisomerism; Structure-Activity Relationship

Topics: Anacardiaceae; Animals; Antimalarials; Belgium; Cyclohexanones; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Female; Flavonoids; HeLa Cells; Humans; Inhibitory Concentration 50; Malaria; Mice; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Parasitic Sensitivity Tests; Plant Leaves; Plasmodium berghei; Plasmodium falciparum; Quercetin; Zebrafish

A series of novel aminoalkylated quercetin analogs, prepared via the Mannich reaction of various primary and secondary amines with formaldehyde, were tested for antimalarial activity. The compounds were screened against three drug resistant malarial strains (D6, C235 and W2) and were found to exhibit sub-micromolar activity across all three strains (0.065-13.0μM). The structure-activity relationship determined from the antimalarial activity data suggests the inclusion of phenethyl amine sidechains on the quercetin scaffolding is necessary for potent activity. Additionally, the most active compounds ((5) and (6)) were tested for both early and late stage anti-gametocytocidal activity. Finally, the antimalarial activity data were utilized to construct comparative molecular field analysis (CoMFA) models to be used for further compound refinement.

Topics: Antimalarials; Humans; Malaria; Models, Molecular; Molecular Structure; Plasmodium falciparum; Quantitative Structure-Activity Relationship; Quercetin; Stereoisomerism