Correlation study on methoxylation pattern of flavonoids and their heme-targeted antiplasmodial activity

• Published in: Bioorganic chemistry Vol. 104; p. 104243
• Main Authors: Ortiz, Sergio, Vásquez-Ocmín, Pedro G., Cojean, Sandrine, Bouzidi, Chouaha, Michel, Sylvie, Figadère, Bruno, Grougnet, Raphaël, Boutefnouchet, Sabrina, Maciuk, Alexandre
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2020; Elsevier
• Subjects: Antimalarials - chemical synthesis; Antimalarials - chemistry; Antimalarials - pharmacology; Cell Survival - drug effects; Chemical Sciences; Dose-Response Relationship, Drug; Flavonoids - chemical synthesis; Flavonoids - chemistry; Flavonoids - pharmacology; Heme - antagonists & inhibitors; Heme-binding; Hemozoin; Human Umbilical Vein Endothelial Cells - drug effects; Human Umbilical Vein Endothelial Cells - metabolism; Humans; Medicinal Chemistry; Molecular Structure; Organic chemistry; Plasmodium falciparum; Plasmodium falciparum - drug effects; Polymethoxyflavone; Structure-Activity Relationship; Plasmodium falciparum; Heme-binding; Hemozoin; Polymethoxyflavone
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2020.104243

[Display omitted] •Methoxyflavones can form adducts with heme and exert antiplasmodial activity.•Heme-binding affects P. falciparum heme detoxification to hemozoin.•Degree of methoxylation increases affinity for heme (DV50)•An increased DV50 is not correlated with antiplasmodial activity.•Pentamethoxyquercetin inhibits P. falciparum intraerythrocytic heme detoxification. A library of 33 polymethoxylated flavones (PMF) was evaluated for heme-binding affinity by biomimetic MS assay and in vitro antiplasmodial activity on two strains of P. falciparum. Stability of heme adducts was discussed using the dissociation voltage at 50% (DV50). No correlation was observed between the methoxylation pattern and the antiparasitic activity, either for the 3D7 chloroquine-sensitive or for the W2 chloroquine-resistant P. falciparum strains. However, in each PMF family an increased DV50 was observed for the derivatives methoxylated in position 5. Measurement of intra-erythrocytic hemozoin formation of selected derivatives was performed and hemozoin concentration was inversely correlated with heme-binding affinity. Kaempferol showed no influence on hemozoin formation, reinforcing the hypothesis that this compound may exert in vitro antiplasmodial activity mostly through other pathways. Pentamethoxyquercetin has simultaneously demonstrated a significant biological activity and a strong interaction with heme, suggesting that inhibition of hemozoin formation is totally or partially responsible for its antiparasitic effect.