Targeting the human malaria parasite Plasmodium falciparum: In vitro identification of a new antiplasmodial hit in 4-phenoxy-2-trichloromethylquinazoline series

From the promising results we previously obtained in quinazoline series and to complete the evaluation of the in vitro antiplasmodial activity of original 2-trichloromethylquinazolines, we synthesized new quinazolines possessing a variously substituted phenoxy group at position 4 through a simple and efficient two-step-synthesis approach. The studies of their activity toward the multi-resistant W2 Plasmodium falciparum strain and of their cytotoxicity on the human hepatocyte HepG2 cell line highlighted a hit compound (molecule 7) displaying a W2 IC50 value of 1.1 μM and a HepG2 CC50 value of 50 μM, comparable to chloroquine and doxycycline. Structure-activity- and toxicity relationships indicate that the trichloromethyl group plays a key role in the antiplasmodial activity of such chemical scaffold and also that the phenoxy group substitution as a direct influence on the molecules selectivity. Moreover, molecule 7 displays significant specific activity against the Plasmodium genus in comparison with Toxoplasma and does not show any mutagenic property at the Ames test.

Graphical abstractThe in vitro antiplasmodial activity of newly synthesized 4-phenoxy-2-trichloromethylquinazoline derivatives is presented herein.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Original 4-phenoxy-2-trichloromethylquinazoline derivatives display antiplasmodial properties. ► This activity was determined on the W2-multi-resistant Plasmodium falciparum strain. ► Cytotoxicity was assessed in parallel on the human HepG2 cell line and indicate that hit compounds display good selectivity toward Plasmodium falciparum.