4-Thiophenoxy-2-trichloromethyquinazolines display in vitro selective antiplasmodial activity against the human malaria parasite Plasmodium falciparum.

A series of original quinazolines bearing a 4-thiophenoxy and a 2-trichloromethyl group was synthesized in a convenient and efficient way and was evaluated toward its in vitro antiplasmodial potential. The series revealed global good activity against the K1-multi-resistant Plasmodium falciparum strain, especially with hit compound 5 (IC(50)=0.9 µM), in comparison with chloroquine and doxycycline chosen as reference-drugs. Both the in vitro cytotoxicity study which was conducted on the human HepG2 cell line and the in vitro antitoxoplasmic screening against Toxoplasma gondii indicate that this series presents an interesting selective antiplasmodial profile. Structure-activity- and toxicity relationships highlight that the trichloromethyl group plays a key role in the antiplasmodial activity and also show that the modulation of the thiophenol moiety influences the toxicity/activity ratio.

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 IC(50) value of 1.1 µM and a HepG2 CC(50) 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.

Access to original vinylic chlorides in the quinazoline series via a monoelectronic transfer reaction approach.

A series of new quinazoline derivatives bearing a vinylic chloride group on the 2-position was prepared by using a consecutive S(RN)1 / E(RC)1 radical strategy.