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.