A DMAP catalyzed synthesis of new 4-benzyloxy- and 4-aryloxy-2-trichloromethylquinazolines was studied, in a view to react 4-chloroquinazolines with poorly nucleophilic alcohols such as benzylic alcohols, via a simple and cheap SNAr reaction approach. A fast (1 h) general operating procedure, affording good reaction yields, was achieved under microwave irradiation. Thus, a series of 35 molecules was obtained and evaluated in vitro on the K1 multi-resistant Plasmodium falciparum strain, in parallel with a cytotoxicity assessment on the human HepG2 cell line. 5 hit-molecules were identified, presenting both promising antiplasmodial activity (1.5 μM < IC50 < 2 μM) and low cytotoxicities (25 μM < CC50 < 45 μM). Apart for 2 molecules, the global series displayed a satisfying solubility in the aqueous biological media. Structure-activity relationships showed that the molecules presenting a benzyloxy moiety were less cytotoxic than the ones bearing a phenoxy moiety at position 4 of the quinazoline ring. It also appeared that the introduction of a heteroaryl moiety afforded inactive compounds. Finally, the most active and selective molecules (Selectivity Index = 22-27) were the ones presenting either an unsubstituted benzyloxy group or a phenoxy group, this last bearing a p-bromo or an o-acetyl substituent.