Synthesis and Antiplasmodial Evaluation of 4-Carboxamido- and 4-Alkoxy-2-Trichloromethyl Quinazolines.

From three previously identified antiplasmodial hit compounds (-) and inactive series (), all based on a 2-trichloromethylquinazoline scaffold, we conducted a structure-activity relationship (SAR) study at position four of the quinazoline ring by synthesizing 42 novel derivatives bearing either a carboxamido- or an alkoxy-group, to identify antiplasmodial compounds and to enrich the knowledge about the 2-trichloromethylquinazoline antiplasmodial pharmacophore. All compounds were evaluated in vitro for their cytotoxicity towards the HepG2 cell line and their activity against the multiresistant K1 strain, using doxorubicin, chloroquine and doxycycline as reference drugs. Four hit-compounds (EC K1 ≤ 2 µM and SI ≥ 20) were identified among 4-carboxamido derivatives (, , and ) and two among 4-alkoxy derivatives ( and ). Regarding the two most potent molecules ( and ), five derivatives without a 2-CCl group were prepared, evaluated, and appeared totally inactive (EC > 50 µM), showing that the 2-trichloromethyl group was mandatory for the antiplasmodial activity.