| Summary: | From three previously identified antiplasmodial hit compounds (<b>A</b>–<b>C</b>) and inactive series (<b>D</b>), 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 <i>P. falciparum</i> strain, using doxorubicin, chloroquine and doxycycline as reference drugs. Four hit-compounds (EC<sub>50</sub> K1 <i>P. falciparum</i> ≤ 2 µM and SI ≥ 20) were identified among 4-carboxamido derivatives (<b>2</b>, <b>9</b>, <b>16,</b> and <b>24</b>) and two among 4-alkoxy derivatives (<b>41</b> and <b>44</b>). Regarding the two most potent molecules (<b>16</b> and <b>41</b>), five derivatives without a 2-CCl<sub>3</sub> group were prepared, evaluated, and appeared totally inactive (EC<sub>50</sub> > 50 µM), showing that the 2-trichloromethyl group was mandatory for the antiplasmodial activity.
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