Design, synthesis and in vitro evaluation of primaquine and diaminoquinazoline hybrid molecules against the malaria parasite

In this study, we built on the known inhibitory potential of diaminoquinazolines (DAQs) against different stages of Plasmodium development and designed a convenient two-step synthesis to combine DAQ with the primaquine (PQ) pharmacophore. The PQ-DAQ hybrids displayed potent in vitro activities in the low nanomolar range (IC50 of 135.20-398.80 nM) against all intraerythrocytic stages of the drug-sensitive 3D7 strain, with significant potency enhancement compared with that of PQ alone (IC50 of 9370 nM). These hybrids were also potent at killing drug-resistant strains (Dd2, Dd2_R539T, IPC4912, CamWT_C580Y, and 7G8) in the nanomolar range, with 11f being the most effective compound (IC50 172.20-396.60 nM). Notably, for the first time, we present evidence that DAQ-based compound 8 and its hybrids can inhibit β-hematin formation in vitro with potency (IC50 0.90-27.80 µM), suggesting that hemozoin formation is one of the potential targets of this series. Finally, two hybrids with potent antiplasmodial activity were also found to be safe at concentrations of up to 10 µM against human hepG2 cells, suggesting the possibility of achieving host vs parasite selectivity with this series.