Primaquine and Chloroquine Fumardiamides as Promising Antiplasmodial Agents.

This paper describes a continuation of our efforts in the pursuit of novel antiplasmodial agents with optimized properties. Following our previous discovery of biologically potent asymmetric primaquine (PQ) and halogenaniline fumardiamides (-), we now report their significant in vitro activity against the hepatic stages of parasites. Furthermore, we successfully prepared chloroquine (CQ) analogue derivatives (-) and evaluated their activity against both the hepatic and erythrocytic stages of . Our results have shown that PQ fumardiamides (-) exert both higher activity against hepatic stages and lower toxicity against human hepatoma cells than the parent drug and CQ derivatives (-). The favourable cytotoxicity profile of the most active compounds, and , was corroborated by assays performed on human cells (human breast adenocarcinoma (MCF-7) and non-tumour embryonic kidney cells (HEK293T)), even when glucose-6-phosphate dehydrogenase (G6PD) was inhibited. The activity of CQ fumardiamides on erythrocytic stages was higher than that of PQ derivatives, comparable to CQ against CQ-resistant strain Dd2, but lower than CQ when tested on the CQ-sensitive strain 3D7. In addition, both sets of compounds showed favourable drug-like properties. Hence, quinoline fumardiamides could serve as a starting point towards the development of safer and more effective antiplasmodial agents.