Primaquine and Chloroquine Fumardiamides as Promising Antiplasmodial Agents

• Main Authors: Maja Beus, Diana Fontinha, Jana Held, Zrinka Rajić, Lidija Uzelac, Marijeta Kralj, Miguel Prudêncio, Branka Zorc
• Format: Article
• Language: English
• Published: MDPI AG 2019-08-01
• Series: Molecules
• Subjects: primaquine; chloroquine; antiplasmodial activity; cytotoxicity; fumardiamide
• Online Access: https://www.mdpi.com/1420-3049/24/15/2812

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 (<b>1</b>&#8722;<b>6</b>), we now report their significant in vitro activity against the hepatic stages of <i>Plasmodium</i> parasites. Furthermore, we successfully prepared chloroquine (CQ) analogue derivatives (<b>11</b>&#8722;<b>16)</b> and evaluated their activity against both the hepatic and erythrocytic stages of <i>Plasmodium</i>. Our results have shown that PQ fumardiamides (<b>1</b>&#8722;<b>6)</b> exert both higher activity against <i>P. berghei</i> hepatic stages and lower toxicity against human hepatoma cells than the parent drug and CQ derivatives (<b>11</b>&#8722;<b>16)</b>. The favourable cytotoxicity profile of the most active compounds, <b>5</b> and <b>6</b>, 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 <i>P. falciparum</i> erythrocytic stages was higher than that of PQ derivatives, comparable to CQ against CQ-resistant strain <i>Pf</i>Dd2, but lower than CQ when tested on the CQ-sensitive strain <i>Pf</i>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.