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Primaquine and Chloroquine Fumardiamides as Promising Antiplasmodial Agents

Beus, Maja; Fontinha, Diana; Held, Jana; Rajić, Zrinka; Uzelac, Lidija; Kralj, Marijeta; Prudêncio, Miguel; Zorc, Branka (2019) Primaquine and Chloroquine Fumardiamides as Promising Antiplasmodial Agents. Molecules, 24 (15). ISSN 1420-3049

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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 (1–6), we now report their significant in vitro activity against the hepatic stages of Plasmodium parasites. Furthermore, we successfully prepared chloroquine (CQ) analogue derivatives (11–16) and evaluated their activity against both the hepatic and erythrocytic stages of Plasmodium. Our results have shown that PQ fumardiamides (1–6) exert both higher activity against P. berghei hepatic stages and lower toxicity against human hepatoma cells than the parent drug and CQ derivatives (11–16). The favourable cytotoxicity profile of the most active compounds, 5 and 6, 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 P. falciparum erythrocytic stages was higher than that of PQ derivatives, comparable to CQ against CQ-resistant strain PfDd2, but lower than CQ when tested on the CQ-sensitive strain Pf3D7. 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.

Item Type: Article
Uncontrolled Keywords: primaquine ; chloroquine ; antiplasmodial activity ; cytotoxicity ; fumardiamide
Subjects: NATURAL SCIENCES > Chemistry
Divisions: Division of Molecular Medicine
Project titleProject leaderProject codeProject type
Dizajniranje, sinteza i evaluacija derivata primakina, vorinostata i sorafeniba kao potencijalnih citostatikaUNSPECIFIEDIP-2014-09-1501HRZZ
Mulitidisciplinarni pristup otkriću lijekova s ciljanim djelovanjem na matične stanice tumora – uloga transporta kalijaKralj, MarijetaIP-2013-11-5660HRZZ
Depositing User: Marijeta Kralj
Date Deposited: 07 Jan 2021 09:26
DOI: 10.3390/molecules24152812

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