Naphthylisoquinoline alkaloids, validated as hit multistage antiplasmodial natural products

• Published in: International journal for parasitology -- drugs and drug resistance Vol. 13; pp. 51 - 58
• Main Authors: Moyo, Phanankosi, Shamburger, William, van der Watt, Mariëtte E., Reader, Janette, de Sousa, Ana Carolina C., Egan, Timothy J., Maharaj, Vinesh J., Bringmann, Gerhard, Birkholtz, Lyn-Marie
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.08.2020; Elsevier
• Subjects: Alkaloids - pharmacology; Alkaloids - toxicity; Animals; Antimalarials - pharmacology; Antimalarials - toxicity; Biological Products - pharmacology; Biological Products - toxicity; Erythrocytes - drug effects; Hit validation; Humans; Isoquinolines - pharmacology; Isoquinolines - toxicity; Life Cycle Stages - drug effects; Malaria; Malaria - drug therapy; Mice; Multistage active antimalarial drug candidates; Naphthols - pharmacology; Naphthols - toxicity; Naphthylisoquinoline alkaloids; Natural products; Plant Extracts - pharmacology; Plant Extracts - toxicity; Plasmodium falciparum; Plasmodium falciparum - drug effects; Rats; Plasmodium falciparum; Naphthylisoquinoline alkaloids; Malaria; Hit validation; Multistage active antimalarial drug candidates; Natural products
• ISSN: 2211-3207; 2211-3207
• DOI: 10.1016/j.ijpddr.2020.05.003

The discovery and development of multistage antimalarial drugs targeting intra-erythrocytic asexual and sexual Plasmodium falciparum parasites is of utmost importance to achieve the ambitious goal of malaria elimination. Here, we report the validation of naphthylisoquinoline (NIQ) alkaloids and their synthetic analogues as multistage active antimalarial drug candidates. A total of 30 compounds were tested, of which 17 exhibited IC50 values <1 μM against drug-sensitive P. falciparum parasites (NF54 strain); 15 of these retained activity against a panel of drug-resistant strains. These compounds showed low in vitro cytotoxicity against HepG2 cells, with selectivity indices of >10. The tested compounds showed activity in vitro against both early- and late-stage P. falciparum gametocytes while blocking male gamete formation (>70% inhibition of exflagellation at 2 μM). Additionally, five selected compounds were found to have good solubility (≥170 μM in PBS at pH 6.5), while metabolic stability towards human, mouse, and rat microsomes ranged from >90% to >7% after 30 min. Dioncophylline C (2a) emerged as a front runner from the study, displaying activity against both asexual parasites and gametocytes, a lack of cross-resistance to chloroquine, good solubility, and microsomal stability. Overall, this is the first report on the multistage activity of NIQs and their synthetic analogues including gametocytocidal and gametocidal effects induced by this class of compounds. [Display omitted] •Naphthylisoquinolines (NIQs) validated as antimalarial hit candidates.•First report on transmission-blocking properties of NIQs and analogues.•15 compounds active across 9 P. falciparum strains, with acceptable RI <10 and SI >10.•5 compounds show good solubility and microsomal stability.•Dioncophylline C is the frontrunner antimalarial candidate with multistage activity.