Naphthylisoquinoline alkaloids, validated as hit multistage antiplasmodial natural products

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 multi-stage active antimalarial drug candidates. A total of 30 compounds were tested, of which 17 exhibited IC50 values 1 mu M 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 mu M). Additionally, five selected compounds were found to have good solubility (>= 170 mu M 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 ga-metocytocidal and gametocidal effects induced by this class of compounds.