期刊
INTERNATIONAL JOURNAL FOR PARASITOLOGY-DRUGS AND DRUG RESISTANCE
卷 13, 期 -, 页码 51-58出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.ijpddr.2020.05.003
关键词
Naphthylisoquinoline alkaloids; Natural products; Hit validation; Plasmodium falciparum; Malaria; Multistage active antimalarial drug candidates
资金
- South African Research Chairs Initiative of the Department of Science and Technology [84627]
- Deutsche Forschungsgesellschaft (DFG) [SFB 630]
- National Institute of Allergy and Infectious Diseases of the National Institutes of Health [R01AI143521]
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.
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