In vivo efficacy and metabolism of the antimalarial cycleanine and improved in vitro antiplasmodial activity of novel semisynthetic analogues.

Ijeoma Uche, Fidelia; Guo, Xiaozhen; Okokon, Jude; Ullah, Imran; Horrocks, Paul; Boateng, Joshua; Huang, Chenggang; Li, Wen-Wu

Abstract

Bisbenzylisoquinoline (BBIQ) alkaloids are a diverse group of natural products that demonstrate a range of biological activities. In this study, the in vitro antiplasmodial activity of three BBIQ alkaloids (cycleanine (1), isochondodendrine (2) and 2'-norcocsuline (3)) isolated from the Triclisia subcordata Oliv. medicinal plant traditionally used for the treatment of malaria in Nigeria are studied alongside two semi-synthetic analogues (4 and 5) of cycleanine. The antiproliferative effects against a chloroquine-resistant Plasmodium falciparum strain were determined using a SYBR Green 1 fluorescence assay. The in vivo antimalarial activity of cycleanine (1) is then investigated in suppressive, prophylactic and curative murine malaria models after infection with a chloroquine-sensitive Plasmodium berghei strain. BBIQ alkaloids (1-5) exerted in vitro antiplasmodial activities with IC50 at low micromolar concentrations with the two semi-synthetic cycleanine analogues showing an improved potency and selectivity than cycleanine. At oral doses of 25 and 50mg/kg body weight of infected mice, cycleanine suppressed the levels of parasitaemia, and increased mean survival times significantly compared to the control groups. The metabolites and metabolic pathways of cycleanine (1) were also studied using high performance liquid chromatography electrospray ionization tandem mass spectrometry. Twelve novel metabolites were detected in rats after intragastic administration of cycleanine. The metabolic pathways of cycleanine were demonstrated to involve hydroxylation, dehydrogenation, and demethylation. Overall, these in vitro and in vivo results provide a basis for the future evaluation of cycleanine and its analogues as leads for further development.

Citation

Ijeoma Uche, F., Guo, X., Okokon, J., Ullah, I., Horrocks, P., Boateng, J., …Li, W. (2020). In vivo efficacy and metabolism of the antimalarial cycleanine and improved in vitro antiplasmodial activity of novel semisynthetic analogues. Antimicrobial Agents and Chemotherapy, https://doi.org/10.1128/AAC.01995-20

• Acceptance Date: Nov 13, 2020
• Publication Date: Nov 30, 2020
• Journal: Antimicrobial Agents and Chemotherapy
• Print ISSN: 0066-4804
• Publisher: American Society for Microbiology
• DOI: https://doi.org/10.1128/AAC.01995-20
• Keywords: Plasmodium falciparum; Plasmodium berghei; bisbenzylisoquinoline alkaloids; cycleanine; metabolism; in vivo activity.
• Publisher URL: https://aac.asm.org/content/early/2020/11/26/AAC.01995-20