Uche, FI, Guo, X, Okokon, J, Ullah, I, Horrocks, P, Boateng, J, Huang, C and Li, W-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, 65 (2). ISSN 0066-4804

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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.

Item Type: Article
Additional Information: Copyright © 2020 Uche et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
Uncontrolled Keywords: Plasmodium falciparum; Plasmodium berghei; bisbenzylisoquinoline alkaloids; cycleanine; metabolism; in vivo activity.
Subjects: Q Science > QR Microbiology
R Medicine > R Medicine (General)
R Medicine > R Medicine (General) > R735 Medical education. Medical schools. Research
Divisions: Faculty of Medicine and Health Sciences > School of Pharmacy and Bioengineering
Related URLs:
Depositing User: Symplectic
Date Deposited: 16 Dec 2020 11:56
Last Modified: 26 Feb 2021 12:36
URI: https://eprints.keele.ac.uk/id/eprint/8987

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