Abstract
The ultimate goal of this study was to identify an orally active, affordable, potent and safe antimalarial drug based on the natural product artemisinin. During these efforts, a series of novel 7β-hydroxyartemisinin analogs were synthesized and characterized in vitro for their antimalarial activity against Plasmodium falciparum. Heterodimerization of 7β-hydroxyartemisinin provided the asymmetrical carbamate (ARB-89) while homodimerization provided the carbonate (ARB-92). These dimers were found to be highly active in vitro with an IC50 ≤ 0.50 nM against P. falciparum infected human red blood cells (RBC). For further development as potential antimalarial agents, a battery of in vitro and in vivo pharmacokinetic experiments was performed to distinguish the fate of the discovery compounds ARB-89 and ARB-92. Two UPLC-MS methods were developed and validated for the analysis of the compounds. Both ARB-89 and ARB-92 exhibited moderate affinity (51 and 56%, respectively) to parasitized RBC, which is a perquisite for antimalarial activity. Following a single dose oral and intravenous pharmacokinetic study in rats, ARB-89 displayed a high clearance (92.8 ± 5.6 L/h kg), short elimination half-life (t1/2, 1.2 ± 0.2 h) and moderate oral bioavailability (23.4%). ARB-89 was found to be excreted unchanged in feces, which may be due to its high lipophilicity, molecular weight and low oral exposure. In an attempt to identify a better lead antimalarial compound, ARB-92 was designed to be more water soluble than ARB-89 by incorporating a protonatable tertiary amine as part of the dimerizing ligand for 7β-hydroxyartemisinin. As anticipated, ARB-92 displayed a lower clearance (2.9 ± 0.7 L/h kg) and subsequently a longer t1/2 (2.3 ± 0.2 h) compared to ARB-89. The oral bioavailability of ARB-92 was found to be 34% in rats, a value somewhat better than the marketed artemisinin derivatives artenimol (19.3%), artemether (19.7%) or artesunate (29.5%).
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Acknowledgements
This work was supported by the CDC Cooperative agreement number U01 CI000211 (M.A.A.), and the content is solely the responsibility of the authors. This investigation was conducted in a facility constructed with support from Research Facilities Improvement Program Grant Number C06 Rr-14503-01 from The National Center for Research Resources, National Institutes of Health. All authors declare that they have no competing interest. All experimental procedures were approved and performed in accordance with the guidelines of the Institutional Animal Care and Use Committee (IACUC) of the University of Mississippi.
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Avery, B.A., Pabbisetty, D., Li, L. et al. A pharmacokinetic comparison of homodimer ARB-92 and heterodimer ARB-89: novel, potent antimalarial candidates derived from 7β-hydroxyartemisinin. J. Pharm. Investig. 48, 585–593 (2018). https://doi.org/10.1007/s40005-017-0352-6
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DOI: https://doi.org/10.1007/s40005-017-0352-6