A pharmacokinetic comparison of homodimer ARB-92 and heterodimer ARB-89: novel, potent antimalarial candidates derived from 7β-hydroxyartemisinin

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 IC 50 ≤ 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 (t 1/2 , 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 7 β -hydroxyartemisinin. As anticipated, ARB-92 displayed a lower clearance (2.9 ± 0.7 L/h kg) and subsequently a longer t 1/2 (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%).