Primaquine Enantiomers: Scalable Preparation and Differential

Hematotoxicity in individuals genetically deficient in glucose-6-phosphate 22 dehydrogenase (G6PD) activity is the major limitation of primaquine (PQ), the only antimalarial 23 drug in clinical use for treatment of relapsing P. vivax malaria. PQ is currently clinically used in 24 its racemic form. A scalable procedure was developed to resolve racemic PQ thus providing pure 25 enantiomers for the first time for detailed preclinical evaluation and potentially for clinical use. 26 These enantiomers were compared for antiparasitic activity in several mouse models, and also 27 for general and hematological toxicities in mice and dogs. (+)-(S)-PQ showed better suppressive 28 and causal prophylactic activity than (-)-(R)-PQ in mice infected with Plasmodium berghei. 29 Similarly, (+)-(S)-PQ was a more potent suppressive agent than (-)-(R)-PQ in a mouse model of 30 Pneumocystis carinii pneumonia. However, at higher doses (+)-(S)-PQ also showed more 31 systemic toxicity to mice. In Beagle dogs (+)-(S)-PQ caused more methemoglobinemia and was 32 toxic at 5 mg/kg/day orally for 3 days, while the (-)-(R)-PQ was well tolerated. In a novel mouse 33 model of hemolytic anemia associated with human glucose-6-phosphate dehydrogenase (G6PD) 34 deficiency, it was also demonstrated that (-)-(R)-PQ was less hemolytic compared to (+)-(S)-PQ 35 to the G6PD deficient human red cells engrafted in the NOD-SCID mice. All these data suggest 36 that while (+)-(S)-PQ shows greater potency in terms of antiparasitic efficacy in rodents, it is also 37 more hematotoxic than (-)-(R)-PQ in mice and dogs. Activity and toxicity differences of PQ 38 enantiomers in different species can be attributed to their different pharmacokinetic and 39 metabolic profiles. Taken together, these studies suggest that (-)-(R)-PQ may have a better safety 40 margin than the racemate in human. 41