Discovery of a Bulky 2-tert-Butyl Group Containing Primaquine Analogue That Exhibits Potent Blood-Schizontocidal Antimalarial Activities and Complete Elimination of Methemoglobin Toxicity

To eliminate an unwarranted metabolic pathway of the quinoline ring, a set of two compounds, where C-2 position of the antimalarial drug primaquine is blocked by metabolically stable bulky alkyl group are synthesized. Compound 2 [R = C(CH(3))(3)] of the series has produced excellent antimalarial efficacy against P. berghei and highly virulent multidrug-resistant P. yoelii nigeriensis strain in vivo. Compound 2 was also evaluated for methemoglobin (MetHb) toxicity. This study describes the discovery of a highly potent blood-schizontocidal antimalarial analogue 2, completely devoid of MetHb toxicity.