Discovery of a Bulky 2-tert-Butyl Group Containing Primaquine Analogue That Exhibits Potent Blood-Schizontocidal Antimalarial Activities and Complete Elimination of Methemoglobin Toxicity
Meenakshi Jain, Suryanarayana Vangapandu, Sandeep Sachdeva, Savita Singh, Prati Pal Singh, Gopa B. Jena, Kulbhushan Tikoo, Poduri Ramarao, Chaman Lal Kaul, Rahul Jain · Journal of Medicinal Chemistry · 2003
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.