Synthesis and Antimalarial Activity of New Isotebuquine Analogs

摘要

Clinical use of amodiaquine (AQ) and tebuquine (TQ) were compromised due to hepatoxicity and agranulocytosis side effects. Lysosomal accumulation and bioactivation to generate reactive quinoneimine metabolite are implicated to be the cause of AQ and TQ toxicities. To avoid the quinoneimine formation and thus the toxicity, a series of isotebuquine analogs (I) and their N~omega-oxides (II) with hydroxy group meta to the amino group of aniline were prepared. The new isoquines are highly active against chloroquine (CQ)-sensitive (D6) and CQ-resistant (W2 and TM91C235) clones of P. falciparum, IC_(50) = 0.3-120 ng/mL and arelOOO fold less toxic (IC_(50) = 0.7-6 mug/mL) to mouse macrophage cell line than to parasites. No appreciable differences in either toxicity or efficacy were observed between the new Mannich bases and tebuquine.