Antimalarial Activity of Novel 5-Aryl-8-Aminoquinoline Derivatives

Abstract

In an attempt to separate the antimalarial activity of tafenoquine (3) from its hemolytic side effects in glucose-6-phosphate dehydrogenase (G6PD) deficiency patients, a series of 5-aryl-8-aminoquinoline derivatives was prepared and assessed for antimalarial activities. The new compounds were found metabolically stable in human and mouse microsomal preparations, with t(1/2) > 60 min, and were equal to or more potent than primaquine (2) and 3 against Plasmodium falciparum cell growth. The new agents were more active against the chloroquine (CQ) resistant clone than to the CQ-sensitive clone. Analogues with electron donating groups showed better activity than those with electron withdrawing substituents. Compounds 4bc, 4bd, and 4be showed comparable therapeutic index (TI) to that of 2 and 3, with TI ranging from 5 to 8 based on IC(50) data. The new compounds showed no significant causal prophylactic activity in mice infected with Plasmodium berghei sporozoites, but are substantially less toxic than 2 and 3 in mouse tests.

Novel Potent Metallocenes against Liver Stage Malaria

“…The hemotoxicity of PQ arises from hydroxylated metabolites such as N-hydroxy-8-amino-6-methoxy-quinoline (MAQ-NOH) or 5-hydroxylated species, which tautomerize into hemotoxic quinoneimines (30). To avoid the formation of the latter, much effort has been put into the development of PQ derivatives substituted at quinoline's C-5, of which tafenoquine (TFQ) has been the emblematic, but not perfect, example (29,30). TFQ is a 5-phenoxyl derivative of PQ with a longer half-life and lower toxicity than those of PQ but is not devoid of hemotoxicity in vivo, so new 5-aryl analogues are now being explored as TFQ surrogates (29).…”

“…To avoid the formation of the latter, much effort has been put into the development of PQ derivatives substituted at quinoline's C-5, of which tafenoquine (TFQ) has been the emblematic, but not perfect, example (29,30). TFQ is a 5-phenoxyl derivative of PQ with a longer half-life and lower toxicity than those of PQ but is not devoid of hemotoxicity in vivo, so new 5-aryl analogues are now being explored as TFQ surrogates (29). Also, as for PQ, TFQ is not protected from undergoing oxidative deamination on its aliphatic chain.…”

Recent advances in the trifluoromethylation methodology and new CF3-containing drugs

“…The general clinical use of this type of drugs is limited by their toxic side effects, specifically, methemoglobinemia and hemolytic anemia, which are apparently caused by the corresponding metabolites of 8-AQ [100].…”

Assessment of the prophylactic activity and pharmacokinetic profile of oral tafenoquine compared to primaquine for inhibition of liver stage malaria infections

“…The World Health Organization recommends PQ in combination with chloroquine for the radical cure of P. vivax malaria, although limited compliance with the 14-day dosing regimen is known to impact effectiveness [1]. The clinical value of this class is compromised by the toxic side effects, however, which include methemoglobinaemia and haemolytic anaemia in patients with deficiency in glucose-6-phosphate dehydrogenase (G6PD) activity [2]. …”