Antiparasitic Activities and Toxicities of Individual Enantiomers of the 8-Aminoquinoline 8-[(4-Amino-1-Methylbutyl)Amino]-6-Methoxy-4-Methyl-5-[3,4-Dichlorophenoxy]Quinoline Succinate

Abstract

8-Aminoquinolines are an important class of antiparasitic agents, with broad utility and excellent efficacy, but also limitations due to hematological toxicities, primarily methemoglobinemia and hemolysis. One representative from this class, (؎)-8-[(4-amino-1-methylbutyl)amino]-6-methoxy-4-methyl-5-[3,4-dichlorophenoxy]quinoline succinate (NPC1161C), proved extremely efficacious in animal models of malaria and pneumocystis pneumonia. This racemic mixture was separated into its component enantiomers by chemical and chromatographic means. The enantiomers were evaluated for antiparasitic activity in murine models of Plasmodium berghei, Pneumocystis carinii, and Leishmania donovani infection, as well as the propensity to elicit hematotoxicity in dogs. The (؊)-enantiomer NPC1161B was found to be more active (by severalfold, depending on the dosing regimen) than the (؉)-enantiomer NPC1161A in all of these murine models. In addition, the (؊) enantiomer showed markedly reduced general toxicity in mice and reduced hematotoxicity in the dog model of methemoglobinemia. It is concluded that the configuration at the asymmetric center in the 8-amino side chain differentially affects efficacy and toxicity profiles and thus may be an important determinant of the "therapeutic window" for compounds in this class.8-Aminoquinolines are an important class of anti-infective drugs with promising utility in the treatment of malaria and other emerging infectious diseases (41). Primaquine (Fig. 1), the only 8-aminoquinoline derivative in clinical use, is the drug of choice for the radical cure of relapsing malaria (2). This drug is also reported to be effective against Trypanosoma (28) and Leishmania (39) species and, in combination with clindamycin, for prophylaxis and treatment of Pneumocystis carinii pneumonia (PCP) in animal models (7,33). Several studies have shown that the primaquine-clindamycin combination was extremely effective for prophylaxis (23) and treatment (10,11,20,23,43,44,45) of mild to severe cases of pneumocystis pneumonia in AIDS patients, especially as a salvage therapy in cases where conventional therapy was ineffective or not tolerated. (Note that, in recent years, the nomenclature Pneumocystis jirovecii has been adopted for the human pathogen.) A serious limitation to widespread use of primaquine, however, is that it produces methemoglobinemia (16, 22, 40) and hemolysis (40), especially in individuals who suffer from hereditary glucose-6-phosphate dehydrogenase deficiency.Over the years, several attempts have been made to improve the therapeutic index of primaquine. In a study sponsored by the U.S. Army, a large number of 8-aminoquinolines chemically related to primaquine have been synthesized and evaluated for antiparasitic activity (31). Some of these compounds were found to have superior activity compared to primaquine against Leishmania (25) and Trypanosoma (24) species and against several Plasmodium species (31) in animal models. Based on these results tafenoquine (WR 238605) was selected for clinical evalua...

Pharmacokinetic Properties of Single-Dose Primaquine in Papua New Guinean Children: Feasibility of Abbreviated High-Dose Regimens for Radical Cure of Vivax Malaria

“…There may be racial differences in the propensity to methemoglobinemia, since short-course high-dose PMQ caused peripheral cyanosis in 5% of Caucasians (21) but no Thai subjects were affected in two separate similar studies (22,23). Although there appears to be no relationship between plasma PMQ or CPMQ concentrations and methemoglobinemia (21), which may reflect the activity of transient toxic metabolites (41), future studies of short-course, high-dose PMQ regimens should include serial methemoglobin monitoring to ensure that such regimens are safe.…”

“…Its relatively slow elimination means that it accumulates during multiple daily or twice-daily dosing. However, this should not have clinical consequences, even after a high-dose abbreviated regimen, since other PMQ metabolites are considered responsible for toxicity, and they appear to be minor and highly labile (41). In any case, the predicted median CPMQ C max after the last dose of the 1.0 mg/kg twice-daily regi-men given over a 3.5-day period in the present study (3,477 g/ liter) were within the absolute range of equivalent median C max from healthy Vietnamese adults given 30 mg PMQ base daily for 14 days (42) and similar to those seen in Caucasians at the end of a week of 0.5 mg/kg twice daily (means Ϯ SD, 3,824 Ϯ 624 g/ liter) (21).…”

The 8-Aminoquinoline Analogue Sitamaquine Causes Oxidative Stress in Leishmania donovani Promastigotes by Targeting Succinate Dehydrogenase

“…This result, together with related findings for tafenoquine, which acts on the next downstream complex in the respiratory chain (2), demonstrates the versatility of the 8-aminoquinoline scaffold for the development of leishmanicidal drugs. The recently described improvement of 8-aminoquinolines (27) therefore appears to be an attractive strategy for development of analogs with promising antimalarial, antimicrobial, and antileishmanial activities, together with lower hematological toxicity. Furthermore, SQ was recently suggested as a candidate for drug combinations (32), thus supporting its use for reduced drug dosage, toxicity, and therapeutic failure.…”

Primaquine revisited six decades after its discovery

“…Other studies indicate that it causes mitochondrial swelling in several Plasmodium strains and stages [85][86][87], including P. falciparum gametocytes [88]. Additional reports suggest that exposure to PQ affects mitochondrial proliferation and inhibits growth on development stages that require functional mitochondria [87,[89][90][91][92][93].…”