1 Antimalarial Activity of the 8-Aminoquinolines

Nodiff, Edward A.; Chatterjee, Sankar; Musallam, H. A.

doi:10.1016/s0079-6468(08)70362-x

Cited by 33 publications

(29 citation statements)

References 119 publications

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“…1), which conferred the best combination of efficacy and tolerability (Edgcomb et al, 1950). This was further demonstrated by extensive structure-activity analysis of 8-AQs (McChesney, 1981;Schmidt, 1983;Nodiff et al, 1991). This side chain contains an asymmetric center at carbon 1, and thus two different configurations (enantiomers) are possible (Fig.…”

Section: Introductionmentioning

confidence: 91%

Enantioselective Pharmacokinetics of Primaquine in Healthy Human Volunteers

Tekwani

Avula

Sahu

et al. 2015

Drug Metabolism and Disposition

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Primaquine (PQ), a racemic drug, is the only treatment available for radical cure of relapsing Plasmodium vivax malaria and blocking transmission of P. falciparum malaria. Recent studies have shown differential pharmacologic and toxicologic profiles of individual PQ enantiomers in rodent, dog, and primate animal models. This study was conducted in six healthy adult human volunteers to determine the plasma pharmacokinetic profile of enantiomers of PQ and carboxyprimaquine (cPQ), the major plasma metabolite. The individuals were orally administered PQ diphosphate, equivalent to 45-mg base, 30 minutes after a normal breakfast. Blood samples were collected at different time intervals, and plasma samples were analyzed for enantiomers of PQ and cPQ. Plasma PQ concentrations were low and variable for both parent enantiomers and peaked around 2-4 hours. Peak (2)-(R)-PQ concentrations ranged from 121 ng/ml to 221 ng/ml, and peak (+)-(S)-PQ concentrations ranged from 168 ng/ml to 299 ng/ml. The cPQ concentrations were much higher and were surprisingly consistent from subject to subject. Essentially all the cPQ detected in plasma was (2)-cPQ. The peak concentrations of (2)-cPQ were observed at 8 hours (range: 1104-1756 ng/ml); however, very high concentrations were sustained through 24 hours. (+)-cPQ was two orders of magnitude lower than (2)-cPQ, and in a few subjects it was detected but only under the limit of quantification. In vitro studies with primary human hepatocytes also suggested more rapid metabolism of (2)-PQ compared with (+)-PQ. The results suggest more rapid metabolism of (2)-PQ to (2) cPQ compared with (+)-PQ. Alternatively, (+)-PQ or (+)-cPQ could be rapidly converted to another metabolite(s) or distributed to tissues. This is the first clinical report on enantioselective pharmacokinetic profiles of PQ and cPQ and supports further clinical evaluation of individual PQ enantiomers.

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Section: Introductionmentioning

confidence: 91%

Enantioselective Pharmacokinetics of Primaquine in Healthy Human Volunteers

Tekwani

Avula

Sahu

et al. 2015

Drug Metabolism and Disposition

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“…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.…”

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confidence: 99%

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

Nanayakkara

Ager

Bartlett

et al. 2008

Antimicrob Agents Chemother

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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...

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“…This result is consistent with the previously mentioned relevance of a free primary amino group for antiplasmodial activity. 17 The potential of compounds 5a, b, e to prevent the transmission of malaria was studied using a model consisting of BalbC mice infected with P. berghei and Anopheles stephensi mosquitoes and compared to that of primaquine. 14,24 The antimalarial activity was assessed based on the percentage of mosquitoes with oocysts and the mean number of oocysts per infected mosquito (Table 2).…”

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confidence: 99%

Imidazolidin-4-one peptidomimetic derivatives of primaquine: Synthesis and antimalarial activity

Vale

Matos

Gut

et al. 2008

Bioorganic & Medicinal Chemistry Letters

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a b s t r a c tThe synthesis of imidazolidin-4-one derivatives of primaquine containing the five-membered ring at the C-terminus of a dipeptide backbone coupled to the parent drug is described. These peptidomimetic derivatives were active against a chloroquine-resistant Plasmodium falciparum strain and inhibited the development of the sporogonic cycle of Plasmodium berghei, affecting the appearance of oocysts in the midguts of the mosquitoes. The novel imidazolidin-4-ones are extremely stable, both in human plasma and in pH 7.4 buffer, as a result of N 1 -acylation. Thus, 'internal' imidazolidin-4-ones derived from dipeptidyl 8-aminoquinolines represent a new entry in antimalarial structure-activity relationships.Ó 2008 Elsevier Ltd. All rights reserved.Primaquine, 1, is the only currently available drug that is active against both the latent liver forms of the relapsing malaria caused by Plasmodium vivax and Plasmodium ovale and the gametocytes from all species of parasite causing human malaria. 1 However, primaquine presents a short plasma half-life (ca. 6 h), 2 presumably due to its rapid oxidative deamination to carboxyprimaquine 2. [3][4][5] Blood toxicity, in particular hemolysis secondary to the ability of primaquine to induce oxidation of oxyhemoglobin to methemoglobin, has also been a source of concern. 6 Peptide and amino acid derivatives of primaquine have been prepared to reduce toxicity of the parent drug as well as to suppress the metabolic pathway leading to 2, 7-10 but many of these derivatives are rapidly hydrolyzed to primaquine by aminopeptidases and endopeptidases. 8,10 Imidazolidin-4-one formation is often used to protect the N-terminal amino acid residue of peptides and peptidomimetics. 11,12 Recently, we prepared imidazolidin-4-ones, 3, as potential peptidase-stable prodrugs of amino acid derivatives of primaquine. [13][14][15] Compounds 3 displayed gametocytocidal activity against Plasmodium berghei comparable to that of primaquine, as well as activity against P. falciparum asexual stages, while presenting high stability in pH 7.4 buffer (half-lives for hydrolysis typically higher than 12 h). 14, 16 We now set out to incorporate the imidazolidin-4-one moiety into dipeptide derivatives of primaquine, for example, 5 (Scheme 1), both to (i) introduce a terminal basic amino group reported as relevant for activity, 17 and (ii) effectively suppress hydrolysis of the imidazolidin-4-one due to acylation of the N 1 nitrogen atom. We herein report the synthesis and evaluation of the antiplasmodial activity of imidazolidin-4-ones 5 (Scheme 1). Compounds 5 were prepared as depicted in Scheme 1. a-Aminoacyl derivatives of primaquine, 4, were converted into the corresponding imidazolidin-4-ones 3 by refluxing with propanone, cyclopentanone, or cyclohexanone in MeOH. 18 Preliminary condensation of 3 with N-Boc-protected amino acids (BocAAOH) using 0960-894X/$ -see front matter Ó

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1 Antimalarial Activity of the 8-Aminoquinolines

Cited by 33 publications

References 119 publications

Enantioselective Pharmacokinetics of Primaquine in Healthy Human Volunteers

Enantioselective Pharmacokinetics of Primaquine in Healthy Human Volunteers

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

Imidazolidin-4-one peptidomimetic derivatives of primaquine: Synthesis and antimalarial activity

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