Relationships between chemical structures of 8-aminoquinolines and their capacities for radical cure of infections with Plasmodium cynomolgi in rhesus monkeys

Schmidt, L. H.

doi:10.1128/aac.24.5.615

Cited by 38 publications

(32 citation statements)

References 48 publications

(75 reference statements)

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“…In contrast with PQ, none of the compounds were able to block oocyst production in mosquitoes' midguts at 3.75 mg/kg, but all of them were found to completely inhibit the formation of oocysts at 15 mg/kg, whereas N-acetylprimaquine is not active at this dose. As a whole, this work has demonstrated that acylation of the PQ's primary amino group effectively prevents the early conversion of PQ into carboxyprimaquine, while confirming that the presence of a terminal [163] amino group, as in the dipeptide derivatives of PQ, is essential for gametocytocidal activity [187]. Recently, Gomes et al worked on the further transformation of the amino acid moiety linked to the PQ's primary amine, upon introduction of an imidazolidin-4-one ring at the amino acid's aamino group (30).…”

Section: Modifications At the Terminal Primary Aminementioning

confidence: 66%

“…This produced almost 200 PQ derivatives (Tables 2-4) bearing diverse groups in one or more given positions of the ring [6,46,[161][162][163][164][165][166][167][168][169][170][171][172][173][174][175][176][177][178][179]. Globally, the most favourable substituent insertions towards anti-malarial activity where those of methyl groups at positions 4 and 2, tert-butyl at position 2, simultaneous insertion of ethyl substituents at positions 2 and 4 and pentyloxy at position 5, as well as insertion at position 5 of alkoxy, fluoro, and 3-or 4-substituted phenoxy groups [51,163]. Many of these compounds present activity comparable or superior to that of PQ both as gametocytocide and schizontocide, as further described below.…”

Section: Modifications At the Quinoline Ringmentioning

confidence: 99%

See 1 more Smart Citation

Primaquine revisited six decades after its discovery

Vale¹,

Moreira²,

Gomes³

2009

European Journal of Medicinal Chemistry

321

308

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Section: Modifications At the Terminal Primary Aminementioning

confidence: 66%

Section: Modifications At the Quinoline Ringmentioning

confidence: 99%

Primaquine revisited six decades after its discovery

Vale¹,

Moreira²,

Gomes³

2009

European Journal of Medicinal Chemistry

321

308

View full text Add to dashboard Cite

“…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: 99%

Enantioselective Pharmacokinetics of Primaquine in Healthy Human Volunteers

et al. 2015

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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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“…Therefore, we first administered subtherapeutic doses of isopentaquine, an 8-aminoquinoline with a liver-stage action comparable with that of primaquine (27)(28)(29). Primaquine and primaquine derivatives are thought to interfere with the cellular respiration, generation of free radicals, and deregulation of electron transport in liver-resident parasites (30).…”

Section: Resultsmentioning

confidence: 99%

Chemical Attenuation of Plasmodium in the Liver Modulates Severe Malaria Disease Progression

Lewis

Behrends

Cunha

et al. 2015

The Journal of Immunology

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Cerebral malaria is one of the most severe complications of malaria disease, attributed to a complicated series of immune reactions in the host. The syndrome is marked by inflammatory immune responses, margination of leukocytes, and parasitized erythrocytes in cerebral vessels leading to breakdown of the blood–brain barrier. We show that chemical attenuation of the parasite at the very early, clinically silent liver stage suppresses parasite development, delays the time until parasites establish blood-stage infection, and provokes an altered host immune response, modifying immunopathogenesis and protecting from cerebral disease. The early response is proinflammatory and cell mediated, with increased T cell activation in the liver and spleen, and greater numbers of effector T cells, cytokine-secreting T cells, and proliferating, proinflammatory cytokine-producing T cells. Dendritic cell numbers, T cell activation, and infiltration of CD8+ T cells to the brain are decreased later in infection, possibly mediated by the anti-inflammatory cytokine IL-10. Strikingly, protection can be transferred to naive animals by adoptive transfer of lymphocytes from the spleen at very early times of infection. Our data suggest that a subpopulation belonging to CD8+ T cells as early as day 2 postinfection is responsible for protection. These data indicate that liver stage–directed early immune responses can moderate the overall downstream host immune response and modulate severe malaria outcome.

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Relationships between chemical structures of 8-aminoquinolines and their capacities for radical cure of infections with Plasmodium cynomolgi in rhesus monkeys

Cited by 38 publications

References 48 publications

Primaquine revisited six decades after its discovery

Primaquine revisited six decades after its discovery

Enantioselective Pharmacokinetics of Primaquine in Healthy Human Volunteers

Chemical Attenuation of Plasmodium in the Liver Modulates Severe Malaria Disease Progression

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