Peptide derivatives of primaquine as potential antimalarial agents

Philip, A.; Kepler, John A.; Johnson, Ben; Carroll, F. Ivy

doi:10.1021/jm00399a032

Cited by 49 publications

(32 citation statements)

References 1 publication

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“…The D-Val-containing derivative was found to be less toxic and more active than both its L-Val counterpart and PQ, whereas the activity of the Ala-bearing compound was comparable to that of the L-Val derivative [182].…”

Section: Modifications At the Terminal Primary Aminementioning

confidence: 90%

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: 90%

Primaquine revisited six decades after its discovery

Vale¹,

Moreira²,

Gomes³

2009

European Journal of Medicinal Chemistry

321

308

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“…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 [15][16][17][18]. Despite the improved activity/toxicity ratio, most of these derivatives are rapidly hydrolyzed to primaquine by aminopeptidases and endopeptidases [16,18], suggesting that they might undergo extensive hydrolysis to the parent drug in the intestinal lumen when given orally.…”

Section: Introductionmentioning

confidence: 99%

Primaquine dipeptide derivatives bearing an imidazolidin-4-one moiety at the N-terminus as potential antimalarial prodrugs

Vale

Nogueira

Rosário

et al. 2009

European Journal of Medicinal Chemistry

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a b s t r a c tPrimaquine dipeptide derivatives bearing an imidazolidin-4-one moiety at the N-terminus were synthesized and evaluated as potential transmission-blocking antimalarial prodrugs. All compounds were hydrolyzed to the parent dipeptide derivative of primaquine in neutral and basic solutions, with half lives ranging from 0.7 to 31 h at 37 C, depending on the nature of the substituents present in the imidazolidin-4-one moiety and in the C-terminal amino acid directly coupled to primaquine. The antimalarial activity was studied for selected compounds using a model consisting of Plasmodium berghei, BalbC mice and Anopheles stephensi mosquitoes. The imidazolidin-4-one derived from Ala-Ala-primaquine and acetone reduced the transmission of the infection to mosquitoes more efficiently than primaquine as shown by the significant decrease in the number of oocysts in the midguts of the mosquitoes at 10 and 50 mmol/kg when compared to the control.

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“…The broad inactivity of compounds 5 against erythrocytic-stage parasites was not particularly surprising, as (i) PQ is itself a modest blood-schizontocidal 5 and (ii) compounds 5 lack a basic amine: the relevance of a basic amino group linked to the 8-aminoquinoline core through a chain of two to six carbons for the activity of PQ against erythrocytic Plasmodia was established three decades ago. 5,13,14 In fact, more recent well-known PQ derivatives displaying some erythrocytic-stage activity have the PQ's basic aliphatic chain either conserved (e.g., tafenoquine) or modified in a way that reasonably preserves its basicity (e.g., bulaquine and sitamaquine). 5 Compared to other cinnamic derivatives, which present low mM activities against Pf Dd2 and W2 strains, 10,15 combining the cinnamic moiety with PQ clearly led to a loss of erythrocytic-stage activity.…”

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confidence: 99%

PRIMACINS, N-cinnamoyl-primaquine conjugates, with improved liver-stage antimalarial activity

Pérez¹,

Teixeira²,

Albuquerque³

et al. 2012

Med. Chem. Commun.

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Novel primaquine derivatives, obtained by conjugation of the drug's aliphatic amine with different cinnamic acids, resulted in increased in vitro activity, compared to primaquine, against liver-stage malarial parasites. The compounds were non-cytotoxic to human hepatoma cells, suggesting that they are a promising new class of agents for the treatment and prevention of malaria.Effective and safe antimalarial drugs active against both liver and erythrocytic parasite stages will be valuable components of malaria eradication strategies.1 Mammalian infection by malarial parasites is initiated by an infected mosquito bite, followed by a clinically silent liver-stage infection, during which thousands of merozoites are formed to be released into the bloodstream and trigger the clinically relevant erythrocytic stage of the life cycle. 2Drugs able to act on the liver stage are highly relevant, as they can be used in chemoprophylaxis to prevent all clinical manifestations of malaria.3 Moreover, such drugs are particularly relevant in P. vivax and P. ovale infections, as in these species latent forms that are called hypnozoites are not eliminated by most available therapies, persist in the liver for long periods, and subsequently cause malaria relapses. At present, drugs acting against parasite liver forms are scarce, and primaquine (PQ, 1 in Scheme 1) remains the only drug in clinical use that acts against liver stages of all Plasmodium species, 4 including P. vivax and P. ovale hypnozoites.5 Unfortunately, PQ's low oral bioavailability and high hemotoxicity hold back its clinical use, especially in vulnerable populations including pregnant women, infants and the elderly. In addition, PQ causes hemolysis in patients with congenital deficiency of glucose-6-phosphate dehydrogenase, 5 complicating its use to treat P. vivax and P. ovale malaria and limiting its use in chemoprophylaxis.For the past decade, we have been working on chemical approaches to mask the PQ aliphatic amine in order to obtain analogues resistant to oxidative deamination, the major metabolic pathway underlying the drug's low oral bioavailability (Scheme 1) by conversion into an inactive metabolite, carboxyprimaquine (2 in Scheme 1).5 To this end, we have successfully developed imidazoquines (3 in Scheme 1) 6,7 and primacenes (4 in Scheme 1), 8,9 peptidomimetic and organometallic derivatives of PQ with promising antimalarial properties, respectively. Now, we disclose a new family of PQ derivatives, the PRIMACINS (5 in Scheme 1), obtained by coupling PQ to cinnamic acids, as the latter was formerly reported to possess interesting antimalarial properties.10 PRIMACINS were found to have higher in vitro activity than PQ against the liver-stage of the rodent malarial parasite P. berghei (Fig. 1).PRIMACINS were tested against liver stages of the rodent parasite P. berghei and against erythrocytic stages of the human parasite P. falciparum (Table 1). Compounds 5 were two-or more-fold more potent than PQ against liver stage P. berghei and were non-toxic to Huh7 hum...

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Peptide derivatives of primaquine as potential antimalarial agents

Cited by 49 publications

References 1 publication

Primaquine revisited six decades after its discovery

Primaquine revisited six decades after its discovery

Primaquine dipeptide derivatives bearing an imidazolidin-4-one moiety at the N-terminus as potential antimalarial prodrugs

PRIMACINS, N-cinnamoyl-primaquine conjugates, with improved liver-stage antimalarial activity

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