PRIMACENES: novel non-cytotoxic primaquine-ferrocene conjugates with anti-Pneumocystis carinii activity

Matos, Joana; Vale, Nuno; Collins, Margaret S.; Gut, Jiří; Rosenthal, Philip J.; Cushion, Melanie T.; Moreira, Rui; Gomes, Paula

doi:10.1039/c0md00082e

Cited by 25 publications

(28 citation statements)

References 34 publications

(56 reference statements)

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“…Since several reports indicate that iron potentiates the leishmanicidal activity of several drugs (21,33), and since we have previously shown that ferrocene (Fc) derivatives of PQ are active against Plasmodium (19) and Pneumocystis (20), we next tested a series of Fc derivatives of PQ for activity against L. infantum promastigotes. The results obtained with compounds 5 to 10 ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Other compounds of the PQ-Pro-Xaa series, i.e., 4a and c to i, were synthesized as previously described for compound 4b (38), and spectroscopic data as well as high-pressure liquid chromatography (HPLC) traces are available upon request. Synthetic procedures and chromatographic/spectroscopic data were reported elsewhere for compounds 5 to 10 (19,20), except for compound 7h, for which relevant procedures and data are available upon request.…”

Section: Methodsmentioning

confidence: 99%

“…1) (2,26,38,40). Compounds 3 and 5 to 10 have previously revealed remarkable activity against PQ-sensitive pathogens, namely, Plasmodium (malaria) and Pneumocystis (pneumocystic pneumonia), in some cases with better performances than that of PQ at the activity and/or toxicity level (19,20,36,40). In view of this and the known antileishmanial properties of 8AQ analogues of PQ, such as sitamaquine, the present work aimed to explore the activity of the peptidomimetic and organometallic PQ derivatives against L. infantum, the causative agent of Mediterranean VL.…”

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confidence: 99%

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Peptidomimetic and Organometallic Derivatives of Primaquine Active against Leishmania infantum

Vale-Costa

Vale

Matos

et al. 2012

Antimicrob Agents Chemother

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The current treatment of visceral leishmaniasis is made difficult by the low efficacy, elevated costs, low bioavailability, and high toxicity of many of the available drugs. Primaquine, an antimalarial 8-aminoquinoline, displays activity against Leishmania spp., and several of its derivatives have been developed as potential antileishmanial drugs. However, primaquine exhibits low oral bioavailability due to oxidative deamination of its aliphatic chain. We previously developed peptidomimetic and organometallic derivatives of primaquine, with higher resistance to proteolytic degradation and oxidative deamination, which presented significant activity against primaquine-sensitive pathogens such as Plasmodium or Pneumocystis. In light of these relevant findings, we decided to evaluate these compounds against both the promastigote and intramacrophagic amastigote forms of Leishmania infantum, the agent of Mediterranean visceral leishmaniasis. We found that several of these compounds had significant activity against L. infantum. One of the peptidomimetic (3c) and one of the organometallic (7a) derivatives of primaquine were active against the clinically relevant intramacrophagic amastigote form of the parasite, causing >96% reductions in the number of amastigotes per 100 macrophages at 60 and 40 M, respectively, while being less cytotoxic for host cells than the reference drugs sitamaquine and miltefosine. Hence, compounds 3c and 7a represent new entries toward the development of new antileishmanial leads.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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confidence: 99%

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Peptidomimetic and Organometallic Derivatives of Primaquine Active against Leishmania infantum

Vale-Costa

Vale

Matos

et al. 2012

Antimicrob Agents Chemother

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“…This result agrees with our previous findings on PQ derivatives 4, as these organometallic compounds were also highly active against liver-stage parasites, regardless of whether a basic aliphatic amine group was present. Yet, compounds 4 which lacked a basic aliphatic amine group Scheme 1 Chemical structures of primaquine (1), its main metabolite, carboxyprimaquine (2), PQ derivatives formerly developed by us, namely, imidazoquines (3) 6,7 and primacenes (4), 8,9 and PRIMACINS herein reported (5): (i) PQ was coupled to cinnamic acids in the presence of 1.1 molar equivalents (eq.) of TBTU and 2 eq.…”

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confidence: 99%

“…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.…”

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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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Quinolone derivatives and their antifungal activities: An overview

Zhang

2019

Archiv der Pharmazie

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More than 300 million people suffer from the incidence of life‐threatening invasive fungal infections, resulting in over 1.35 million deaths annually. Currently, the antifungal agents available in clinics are rather limited, and the rapid development of resistance to the existing antifungal drugs has further aggravated mortality. Quinolones possess a broad spectrum of chemotherapeutic properties and demonstrate considerable antifungal activities as well. Various quinolone derivatives have been screened for their antifungal activities, and some of them exhibit excellent potency against both drug‐susceptible and drug‐resistant fungi. This review aims to outline the recent advances in quinolone derivatives as potential antifungal agents and summarize the structure–activity relationship, to provide insights for the rational design of more active candidates.

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PRIMACENES: novel non-cytotoxic primaquine-ferrocene conjugates with anti-Pneumocystis carinii activity

Cited by 25 publications

References 34 publications

Peptidomimetic and Organometallic Derivatives of Primaquine Active against Leishmania infantum

Peptidomimetic and Organometallic Derivatives of Primaquine Active against Leishmania infantum

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

Quinolone derivatives and their antifungal activities: An overview

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