New quinoline-5,8-dione and hydroxynaphthoquinone derivatives inhibit a chloroquine resistant Plasmodium falciparum strain

Hussain, Hidayat; Specht, Sabine; Sarite, Salem Ramadan; Hoerauf, Achim; Krohn, Karsten

doi:10.1016/j.ejmech.2012.06.046

Cited by 21 publications

(16 citation statements)

References 16 publications

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“…This high anti-malarial activity is probably due to the instability of the radical trifluormethylbenzene, which leads to the formation of free radicals that are toxic to the parasite [11]. However, a study with three derivatives hydroxy-naphthoquinone aminated, showed that only one was effective against the P. falciparum NF54; strain sensitive to most anti-malarials [7]. Their radical was a phenylpiperazine on carbon 6, with the same root added to other lead compounds.…”

Section: Discussionmentioning

confidence: 99%

In vitro antiplasmodial activity, pharmacokinetic profiles and interference in isoprenoid pathway of 2-aniline-3-hydroxy-1.4-naphthoquinone derivatives

Pereira

Emery

Lobo

et al. 2018

Malar J

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BackgroundPlasmodium falciparum has shown multidrug resistance, leading to the necessity for the development of new drugs with novel targets, such as the synthesis of isoprenic precursors, which are excellent targets because the pathway is different in several steps when compared with the human host. Naphthoquinone derivatives have been described as potentially promising for the development of anti-malarial leader molecules. In view of that, the focus in this work is twofold: first, evaluate the in vitro naphthoquinone antiplasmodial activity and cytotoxicity; secondly, investigate one possible action mechanism of two derivatives of hydroxy-naphthoquinones.ResultsThe two hydroxy-naphthoquinones derivatives have been tested against P. falciparum in vitro, using strains of parasites chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2), causing 50% inhibition of parasite growth with concentrations that varied from 7 to 44.5 μM. The cell viability in vitro against RAW Cell Line displayed IC50 = 483.5 and 714.9 μM, whereas, in primary culture tests using murine macrophages, IC50 were 315.8 and 532.6 μM for the two selected compounds, causing no haemolysis at the doses tested. The in vivo acute toxicity assays exhibited a significant safety margin indicated by a lack of systemic and behavioural toxicity up to 300 mg/kg. It is suggested that this drug seems to inhibit the biosynthesis of isoprenic compounds, particularly the menaquinone and tocopherol.ConclusionsThese derivatives have a high potential for the development of new anti-malarial drugs since they showed low toxicity associated to a satisfactory antiplasmodial activity and possible inhibition of a metabolic pathway distinct from the pathways found in the mammalian host.

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Section: Discussionmentioning

confidence: 99%

In vitro antiplasmodial activity, pharmacokinetic profiles and interference in isoprenoid pathway of 2-aniline-3-hydroxy-1.4-naphthoquinone derivatives

Pereira

Emery

Lobo

et al. 2018

Malar J

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“…The 6-substituted derivatives of 7-bromo-5,8-quinolinedione ( 118 – 120 ) and 5,8-quinolinedione ( 121 – 123 ) (Figure 20) were tested on a chloroquine-sensitive strain of P. falciparum (NF54) [102].…”

Section: Biological Activitymentioning

confidence: 99%

“…In the series of tested compounds, only 118 showed antiplasmodial activity (IC 50 equal to 3 µM). Comparing the activities of 5,8-quinoinediones 118 and 122 , it was found that the bromine atom at the C-7 position was necessary to maintain the antimalarial activity [102].…”

Section: Biological Activitymentioning

confidence: 99%

5,8-Quinolinedione Scaffold as a Promising Moiety of Bioactive Agents

et al. 2019

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Natural 5,8-quinolinedione antibiotics exhibit a broad spectrum of activities including anticancer, antibacterial, antifungal, and antimalarial activities. The structure–activity research showed that the 5,8-quinolinedione scaffold is responsible for its biological effect. The subject of this review report is a presentation of the pharmacological activity of synthetic 5,8-quinolinedione compounds containing different groups at C-6 and/or C-7 positions. The relationship between the activity and the mechanism of action is included if these data have been included in the original literature. The review mostly covers the period between 2000 and 2019. Previously published literature data were used to present historical points.

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“…Side chains containing quinoline analogs are an important class of antimalarial drugs in the history of antimalarials. In fact, these analogs compromised by the resistance, remain a choice of interest to make better novel side chains containing antimalarials [1]. Thus, novel anti-malarial resistance combating approaches and low-cost new drugs with favorable safety profiles are urgently needed [2][3][4][5].…”

Section: Introductionmentioning

confidence: 99%

Biological evaluation of novel side chain containing CQTrICh-analogs as antimalarials and their development as PfCDPK1 kinase inhibitors

Irfan¹,

Uddin

Jain

et al. 2022

Preprint

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To combat the emergence of drug resistance against the existing antimalarials, novel side chain containing 7-chloroquinoline-indole-chalcones tethered with a triazole (CQTrICh-analogs 7 (a-s) and 9) were designed and synthesized by reacting substituted 1-phenyl-3-(1-(prop-2-yn-1-yl)-1H-indol-3-yl) prop-2-en-1-one and 1-(prop-2-yn-1-yl)-1H-indole-3-carbaldehyde with 4-azido-7-chloroquinoline, respectively via a click reaction. The selected CQTrICh-analogs: 7l and 7r inhibited chloroquine-sensitive (3D7) and resistant (RKL-9) strains of Plasmodium falciparum, with IC50 values of 2.4 μM & 1.8 μM (7l), and 3.5 μM & 2.7 μM (7r), respectively, and showed insignificant hemolysis and cytotoxicity in mammalian cells. Intra-erythrocytic progression studies revealed that the active hybrids: 7l and 7r are effective against the mature stages of the parasite. Given the importance of Calcium-Dependent Protein Kinase 1 (PfCDPK1) in the parasite biology, notably during late schizogony and subsequent invasion of merozoites into host RBCs, we identified this protein as a possible molecular target of these active hybrids. In silico interaction analysis indicated that 7l and 7r stably interact with the catalytically active ATP-binding pocket of PfCDPK1, by the formation of energetically favorable H-bonds. Furthermore, in vitro Microscale Thermophoresis and kinase assays with recombinant PfCDPK1 demonstrated that the active hybrids interact with and inhibit the kinase activity, thus presumably responsible for the parasite growth inhibition. Interestingly, 7l and 7r showed no inhibitory effect on the human kinases, indicating that they are selective for the parasite kinase. Conceivably, we report the antiplasmodial potential of novel kinase targeting bio-conjugates, a step towards developing pan-kinase inhibitors, which is a prerequisite for cross-stage anti-malarial protection.

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New quinoline-5,8-dione and hydroxynaphthoquinone derivatives inhibit a chloroquine resistant Plasmodium falciparum strain

Cited by 21 publications

References 16 publications

In vitro antiplasmodial activity, pharmacokinetic profiles and interference in isoprenoid pathway of 2-aniline-3-hydroxy-1.4-naphthoquinone derivatives

In vitro antiplasmodial activity, pharmacokinetic profiles and interference in isoprenoid pathway of 2-aniline-3-hydroxy-1.4-naphthoquinone derivatives

5,8-Quinolinedione Scaffold as a Promising Moiety of Bioactive Agents

Biological evaluation of novel side chain containing CQTrICh-analogs as antimalarials and their development as PfCDPK1 kinase inhibitors

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