Acridine and Acridinones: Old and New Structures with Antimalarial Activity

Valdés, Aymé Fernández-Calienes

doi:10.2174/1874104501105010011

Cited by 76 publications

(45 citation statements)

References 58 publications

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“…The resistance in the FOS r is due to an increase in the copy number of the Pfdxr gene, which encodes the enzyme targeted by FOS, allowing the parasite to overcome FOS-mediated inhibition of isoprenoid biosynthesis (22). Intriguingly, whereas FOS showed a 4-fold increase in the IC 50 for the FOS r , relative to its parental strain Dd2, MMV008138 exhibited no increase in its IC 50 against FOS r ( Table 1, compare Dd2 and FOS r IC 50 s at 72 h). T. gondii is an apicomplexan parasite that, like P. falciparum, harbors an apicoplast that is essential for survival of the parasite.…”

Section: Resultsmentioning

confidence: 99%

“…Ten-point dilutions were used to test the dose responses at concentrations ranging from 5 M to 0.002 M. The IC 50 calculation was performed with GraFit 5 (Erithacus Software Ltd.) using nonlinear regression curve fitting and represents the average of two independent experiments and the standard deviation (SD). We determined the IC 50 (8). We assessed whether compounds from the Malaria Box were targeting the apicoplast by measuring their growth recoveries in the presence of inhibitor and IPP as described previously (8).…”

Section: Methodsmentioning

confidence: 99%

“…The in vitro antimalarial activities of the Malaria Box compounds span a range of 50% inhibitory concentration (IC 50 ) values from 30 nM to 4 M (2). The 400 compounds in the Malaria Box were selected based on several factors, including low toxicity, oral bioavailability, and chemical diversity; however, the primary selection was based on their commercial availability to ensure accessibility for follow-up experiments (2).…”

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confidence: 99%

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Antiapicoplast and Gametocytocidal Screening To Identify the Mechanisms of Action of Compounds within the Malaria Box

Bowman

Merino

Brooks

et al. 2014

Antimicrob Agents Chemother

129

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cMalaria remains a significant infectious disease that causes millions of clinical cases and >800,000 deaths per year. The Malaria Box is a collection of 400 commercially available chemical entities that have antimalarial activity. The collection contains 200 drug-like compounds, based on their oral absorption and the presence of known toxicophores, and 200 probe-like compounds, which are intended to represent a broad structural diversity. These compounds have confirmed activities against the asexual intraerythrocytic stages of Plasmodium falciparum and low cytotoxicities, but their mechanisms of action and their activities in other stages of the parasite's life cycle remain to be determined. The apicoplast is considered to be a promising source of malaria-specific targets, and its main function during intraerythrocytic stages is to provide the isoprenoid precursor isopentenyl diphosphate, which can be used for phenotype-based screens to identify compounds targeting this organelle. We screened 400 compounds from the Malaria Box using apicoplast-targeting phenotypic assays to identify their potential mechanisms of action. We identified one compound that specifically targeted the apicoplast. Further analyses indicated that the molecular target of this compound may differ from those of the current antiapicoplast drugs, such as fosmidomycin. Moreover, in our efforts to elucidate the mechanisms of action of compounds from the Malaria Box, we evaluated their activities against other stages of the life cycle of the parasite. Gametocytes are the transmission stage of the malaria parasite and are recognized as a priority target in efforts to eradicate malaria. We identified 12 compounds that were active against gametocytes with 50% inhibitory concentration values of <1 M.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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confidence: 99%

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Antiapicoplast and Gametocytocidal Screening To Identify the Mechanisms of Action of Compounds within the Malaria Box

Bowman

Merino

Brooks

et al. 2014

Antimicrob Agents Chemother

129

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“…Still, compounds 6 are active against Plasmodium, and this may be due to one of the other mechanisms earlier proposed for acridines with antimalarial activity, such as inhibition of mitochondrial bc1 complex or DNA Topoisomerase II, and interaction with DNA. 12 Therefore, it would be interesting to explore, in further studies, if the acridine derivatives 6 act through any of Table 1 In vitro data on compounds 6 for their blood-and liver-stage antimalarial activity…”

Section: Introductionmentioning

confidence: 99%

In vitro efficiency of 9-(N-cinnamoylbutyl)aminoacridines against blood- and liver-stage malaria parasites

Pérez

Teixeira

Gomes

et al. 2013

Bioorganic & Medicinal Chemistry Letters

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a b s t r a c tNovel 9-aminoacridine derivatives were synthesized by linking the heteroaromatic core to different cinnamic acids through an aminobutyl chain. The test compounds demonstrated mid-nanomolar in vitro activity against erythrocytic stages of the chloroquine-resistant W2 strain of the human malaria parasite Plasmodium falciparum. Two of the most active derivatives also showed in vitro activity against liver-stage Plasmodium berghei, with activity greater than that of the reference liver-stage antimalarial primaquine.The compounds were not toxic to human hepatoma cells at concentrations up to 5 lM. Hence, 9-(N-cinnamoylbutyl)aminoacridines are a new class of leads for prevention and treatment of malaria.

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“…There are numerous functions of the acridone nucleus in addition to its derivatives that have been reported in previous studies, including anticancer (13-16), anti-herpes (17), anti-malarial (18,19), antivirus (20), anti-allergy (21) and anti-leishmanial (22) activities. These features are attributed to the semi planar heterocyclic structure, which interacts with different biomolecular targets.…”

Section: Discussionmentioning

confidence: 98%

Acridone suppresses the proliferation of human breast cancer cells inï¿½vitro via ATP-binding cassette subfamily G member 2

Liu

et al. 2017

Oncol Lett

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Abstract. In the past decades, the tricyclic acridone ring system has become a focus of major research by medicinal chemists due to the biological significance of this moiety in drug design and discovery. Acridone has substantial bio-potential since it performs crucial functions, including antibacterial, antimalarial, antiviral and anti-neoplastic activities. However, the anticancer effect and the underlying mechanisms of acridone on breast cancer cells remains unclear. In the present study, the anti-tumor function and the underlying mechanisms of acridone were evaluated in vitro. Firstly, an MTT assay was used to evaluate the inhibitory effect of acridone. Subsequently, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to investigate whether ATP binding cassette subfamily G member 2 (ABCG2) was associated with the function of acridone. Finally, western blotting was used to confirm the results of RT-qPCR. The present study demonstrated that acridone may decrease the proliferation of MDA-MB-231 cells dose-dependently. Further experiments revealed that acridone may downregulate the mRNA and protein expression levels of ABCG2, supporting the potential application of acridone in breast cancer treatment. These findings suggested that acridone is a potential agent in the treatment of human breast cancer.

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Acridine and Acridinones: Old and New Structures with Antimalarial Activity

Cited by 76 publications

References 58 publications

Antiapicoplast and Gametocytocidal Screening To Identify the Mechanisms of Action of Compounds within the Malaria Box

Antiapicoplast and Gametocytocidal Screening To Identify the Mechanisms of Action of Compounds within the Malaria Box

In vitro efficiency of 9-(N-cinnamoylbutyl)aminoacridines against blood- and liver-stage malaria parasites

Acridone suppresses the proliferation of human breast cancer cells inï¿½vitro via ATP-binding cassette subfamily G member 2

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