A new 1-nitro-9-aminoacridine derivative targeting yeast topoisomerase II able to overcome fluconazole-resistance

Rząd, Kamila; Paluszkiewicz, Ewa; Gabriel, Iwona

doi:10.1016/j.bmcl.2021.127815

Cited by 7 publications

(15 citation statements)

References 54 publications

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“…1-Nitro-9-aminoacridine derivative Capridine β, 9[2′-hydroxyethylamino]-4-methyl-1-nitroacridine (also known as C-1748) ( Figure 1), similar to m-AMSA, exhibited anticancer and antifungal properties [14][15][16]. Moreover, previous studies, performed for Capridine β in cancer cell cultures and human xenograft animal models indicated a high therapeutic index and low cytotoxicity with the potential for clinical development [14,15,[17][18][19].…”

Section: Introductionmentioning

confidence: 94%

“…As Capridine β antifungal activity has been previously observed [16], we have decided to analyze the m-AMSA in vitro antifungal activity against five corresponding strains. Minimal inhibitory concentrations (MICs) of the studied compounds determined by the microplate serial dilution method are shown in Table 1.…”

Section: Antifungal Activitymentioning

confidence: 99%

“…Both compounds, m-AMSA, as well as Capridine β, contain an acridine chromophore ( Figure 1). Due to the fact that m-AMSA, a 9-aminoacridine derivative, is a human topoisomerase II poison and has been shown to have a moderate inhibitory effect on fungal topoisomerase II [11] along with a high therapeutic index, low cytotoxicity of Capridine β [14,15,[17][18][19], antifungal activity [16], and acridine chromophore similarity to m-AMSA, we have decided to deeply analyze its antifungal potential as well as mechanism of action.…”

Section: Introductionmentioning

confidence: 99%

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Antifungal Activity of Capridine β as a Consequence of Its Biotransformation into Metabolite Affecting Yeast Topoisomerase II Activity

et al. 2021

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In the last few years, increasing importance is attached to problems caused by fungal pathogens. Current methods of preventing fungal infections remain unsatisfactory. There are several antifungal compounds which are highly effective in some cases, however, they have limitations in usage: Nephrotoxicity and other adverse effects. In addition, the frequent use of available fungistatic drugs promotes drug resistance. Therefore, there is an urgent need for the development of a novel antifungal drug with a different mechanism of action, blocking of the fungal DNA topoisomerases activity appear to be a promising idea. According to previous studies on the m-AMSA moderate inhibitory effect on fungal topoisomerase II, we have decided to study Capridine β (also acridine derivative) antifungal activity, as well as its inhibitory potential on yeast topoisomerase II (yTOPOII). Results indicated that Capridine β antifungal activity depends on the kind of strains analyzed (MICs range 0.5–64 μg mL−1) and is related to its biotransformation in the cells. An investigation of metabolite formation, identified as Capridine β reduction product (IE1) by the fungus Candida albicans was performed. IE1 exhibited no activity against fungal cells due to an inability to enter the cells. Although no antifungal activity was observed, in contrast to Capridine β, biotransformation metabolite totally inhibited the yTOPOII-mediated relaxation at concentrations lower than detected for m-AMSA. The closely related Capridine β only slightly diminished the catalytic activity of yTOPOII.

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Section: Introductionmentioning

confidence: 94%

Section: Antifungal Activitymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Antifungal Activity of Capridine β as a Consequence of Its Biotransformation into Metabolite Affecting Yeast Topoisomerase II Activity

et al. 2021

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“…Concerning their mode of action, these compounds are able to render DNA damage, disrupt DNA repair and replication, inhibit topoisomerase I and II enzymes [1], and induce cell death [2]. A lot of derivatives have been obtained with antitumor, antibacterial, and antifungal activity [3][4][5][6][7]. As far as antimicrobial activity is concerned in many cases, their application is limited and excluded because of transport inefficiency.…”

Section: Introductionmentioning

confidence: 99%

“…The differences between fungal and human topoisomerases have also led to the suggestion that this class of enzymes may be potential targets for the development of novel antifungal agents [23,24]. Our previously published data indicate that yeast topoisomerase II's relaxation ability has been effectively inhibited by an acridine derivative with antifungal activity [7].…”

Section: Introductionmentioning

confidence: 99%

The Effect of Conjugation with Octaarginine, a Cell-Penetrating Peptide on Antifungal Activity of Imidazoacridinone Derivative

Rząd

Paluszkiewicz

Neubauer

et al. 2021

IJMS

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Acridine cell-penetrating peptide conjugates are an extremely important family of compounds in antitumor chemotherapy. These conjugates are not so widely analysed in antimicrobial therapy, although bioactive peptides could be used as nanocarriers to smuggle antimicrobial compounds. An octaarginine conjugate of an imidazoacridinone derivative (Compound 1-R8) synthetized by us exhibited high antifungal activity against reference and fluconazole-resistant clinical strains (MICs ≤ 4 μg mL−1). Our results clearly demonstrate the qualitative difference in accumulation of the mother compound and Compound 1-R8 conjugate into fungal cells. Only the latter was transported and accumulated effectively. Microscopic and flow cytometry analysis provide some evidence that the killing activity of Compound 1-R8 may be associated with a change in the permeability of the fungal cell membrane. The conjugate exhibited low cytotoxicity against human embryonic kidney (HEK-293) and human liver (HEPG2) cancer cell lines. Nevertheless, the selectivity index value of the conjugate for human pathogenic strains remained favourable and no hemolytic activity was observed. The inhibitory effect of the analysed compound on yeast topoisomerase II activity suggested its molecular target. In summary, conjugation with R8 effectively increased imidazoacridinone derivative ability to enter the fungal cell and achieve a concentration inside the cell that resulted in a high antifungal effect.

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Preparation and characterization of Gum Arabic Schiff's bases based on 9-aminoacridine with in vitro evaluation of their antimicrobial and antitumor potentiality

El-Sayed

Hashem

Kamel

2022

Carbohydrate Polymers

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A new 1-nitro-9-aminoacridine derivative targeting yeast topoisomerase II able to overcome fluconazole-resistance

Cited by 7 publications

References 54 publications

Antifungal Activity of Capridine β as a Consequence of Its Biotransformation into Metabolite Affecting Yeast Topoisomerase II Activity

Antifungal Activity of Capridine β as a Consequence of Its Biotransformation into Metabolite Affecting Yeast Topoisomerase II Activity

The Effect of Conjugation with Octaarginine, a Cell-Penetrating Peptide on Antifungal Activity of Imidazoacridinone Derivative

Preparation and characterization of Gum Arabic Schiff's bases based on 9-aminoacridine with in vitro evaluation of their antimicrobial and antitumor potentiality

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