New spiroacridine derivatives with DNA-binding and topoisomerase I inhibition activity

Sabolová, Danica; Vilková, Mária; Imrich, Ján; Potočňák, Ivan

doi:10.1016/j.tetlet.2016.10.108

Cited by 10 publications

(3 citation statements)

References 19 publications

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“…They can be reduced to several synthetically important compounds such as β-hydroxy ketones, β-hydroxy esters, α,β-unsaturated carbonyl compounds or iminoketones [ 5 , 6 ]. Cycloadditions with monosubstituted alkenes proceed rapidly and regioselectively [ 7 , 8 , 9 , 10 ]. On the other hand, the reaction of nitrile oxides with non-activated 1,2-disubstituted alkenes tends to be slower and usually affords mixtures of regio- and stereoisomers.…”

Section: Introductionmentioning

confidence: 99%

Spectral Assignment in the [3 + 2] Cycloadditions of Methyl (2E)-3-(Acridin-4-yl)-prop-2-enoate and 4-[(E)-2-Phenylethenyl]acridin with Unstable Nitrile N-Oxides

Maľučká,

Vilková

2024

Molecules

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The investigation of cycloaddition reactions involving acridine-based dipolarophiles revealed distinct regioselectivity patterns influenced mainly by the electronic factor. Specifically, the reactions of methyl-(2E)-3-(acridin-4-yl)-prop-2-enoate and 4-[(1E)-2-phenylethenyl]acridine with unstable benzonitrile N-oxides were studied. For methyl-(2E)-3-(acridin-4-yl)-prop-2-enoate, the formation of two regioisomers favoured the 5-(acridin-4-yl)-4,5-dihydro-1,2-oxazole-4-carboxylates, with remarkable exclusivity in the case of 4-methoxybenzonitrile oxide. Conversely, 4-[(1E)-2-phenylethenyl]acridine displayed reversed regioselectivity, favouring products 4-[3-(substituted phenyl)-5-phenyl-4,5-dihydro-1,2-oxazol-4-yl]acridine. Subsequent hydrolysis of isolated methyl 5-(acridin-4-yl)-3-phenyl-4,5-dihydro-1,2-oxazole-4-carboxylates resulted in the production of carboxylic acids, with nearly complete conversion. During NMR measurements of carboxylic acids in CDCl3, decarboxylation was observed, indicating the formation of a new prochiral carbon centre C-4, further confirmed by a noticeable colour change. Overall, this investigation provides valuable insights into regioselectivity in cycloaddition reactions and subsequent transformations, suggesting potential applications across diverse scientific domains.

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Section: Introductionmentioning

confidence: 99%

Spectral Assignment in the [3 + 2] Cycloadditions of Methyl (2E)-3-(Acridin-4-yl)-prop-2-enoate and 4-[(E)-2-Phenylethenyl]acridin with Unstable Nitrile N-Oxides

Maľučká,

Vilková

2024

Molecules

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“…These derivatives display good potential against a variety of therapeutic targets, as these compounds show antiparasitic, antiviral, antibacterial, and antitumor activities 17 – 19 . These effects are usually linked to the inhibition of DNA replication, since these compounds can inhibit type I and II topoisomerase, and telomerases 20 . However, the potential activity of acridine derivatives against other potential targets still needs to be addressed.…”

Section: Introductionmentioning

confidence: 99%

Scaffold repositioning of spiro-acridine derivatives as fungi chitinase inhibitor by target fishing and in vitro studies

Viana

Souza

Sbaraini

et al. 2023

Sci Rep

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The concept of “one target, one drug, one disease” is not always true, as compounds with previously described therapeutic applications can be useful to treat other maladies. For example, acridine derivatives have several potential therapeutic applications. In this way, identifying new potential targets for available drugs is crucial for the rational management of diseases. Computational methodologies are interesting tools in this field, as they use rational and direct methods. Thus, this study focused on identifying other rational targets for acridine derivatives by employing inverse virtual screening (IVS). This analysis revealed that chitinase enzymes can be potential targets for these compounds. Subsequently, we coupled molecular docking consensus analysis to screen the best chitinase inhibitor among acridine derivatives. We observed that 3 compounds displayed potential enhanced activity as fungal chitinase inhibitors, showing that compound 5 is the most active molecule, with an IC50 of 0.6 ng/µL. In addition, this compound demonstrated a good interaction with the active site of chitinases from Aspergillus fumigatus and Trichoderma harzianum. Additionally, molecular dynamics and free energy demonstrated complex stability for compound 5. Therefore, this study recommends IVS as a powerful tool for drug development. The potential applications are highlighted as this is the first report of spiro-acridine derivatives acting as chitinase inhibitors that can be potentially used as antifungal and antibacterial candidates.

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“…These derivatives display good potential against a variety of therapeutic targets, as these compounds show antiparasitic, antiviral, antibacterial, and antitumor activities [16][17][18]. These effects are usually linked to the inhibition of DNA replication, since these compounds can inhibit type I and II topoisomerase, and telomerases [19].…”

Section: Introductionmentioning

confidence: 99%

Identification of spiro-acridine derivatives as fungi chitinase inhibitor by target fishing and in vitro studies

Viana

Souza

Sbaraini

et al. 2022

Preprint

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The concept of “one target, one drug, one disease” is not always true, as compounds with previously described therapeutic applications can be useful to treat other maladies. Acridine derivatives have several potential therapeutic applications. In this way, identifying new potential targets for available drugs is crucial for the rational management of diseases. Computational methodologies are interesting tools in this field, using rational and direct methods. Thus, this study focused on identifying other rational targets for acridine derivatives by employing inverse virtual screening (IVS). This analysis revealed that chitinase enzymes can be potential targets for these compounds. Subsequently, we coupled molecular docking consensus analysis to screen the best chitinase inhibitor among the acridine derivatives. We observed that 3 compounds displayed potential enhanced activity as fungal chitinase inhibitors, showing that compound 5 is the most active molecule, with an IC50 of 0.07 µg. In addition, this compound demonstrated a good interaction with the active site of chitinases from Aspergillus fumigatus and Trichoderma harzianum. Therefore, this study recommends IVS as a powerful tool for drug development. The potential applications are highlighted as this is the first report of spiro-acridine derivatives acting as chitinase inhibitors that can be potentially used as antifungal and antibacterial candidates.

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New spiroacridine derivatives with DNA-binding and topoisomerase I inhibition activity

Cited by 10 publications

References 19 publications

Spectral Assignment in the [3 + 2] Cycloadditions of Methyl (2E)-3-(Acridin-4-yl)-prop-2-enoate and 4-[(E)-2-Phenylethenyl]acridin with Unstable Nitrile N-Oxides

Spectral Assignment in the [3 + 2] Cycloadditions of Methyl (2E)-3-(Acridin-4-yl)-prop-2-enoate and 4-[(E)-2-Phenylethenyl]acridin with Unstable Nitrile N-Oxides

Scaffold repositioning of spiro-acridine derivatives as fungi chitinase inhibitor by target fishing and in vitro studies

Identification of spiro-acridine derivatives as fungi chitinase inhibitor by target fishing and in vitro studies

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