Alkyl Derivatives of Perylene Photosensitizing Antivirals:
Towards Understanding the Influence of Lipophilicity

J 2023

Alkyl Derivatives of Perylene Photosensitizing Antivirals: Towards Understanding the Influence of Lipophilicity

MIKHNOVETS, Igor E., Jiří HOLOUBEK, Irina S. PANINA, Jan KOTOUČEK, Daniil A. GVOZDEV et. al.

Basic information

Original name

Alkyl Derivatives of Perylene Photosensitizing Antivirals: Towards Understanding the Influence of Lipophilicity

Authors

MIKHNOVETS, Igor E., Jiří HOLOUBEK (203 Czech Republic, belonging to the institution), Irina S. PANINA, Jan KOTOUČEK, Daniil A. GVOZDEV, Stepan P. CHUMAKOV, Maxim S. KRASILNIKOV, Mikhail Y. ZHITLOV, Evgeny L. GULYAK, Alexey A. CHISTOV, Timofei D. NIKITIN, Vladimir A. KORSHUN, Roman G. EFREMOV, Vera A. ALFEROVA, Daniel RŮŽEK (203 Czech Republic, belonging to the institution), Luděk EYER (203 Czech Republic, belonging to the institution) and Alexey V. USTINOV

Edition

International Journal of Molecular Sciences, MDPI, 2023, 1661-6596

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

10607 Virology

Country of publisher

Switzerland

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 5.600 in 2022

RIV identification code

RIV/00216224:14310/23:00132548

Organization unit

Faculty of Science

DOI

http://dx.doi.org/10.3390/ijms242216483

UT WoS

001113794700001

Keywords (in Czech)

virus; antivirotika; peryleny; fotodynamický účinek; herpes virus

Keywords in English

antivirals; perylene; photosensitizers; singlet oxygen; lipophilicity

Abstract

V originále

Amphipathic perylene derivatives are broad-spectrum antivirals against enveloped viruses that act as fusion inhibitors in a light-dependent manner. The compounds target the lipid bilayer of the viral envelope using the lipophilic perylene moiety and photogenerating singlet oxygen, thereby causing damage to unsaturated lipids. Previous studies show that variation of the polar part of the molecule is important for antiviral activity. Here, we report modification of the lipophilic part of the molecule, perylene, by the introduction of 4-, 8-, and 12-carbon alkyls into position 9(10) of the perylene residue. Using Friedel–Crafts acylation and Wolff–Kishner reduction, three 3-acetyl-9(10)-alkylperylenes were synthesized from perylene and used to prepare 9 nucleoside and 12 non-nucleoside amphipathic derivatives. These compounds were characterized as fluorophores and singlet oxygen generators, as well as tested as antivirals against herpes virus-1 (HSV-1) and vesicular stomatitis virus (VSV), both known for causing superficial skin/mucosa lesions and thus serving as suitable candidates for photodynamic therapy. The results suggest that derivatives with a short alkyl chain (butyl) have strong antiviral activity, whereas the introduction of longer alkyl substituents (n = 8 and 12) to the perylenyethynyl scaffold results in a dramatic reduction of antiviral activity. This phenomenon is likely attributable to the increased lipophilicity of the compounds and their ability to form insoluble aggregates. Moreover, molecular dynamic studies revealed that alkylated perylene derivatives are predominately located closer to the middle of the bilayer compared to non-alkylated derivatives. The predicted probability of superficial positioning correlated with antiviral activity, suggesting that singlet oxygen generation is achieved in the subsurface layer of the membrane, where the perylene group is more accessible to dissolved oxygen.

Citovat

MIKHNOVETS, Igor E., Jiří HOLOUBEK, Irina S. PANINA, Jan KOTOUČEK, Daniil A. GVOZDEV, Stepan P. CHUMAKOV, Maxim S. KRASILNIKOV, Mikhail Y. ZHITLOV, Evgeny L. GULYAK, Alexey A. CHISTOV, Timofei D. NIKITIN, Vladimir A. KORSHUN, Roman G. EFREMOV, Vera A. ALFEROVA, Daniel RŮŽEK, Luděk EYER and Alexey V. USTINOV. Alkyl Derivatives of Perylene Photosensitizing Antivirals: Towards Understanding the Influence of Lipophilicity. International Journal of Molecular Sciences. MDPI, 2023, vol. 24, No 22, p. 1-37. ISSN 1661-6596. Available from: https://dx.doi.org/10.3390/ijms242216483.

@article{2350361,
   author = {Mikhnovets, Igor E. and Holoubek, Jiří and Panina, Irina S. and Kotouček, Jan and Gvozdev, Daniil A. and Chumakov, Stepan P. and Krasilnikov, Maxim S. and Zhitlov, Mikhail Y. and Gulyak, Evgeny L. and Chistov, Alexey A. and Nikitin, Timofei D. and Korshun, Vladimir A. and Efremov, Roman G. and Alferova, Vera A. and Růžek, Daniel and Eyer, Luděk and Ustinov, Alexey V.},
   article_number = {22},
   doi = {http://dx.doi.org/10.3390/ijms242216483},
   keywords = {antivirals; perylene; photosensitizers; singlet oxygen; lipophilicity},
   language = {eng},
   issn = {1661-6596},
   journal = {International Journal of Molecular Sciences},
   title = {Alkyl Derivatives of Perylene Photosensitizing Antivirals: Towards Understanding the Influence of Lipophilicity},
   url = {https://www.mdpi.com/1422-0067/24/22/16483},
   volume = {24},
   year = {2023}
}

TY  - JOUR
ID  - 2350361
AU  - Mikhnovets, Igor E. - Holoubek, Jiří - Panina, Irina S. - Kotouček, Jan - Gvozdev, Daniil A. - Chumakov, Stepan P. - Krasilnikov, Maxim S. - Zhitlov, Mikhail Y. - Gulyak, Evgeny L. - Chistov, Alexey A. - Nikitin, Timofei D. - Korshun, Vladimir A. - Efremov, Roman G. - Alferova, Vera A. - Růžek, Daniel - Eyer, Luděk - Ustinov, Alexey V.
PY  - 2023
TI  - Alkyl Derivatives of Perylene Photosensitizing Antivirals: Towards Understanding the Influence of Lipophilicity
JF  - International Journal of Molecular Sciences
VL  - 24
IS  - 22
SP  - 1-37
EP  - 1-37
PB  - MDPI
SN  - 16616596
KW  - antivirals
KW  - perylene
KW  - photosensitizers
KW  - singlet oxygen
KW  - lipophilicity
UR  - https://www.mdpi.com/1422-0067/24/22/16483
N2  - Amphipathic perylene derivatives are broad-spectrum antivirals against enveloped viruses that act as fusion inhibitors in a light-dependent manner. The compounds target the lipid bilayer of the viral envelope using the lipophilic perylene moiety and photogenerating singlet oxygen, thereby causing damage to unsaturated lipids. Previous studies show that variation of the polar part of the molecule is important for antiviral activity. Here, we report modification of the lipophilic part of the molecule, perylene, by the introduction of 4-, 8-, and 12-carbon alkyls into position 9(10) of the perylene residue. Using Friedel–Crafts acylation and Wolff–Kishner reduction, three 3-acetyl-9(10)-alkylperylenes were synthesized from perylene and used to prepare 9 nucleoside and 12 non-nucleoside amphipathic derivatives. These compounds were characterized as fluorophores and singlet oxygen generators, as well as tested as antivirals against herpes virus-1 (HSV-1) and vesicular stomatitis virus (VSV), both known for causing superficial skin/mucosa lesions and thus serving as suitable candidates for photodynamic therapy. The results suggest that derivatives with a short alkyl chain (butyl) have strong antiviral activity, whereas the introduction of longer alkyl substituents (n = 8 and 12) to the perylenyethynyl scaffold results in a dramatic reduction of antiviral activity. This phenomenon is likely attributable to the increased lipophilicity of the compounds and their ability to form insoluble aggregates. Moreover, molecular dynamic studies revealed that alkylated perylene derivatives are predominately located closer to the middle of the bilayer compared to non-alkylated derivatives. The predicted probability of superficial positioning correlated with antiviral activity, suggesting that singlet oxygen generation is achieved in the subsurface layer of the membrane, where the perylene group is more accessible to dissolved oxygen.
ER  -

MIKHNOVETS, Igor E., Jiří HOLOUBEK, Irina S. PANINA, Jan KOTOUČEK, Daniil A. GVOZDEV, Stepan P. CHUMAKOV, Maxim S. KRASILNIKOV, Mikhail Y. ZHITLOV, Evgeny L. GULYAK, Alexey A. CHISTOV, Timofei D. NIKITIN, Vladimir A. KORSHUN, Roman G. EFREMOV, Vera A. ALFEROVA, Daniel RŮŽEK, Luděk EYER and Alexey V. USTINOV. Alkyl Derivatives of Perylene Photosensitizing Antivirals: Towards Understanding the Influence of Lipophilicity. \textit{International Journal of Molecular Sciences}. MDPI, 2023, vol.~24, No~22, p.~1-37. ISSN~1661-6596. Available from: https://dx.doi.org/10.3390/ijms242216483.

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