Rational Design of New Monoterpene-Containing Azoles and Their Antifungal Activity
Azole antifungals, including fluconazole, have long been the first-line antifungal agents in the fight against fungal infections. The emergence of drug-resistant strains and the associated increase in mortality from systemic mycoses has prompted the development of new agents based on azoles. We repo...
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| Format: | Article |
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MDPI AG
2023-04-01
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| Series: | Antibiotics |
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| Online Access: | https://www.mdpi.com/2079-6382/12/5/818 |
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| author | Nikolai S. Li-Zhulanov Nadezhda P. Zaikova Suat Sari Dolunay Gülmez Suna Sabuncuoğlu Keriman Ozadali-Sari Sevtap Arikan-Akdagli Andrey A. Nefedov Tatyana V. Rybalova Konstantin P. Volcho Nariman F. Salakhutdinov |
| author_facet | Nikolai S. Li-Zhulanov Nadezhda P. Zaikova Suat Sari Dolunay Gülmez Suna Sabuncuoğlu Keriman Ozadali-Sari Sevtap Arikan-Akdagli Andrey A. Nefedov Tatyana V. Rybalova Konstantin P. Volcho Nariman F. Salakhutdinov |
| author_sort | Nikolai S. Li-Zhulanov |
| collection | DOAJ |
| description | Azole antifungals, including fluconazole, have long been the first-line antifungal agents in the fight against fungal infections. The emergence of drug-resistant strains and the associated increase in mortality from systemic mycoses has prompted the development of new agents based on azoles. We reported a synthesis of novel monoterpene-containing azoles with high antifungal activity and low cytotoxicity. These hybrids demonstrated broad-spectrum activity against all tested fungal strains, with excellent minimum inhibitory concentration (MIC) values against both fluconazole-susceptible and fluconazole-resistant strains of <i>Candida</i> spp. Compounds <b>10a</b> and <b>10c</b> with cuminyl and pinenyl fragments demonstrated up to 100 times lower MICs than fluconazole against clinical isolates. The results indicated that the monoterpene-containing azoles had much lower MICs against fluconazole-resistant clinical isolates of <i>Candida parapsilosis</i> than their phenyl-containing counterpart. In addition, the compounds did not exhibit cytotoxicity at active concentrations in the MTT assay, indicating potential for further development as antifungal agents. |
| first_indexed | 2024-03-11T04:00:20Z |
| format | Article |
| id | doaj.art-213ab024b8e348f0b979f76e52e7d28d |
| institution | Directory Open Access Journal |
| issn | 2079-6382 |
| language | English |
| last_indexed | 2024-03-11T04:00:20Z |
| publishDate | 2023-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antibiotics |
| spelling | doaj.art-213ab024b8e348f0b979f76e52e7d28d2023-11-18T00:11:43ZengMDPI AGAntibiotics2079-63822023-04-0112581810.3390/antibiotics12050818Rational Design of New Monoterpene-Containing Azoles and Their Antifungal ActivityNikolai S. Li-Zhulanov0Nadezhda P. Zaikova1Suat Sari2Dolunay Gülmez3Suna Sabuncuoğlu4Keriman Ozadali-Sari5Sevtap Arikan-Akdagli6Andrey A. Nefedov7Tatyana V. Rybalova8Konstantin P. Volcho9Nariman F. Salakhutdinov10N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, Lavrentiev Ave., 9, 630090 Novosibirsk, RussiaN. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, Lavrentiev Ave., 9, 630090 Novosibirsk, RussiaDepartment of Pharmaceutical Chemistry, Hacettepe University Faculty of Pharmacy, Sihhiye, Ankara 06100, TurkeyDepartment of Medical Microbiology, Hacettepe University Faculty of Medicine, Sihhiye, Ankara 06100, TurkeyDepartment of Pharmaceutical Toxicology, Hacettepe University Faculty of Pharmacy, Sihhiye, Ankara 06100, TurkeyDepartment of Pharmaceutical Chemistry, Hacettepe University Faculty of Pharmacy, Sihhiye, Ankara 06100, TurkeyDepartment of Medical Microbiology, Hacettepe University Faculty of Medicine, Sihhiye, Ankara 06100, TurkeyN. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, Lavrentiev Ave., 9, 630090 Novosibirsk, RussiaN. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, Lavrentiev Ave., 9, 630090 Novosibirsk, RussiaN. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, Lavrentiev Ave., 9, 630090 Novosibirsk, RussiaN. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, Lavrentiev Ave., 9, 630090 Novosibirsk, RussiaAzole antifungals, including fluconazole, have long been the first-line antifungal agents in the fight against fungal infections. The emergence of drug-resistant strains and the associated increase in mortality from systemic mycoses has prompted the development of new agents based on azoles. We reported a synthesis of novel monoterpene-containing azoles with high antifungal activity and low cytotoxicity. These hybrids demonstrated broad-spectrum activity against all tested fungal strains, with excellent minimum inhibitory concentration (MIC) values against both fluconazole-susceptible and fluconazole-resistant strains of <i>Candida</i> spp. Compounds <b>10a</b> and <b>10c</b> with cuminyl and pinenyl fragments demonstrated up to 100 times lower MICs than fluconazole against clinical isolates. The results indicated that the monoterpene-containing azoles had much lower MICs against fluconazole-resistant clinical isolates of <i>Candida parapsilosis</i> than their phenyl-containing counterpart. In addition, the compounds did not exhibit cytotoxicity at active concentrations in the MTT assay, indicating potential for further development as antifungal agents.https://www.mdpi.com/2079-6382/12/5/818triazole antifungalsmonoterpenoidshybridsclinical isolatesCYP51<i>Candida</i> spp. |
| spellingShingle | Nikolai S. Li-Zhulanov Nadezhda P. Zaikova Suat Sari Dolunay Gülmez Suna Sabuncuoğlu Keriman Ozadali-Sari Sevtap Arikan-Akdagli Andrey A. Nefedov Tatyana V. Rybalova Konstantin P. Volcho Nariman F. Salakhutdinov Rational Design of New Monoterpene-Containing Azoles and Their Antifungal Activity Antibiotics triazole antifungals monoterpenoids hybrids clinical isolates CYP51 <i>Candida</i> spp. |
| title | Rational Design of New Monoterpene-Containing Azoles and Their Antifungal Activity |
| title_full | Rational Design of New Monoterpene-Containing Azoles and Their Antifungal Activity |
| title_fullStr | Rational Design of New Monoterpene-Containing Azoles and Their Antifungal Activity |
| title_full_unstemmed | Rational Design of New Monoterpene-Containing Azoles and Their Antifungal Activity |
| title_short | Rational Design of New Monoterpene-Containing Azoles and Their Antifungal Activity |
| title_sort | rational design of new monoterpene containing azoles and their antifungal activity |
| topic | triazole antifungals monoterpenoids hybrids clinical isolates CYP51 <i>Candida</i> spp. |
| url | https://www.mdpi.com/2079-6382/12/5/818 |
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