Mechanism Insight of Cell Death Signaling by Thymol Derivatives on Trypanosomatidae Protozoan Parasites
Leishmaniasis and Chagas disease are parasitic diseases considered to be among the most important neglected diseases, with implications for both developed and developing countries. Currently, there are no effective therapeutic treatments for these diseases due to challenges in drug administration, h...
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MDPI AG
2025-04-01
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| Series: | Antibiotics |
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| Online Access: | https://www.mdpi.com/2079-6382/14/4/383 |
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| author | Amani Omrani Meriam Ben Youssef Ines Sifaoui Eduardo Hernández-Álvarez Carlos J. Bethencourt-Estrella Isabel L. Bazzocchi Hichem Sebai Jacob Lorenzo-Morales Ignacio A. Jiménez José E. Piñero |
| author_facet | Amani Omrani Meriam Ben Youssef Ines Sifaoui Eduardo Hernández-Álvarez Carlos J. Bethencourt-Estrella Isabel L. Bazzocchi Hichem Sebai Jacob Lorenzo-Morales Ignacio A. Jiménez José E. Piñero |
| author_sort | Amani Omrani |
| collection | DOAJ |
| description | Leishmaniasis and Chagas disease are parasitic diseases considered to be among the most important neglected diseases, with implications for both developed and developing countries. Currently, there are no effective therapeutic treatments for these diseases due to challenges in drug administration, high toxicity, high costs, and drug resistance. In this study, a series of eleven thymol derivatives were designed, synthesized, and evaluated for their in vitro kinetoplastid activity against <i>Leishmania amazonensis</i> and <i>Trypanosoma cruzi</i>, as well as their cytotoxicity against a murine macrophage cell line. The most active compounds, thymol anysoate (<b>9</b>) and thymol picolinate (<b>10</b>), displayed the highest kinetoplastid activity with IC<sub>50</sub> values of 22.87 and 25.16 µM against <i>L. amazonensis</i> and <i>T. cruzi</i>, respectively. Notably, both compounds demonstrated an excellent selectivity index against the mammal cell line. Structure–activity relationship studies revealed that the ester group plays a crucial role in activity. The most promising derivatives, <b>9</b> and <b>10</b>, activate autophagy and apoptosis-like processes in the treated cells. Atomic force microscopy observations showed that derivative <b>9</b> induces the formation of cytoplasmic vacuoles, indicating an autophagic process, and drug-likeness analysis revealed that it meets all the pharmacokinetic criteria. Overall, these results highlight derivative <b>9</b> as a potential lead compound for the development of new drugs for the treatment of Trypanosomatidae infections and warrants further studies to elucidate the cell death cascade involved. |
| format | Article |
| id | doaj-art-d6872f447608449b83a4f01abd48d93f |
| institution | OA Journals |
| issn | 2079-6382 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antibiotics |
| spelling | doaj-art-d6872f447608449b83a4f01abd48d93f2025-08-20T02:17:25ZengMDPI AGAntibiotics2079-63822025-04-0114438310.3390/antibiotics14040383Mechanism Insight of Cell Death Signaling by Thymol Derivatives on Trypanosomatidae Protozoan ParasitesAmani Omrani0Meriam Ben Youssef1Ines Sifaoui2Eduardo Hernández-Álvarez3Carlos J. Bethencourt-Estrella4Isabel L. Bazzocchi5Hichem Sebai6Jacob Lorenzo-Morales7Ignacio A. Jiménez8José E. Piñero9Instituto Universitario de Enfermedades Tropicales y Salud Pública de Canarias, Universidad de La Laguna, 38296 La Laguna, Tenerife, SpainInstituto Universitario de Enfermedades Tropicales y Salud Pública de Canarias, Universidad de La Laguna, 38296 La Laguna, Tenerife, SpainInstituto Universitario de Enfermedades Tropicales y Salud Pública de Canarias, Universidad de La Laguna, 38296 La Laguna, Tenerife, SpainInstituto Universitario de Bio-Orgánica Antonio González, Departamento de Química Orgánica, Universidad de La Laguna, Avenida Astrofísico Francisco Sánchez 2, 38206 La Laguna, Tenerife, SpainInstituto Universitario de Enfermedades Tropicales y Salud Pública de Canarias, Universidad de La Laguna, 38296 La Laguna, Tenerife, SpainInstituto Universitario de Bio-Orgánica Antonio González, Departamento de Química Orgánica, Universidad de La Laguna, Avenida Astrofísico Francisco Sánchez 2, 38206 La Laguna, Tenerife, SpainLaboratory of Functional Physiology and Valorization of Bio-Ressources, Higher Institute of Biotechnology of Beja, University of Jendouba, Beja 382-9000, TunisiaInstituto Universitario de Enfermedades Tropicales y Salud Pública de Canarias, Universidad de La Laguna, 38296 La Laguna, Tenerife, SpainInstituto Universitario de Bio-Orgánica Antonio González, Departamento de Química Orgánica, Universidad de La Laguna, Avenida Astrofísico Francisco Sánchez 2, 38206 La Laguna, Tenerife, SpainInstituto Universitario de Enfermedades Tropicales y Salud Pública de Canarias, Universidad de La Laguna, 38296 La Laguna, Tenerife, SpainLeishmaniasis and Chagas disease are parasitic diseases considered to be among the most important neglected diseases, with implications for both developed and developing countries. Currently, there are no effective therapeutic treatments for these diseases due to challenges in drug administration, high toxicity, high costs, and drug resistance. In this study, a series of eleven thymol derivatives were designed, synthesized, and evaluated for their in vitro kinetoplastid activity against <i>Leishmania amazonensis</i> and <i>Trypanosoma cruzi</i>, as well as their cytotoxicity against a murine macrophage cell line. The most active compounds, thymol anysoate (<b>9</b>) and thymol picolinate (<b>10</b>), displayed the highest kinetoplastid activity with IC<sub>50</sub> values of 22.87 and 25.16 µM against <i>L. amazonensis</i> and <i>T. cruzi</i>, respectively. Notably, both compounds demonstrated an excellent selectivity index against the mammal cell line. Structure–activity relationship studies revealed that the ester group plays a crucial role in activity. The most promising derivatives, <b>9</b> and <b>10</b>, activate autophagy and apoptosis-like processes in the treated cells. Atomic force microscopy observations showed that derivative <b>9</b> induces the formation of cytoplasmic vacuoles, indicating an autophagic process, and drug-likeness analysis revealed that it meets all the pharmacokinetic criteria. Overall, these results highlight derivative <b>9</b> as a potential lead compound for the development of new drugs for the treatment of Trypanosomatidae infections and warrants further studies to elucidate the cell death cascade involved.https://www.mdpi.com/2079-6382/14/4/383thymol derivatives<i>Leishmania amazonensis</i><i>Trypanosoma cruzi</i>structure–activity relationshipmechanism of actiondrug-likeness |
| spellingShingle | Amani Omrani Meriam Ben Youssef Ines Sifaoui Eduardo Hernández-Álvarez Carlos J. Bethencourt-Estrella Isabel L. Bazzocchi Hichem Sebai Jacob Lorenzo-Morales Ignacio A. Jiménez José E. Piñero Mechanism Insight of Cell Death Signaling by Thymol Derivatives on Trypanosomatidae Protozoan Parasites Antibiotics thymol derivatives <i>Leishmania amazonensis</i> <i>Trypanosoma cruzi</i> structure–activity relationship mechanism of action drug-likeness |
| title | Mechanism Insight of Cell Death Signaling by Thymol Derivatives on Trypanosomatidae Protozoan Parasites |
| title_full | Mechanism Insight of Cell Death Signaling by Thymol Derivatives on Trypanosomatidae Protozoan Parasites |
| title_fullStr | Mechanism Insight of Cell Death Signaling by Thymol Derivatives on Trypanosomatidae Protozoan Parasites |
| title_full_unstemmed | Mechanism Insight of Cell Death Signaling by Thymol Derivatives on Trypanosomatidae Protozoan Parasites |
| title_short | Mechanism Insight of Cell Death Signaling by Thymol Derivatives on Trypanosomatidae Protozoan Parasites |
| title_sort | mechanism insight of cell death signaling by thymol derivatives on trypanosomatidae protozoan parasites |
| topic | thymol derivatives <i>Leishmania amazonensis</i> <i>Trypanosoma cruzi</i> structure–activity relationship mechanism of action drug-likeness |
| url | https://www.mdpi.com/2079-6382/14/4/383 |
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