Novel Butyrylcholinesterase Inhibitor Alkaloids from Cannabis sativa Roots: Bioguided Isolation and In Silico Study
Neurodegenerative diseases, including Alzheimer’s disease (AD), represent one of the main global health challenges. Cannabis sativa synthesizes spermidine-type alkaloids, whose potential biological activities have been little studied. This study aimed to isolate bioactive alkaloids from an alkaloid-...
| Main Authors: | , , , , , |
|---|---|
| Format: | Artículo |
| Language: | Inglés |
| Published: |
Multidisciplinary Digital Publishing Institute (MDPI)
2025
|
| Subjects: | |
| Online Access: | http://hdl.handle.net/20.500.12123/23831 https://www.mdpi.com/2673-6918/5/3/35 https://doi.org/10.3390/compounds5030035 |
| _version_ | 1855487204673978368 |
|---|---|
| author | Ortiz, Javier Esteban Adarvez Feresin, Camila Wadía Llalla Cordova, Olimpia Cristos, Diego Sebastian Garro, Adriana Deolinda Feresin, Gabriela Egly |
| author_browse | Adarvez Feresin, Camila Wadía Cristos, Diego Sebastian Feresin, Gabriela Egly Garro, Adriana Deolinda Llalla Cordova, Olimpia Ortiz, Javier Esteban |
| author_facet | Ortiz, Javier Esteban Adarvez Feresin, Camila Wadía Llalla Cordova, Olimpia Cristos, Diego Sebastian Garro, Adriana Deolinda Feresin, Gabriela Egly |
| author_sort | Ortiz, Javier Esteban |
| collection | INTA Digital |
| description | Neurodegenerative diseases, including Alzheimer’s disease (AD), represent one of the main global health challenges. Cannabis sativa synthesizes spermidine-type alkaloids, whose potential biological activities have been little studied. This study aimed to isolate bioactive alkaloids from an alkaloid-enriched extract (AEE) of C. sativa roots throughout a bioguided approach using conventional chromatographic techniques based on AChE and BuChE inhibitory activities. A qualitative and semiquantitative analysis by UPLC-ESI-MS/MS as well as molecular modeling simulations were performed. In addition, predictive in silico analyses were conducted to assess toxicity properties. The alkaloids cannabisativine (CS) and anhydrocannabisativine (ACS) were isolated, and showed highly selective BuChE inhibitory activity. The molecular modeling study revealed a conserved interaction profile across both alkaloids, indicating the amino acids TRP82, GLU197, TYR440, and HIS438 as the major contributors involved in the complex formation. Finally, CS and ACS exhibited low in silico predictive toxicity values. In conclusion, CS and ACS alkaloids emerge as new selective BuChE inhibitors with therapeutic potential that deserves the attention from the field of pharmacology in neurodegenerative disease research. Additionally, this approach promotes innovation and environmental sustainability through the use of C. sativa roots. |
| format | Artículo |
| id | INTA23831 |
| institution | Instituto Nacional de Tecnología Agropecuaria (INTA -Argentina) |
| language | Inglés |
| publishDate | 2025 |
| publishDateRange | 2025 |
| publishDateSort | 2025 |
| publisher | Multidisciplinary Digital Publishing Institute (MDPI) |
| publisherStr | Multidisciplinary Digital Publishing Institute (MDPI) |
| record_format | dspace |
| spelling | INTA238312025-09-17T12:52:53Z Novel Butyrylcholinesterase Inhibitor Alkaloids from Cannabis sativa Roots: Bioguided Isolation and In Silico Study Ortiz, Javier Esteban Adarvez Feresin, Camila Wadía Llalla Cordova, Olimpia Cristos, Diego Sebastian Garro, Adriana Deolinda Feresin, Gabriela Egly Cannabis sativa Raíz Espermidina Alcaloide Roots Spermidine Alkaloids Butyrylcholinesterase Cannabisativine Anhydrocannabisativine Neurodegenerative diseases, including Alzheimer’s disease (AD), represent one of the main global health challenges. Cannabis sativa synthesizes spermidine-type alkaloids, whose potential biological activities have been little studied. This study aimed to isolate bioactive alkaloids from an alkaloid-enriched extract (AEE) of C. sativa roots throughout a bioguided approach using conventional chromatographic techniques based on AChE and BuChE inhibitory activities. A qualitative and semiquantitative analysis by UPLC-ESI-MS/MS as well as molecular modeling simulations were performed. In addition, predictive in silico analyses were conducted to assess toxicity properties. The alkaloids cannabisativine (CS) and anhydrocannabisativine (ACS) were isolated, and showed highly selective BuChE inhibitory activity. The molecular modeling study revealed a conserved interaction profile across both alkaloids, indicating the amino acids TRP82, GLU197, TYR440, and HIS438 as the major contributors involved in the complex formation. Finally, CS and ACS exhibited low in silico predictive toxicity values. In conclusion, CS and ACS alkaloids emerge as new selective BuChE inhibitors with therapeutic potential that deserves the attention from the field of pharmacology in neurodegenerative disease research. Additionally, this approach promotes innovation and environmental sustainability through the use of C. sativa roots. Las enfermedades neurodegenerativas, incluyendo la enfermedad de Alzheimer (EA), representan uno de los principales desafíos de salud global. Cannabis sativa sintetiza alcaloides de tipo espermidina, cuyas potenciales actividades biológicas han sido poco estudiadas. Este estudio tuvo como objetivo aislar alcaloides bioactivos de un extracto enriquecido con alcaloides (AEE) de raíces de C. sativa a través de un enfoque bioguiado utilizando técnicas cromatográficas convencionales basadas en actividades inhibitorias de AChE y BuChE. Se realizó un análisis cualitativo y semicuantitativo por UPLC-ESI-MS/MS así como simulaciones de modelado molecular. Además, se realizaron análisis predictivos in silico para evaluar las propiedades de toxicidad. Se aislaron los alcaloides cannabisativina (CS) y anhidrocannabisativina (ACS), que mostraron una actividad inhibitoria altamente selectiva de BuChE. El estudio de modelado molecular reveló un perfil de interacción conservado entre ambos alcaloides, lo que indica que los aminoácidos TRP82, GLU197, TYR440 y HIS438 son los principales contribuyentes a la formación del complejo. Finalmente, CS y ACS mostraron bajos valores de toxicidad predictiva in silico. En conclusión, los alcaloides CS y ACS emergen como nuevos inhibidores selectivos de BuChE con potencial terapéutico que merece la atención del campo de la farmacología en la investigación de enfermedades neurodegenerativas. Además, este enfoque promueve la innovación y la sostenibilidad ambiental mediante el uso de raíces de C. sativa. Instituto de Investigación Tecnología de Alimentos (ITA) Fil: Ortiz, Javier Esteban. Universidad Nacional de San Juan. Facultad de Ingeniería. Instituto de Biotecnología; Argentina. Fil: Adarvez Feresin, Camila Wadía. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina. Fil: Llalla Cordova, Olimpia. Universidad Nacional de San Juan. Facultad de Ingeniería. Instituto de Biotecnología; Argentina. Fil: Llalla Cordova, Olimpia. Consejo Nacional de Ciencia y Tecnología. CCT San Juan; Argentina. Fil: Cristos, Diego Sebastian. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Investigación Tecnología de Alimentos; Argentina. Fil: Garro, Adriana Deolinda. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina. Fil: Feresin, Gabriela Egly. Universidad Nacional de San Juan. Facultad de Ingeniería. Instituto de Biotecnología; Argentina. Fil: Feresin, Gabriela Egly. Consejo Nacional de Ciencia y Tecnología. CCT San Juan; Argentina. 2025-09-17T12:39:43Z 2025-09-17T12:39:43Z 2025-09 info:ar-repo/semantics/artículo info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion http://hdl.handle.net/20.500.12123/23831 https://www.mdpi.com/2673-6918/5/3/35 2673-6918 https://doi.org/10.3390/compounds5030035 eng info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by-nc-sa/4.0/ Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) application/pdf Multidisciplinary Digital Publishing Institute (MDPI) Journal Compounds 5 (3) : 35. (September 2025). |
| spellingShingle | Cannabis sativa Raíz Espermidina Alcaloide Roots Spermidine Alkaloids Butyrylcholinesterase Cannabisativine Anhydrocannabisativine Ortiz, Javier Esteban Adarvez Feresin, Camila Wadía Llalla Cordova, Olimpia Cristos, Diego Sebastian Garro, Adriana Deolinda Feresin, Gabriela Egly Novel Butyrylcholinesterase Inhibitor Alkaloids from Cannabis sativa Roots: Bioguided Isolation and In Silico Study |
| title | Novel Butyrylcholinesterase Inhibitor Alkaloids from Cannabis sativa Roots: Bioguided Isolation and In Silico Study |
| title_full | Novel Butyrylcholinesterase Inhibitor Alkaloids from Cannabis sativa Roots: Bioguided Isolation and In Silico Study |
| title_fullStr | Novel Butyrylcholinesterase Inhibitor Alkaloids from Cannabis sativa Roots: Bioguided Isolation and In Silico Study |
| title_full_unstemmed | Novel Butyrylcholinesterase Inhibitor Alkaloids from Cannabis sativa Roots: Bioguided Isolation and In Silico Study |
| title_short | Novel Butyrylcholinesterase Inhibitor Alkaloids from Cannabis sativa Roots: Bioguided Isolation and In Silico Study |
| title_sort | novel butyrylcholinesterase inhibitor alkaloids from cannabis sativa roots bioguided isolation and in silico study |
| topic | Cannabis sativa Raíz Espermidina Alcaloide Roots Spermidine Alkaloids Butyrylcholinesterase Cannabisativine Anhydrocannabisativine |
| url | http://hdl.handle.net/20.500.12123/23831 https://www.mdpi.com/2673-6918/5/3/35 https://doi.org/10.3390/compounds5030035 |
| work_keys_str_mv | AT ortizjavieresteban novelbutyrylcholinesteraseinhibitoralkaloidsfromcannabissativarootsbioguidedisolationandinsilicostudy AT adarvezferesincamilawadia novelbutyrylcholinesteraseinhibitoralkaloidsfromcannabissativarootsbioguidedisolationandinsilicostudy AT llallacordovaolimpia novelbutyrylcholinesteraseinhibitoralkaloidsfromcannabissativarootsbioguidedisolationandinsilicostudy AT cristosdiegosebastian novelbutyrylcholinesteraseinhibitoralkaloidsfromcannabissativarootsbioguidedisolationandinsilicostudy AT garroadrianadeolinda novelbutyrylcholinesteraseinhibitoralkaloidsfromcannabissativarootsbioguidedisolationandinsilicostudy AT feresingabrielaegly novelbutyrylcholinesteraseinhibitoralkaloidsfromcannabissativarootsbioguidedisolationandinsilicostudy |