In vitro assays identified thiohydantoins with anti-trypanosomatid activity and molecular modelling studies indicated possible selective CYP51 inhibition
Abstract This work investigates the anti-trypanosomal activities of ten thiohydantoin derivatives against the parasite Trypanosoma cruzi. Compounds with aliphatic chains (THD1, THD3, and THD5) exhibited the most promising IC50 against the epimastigote form of T. cruzi. Also, it showed lower cytotoxi...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-01-01
|
| Series: | Scientific Reports |
| Subjects: | |
| Online Access: | https://doi.org/10.1038/s41598-024-84697-2 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1841559737255067648 |
|---|---|
| author | Priscila Goes Camargo Helena Tiemi Suzukawa Patrícia Morais Lopes Pereira Mariana Luiza Silva Fernando Macedo Jr Magaly Girão Albuquerque Carlos Rangel Rodrigues Sueli Fumie Yamada-Ogatta Camilo Henrique da Silva Lima Marcelle de Lima Ferreira Bispo |
| author_facet | Priscila Goes Camargo Helena Tiemi Suzukawa Patrícia Morais Lopes Pereira Mariana Luiza Silva Fernando Macedo Jr Magaly Girão Albuquerque Carlos Rangel Rodrigues Sueli Fumie Yamada-Ogatta Camilo Henrique da Silva Lima Marcelle de Lima Ferreira Bispo |
| author_sort | Priscila Goes Camargo |
| collection | DOAJ |
| description | Abstract This work investigates the anti-trypanosomal activities of ten thiohydantoin derivatives against the parasite Trypanosoma cruzi. Compounds with aliphatic chains (THD1, THD3, and THD5) exhibited the most promising IC50 against the epimastigote form of T. cruzi. Also, it showed lower cytotoxicity to mammalian cells. THD3 and THD5 (IC50 = 72.4 µg/mL and 115 µg/mL) presented great activity against trypomastigote and amastigote forms (IC50 = 47.7 µg/mL and 34.1 µg/mL). THD5 had high selectivity index (SI = 15.1) against the amastigote form. The molecular docking and molecular dynamics simulations were performed to understand the interaction between the THD and the important target CYP51 enzyme essential to T. cruzi. THD3 and THD5 were found to have strong interactions within the hydrophobic channel of CYP51 due to their aliphatic side chains, leading to favorable binding free energies. Despite the possibility of cross-reactivity between THD5 and human CYP2C9, the results indicate low identity and similarity between the homolog enzymes and possible selectivity of THD5 for the protozoan one, suggesting that these compounds could inhibit sterol biosynthesis, crucial for the parasite’s survival. These findings indicate that THD3 and THD5 are promising hits for the development of Chagas disease treatments. To fully validate this potential, carrying out enzymatic and other in vitro and in vivo assays is essential in the future. |
| format | Article |
| id | doaj-art-639b5097966b47c7a4210b9ce3d8f04b |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-639b5097966b47c7a4210b9ce3d8f04b2025-01-05T12:15:00ZengNature PortfolioScientific Reports2045-23222025-01-0115111410.1038/s41598-024-84697-2In vitro assays identified thiohydantoins with anti-trypanosomatid activity and molecular modelling studies indicated possible selective CYP51 inhibitionPriscila Goes Camargo0Helena Tiemi Suzukawa1Patrícia Morais Lopes Pereira2Mariana Luiza Silva3Fernando Macedo Jr4Magaly Girão Albuquerque5Carlos Rangel Rodrigues6Sueli Fumie Yamada-Ogatta7Camilo Henrique da Silva Lima8Marcelle de Lima Ferreira Bispo9Departamento de Química, Centro de Ciências Exatas, Universidade Estadual de LondrinaDepartamento de Microbiologia, Centro de Ciências Biológicas, Universidade Estadual de LondrinaDepartamento de Microbiologia, Centro de Ciências Biológicas, Universidade Estadual de LondrinaDepartamento de Química, Centro de Ciências Exatas, Universidade Estadual de LondrinaDepartamento de Química, Centro de Ciências Exatas, Universidade Estadual de LondrinaInstituto de Química, Universidade Federal do Rio de JaneiroFaculdade de Farmácia, Departamento de Fármacos e Medicamentos, Universidade Federal do Rio de JaneiroDepartamento de Microbiologia, Centro de Ciências Biológicas, Universidade Estadual de LondrinaInstituto de Química, Universidade Federal do Rio de JaneiroDepartamento de Química, Centro de Ciências Exatas, Universidade Estadual de LondrinaAbstract This work investigates the anti-trypanosomal activities of ten thiohydantoin derivatives against the parasite Trypanosoma cruzi. Compounds with aliphatic chains (THD1, THD3, and THD5) exhibited the most promising IC50 against the epimastigote form of T. cruzi. Also, it showed lower cytotoxicity to mammalian cells. THD3 and THD5 (IC50 = 72.4 µg/mL and 115 µg/mL) presented great activity against trypomastigote and amastigote forms (IC50 = 47.7 µg/mL and 34.1 µg/mL). THD5 had high selectivity index (SI = 15.1) against the amastigote form. The molecular docking and molecular dynamics simulations were performed to understand the interaction between the THD and the important target CYP51 enzyme essential to T. cruzi. THD3 and THD5 were found to have strong interactions within the hydrophobic channel of CYP51 due to their aliphatic side chains, leading to favorable binding free energies. Despite the possibility of cross-reactivity between THD5 and human CYP2C9, the results indicate low identity and similarity between the homolog enzymes and possible selectivity of THD5 for the protozoan one, suggesting that these compounds could inhibit sterol biosynthesis, crucial for the parasite’s survival. These findings indicate that THD3 and THD5 are promising hits for the development of Chagas disease treatments. To fully validate this potential, carrying out enzymatic and other in vitro and in vivo assays is essential in the future.https://doi.org/10.1038/s41598-024-84697-2Trypanosoma CruziMolecular dockingMolecular dynamicsCytochrome P450 |
| spellingShingle | Priscila Goes Camargo Helena Tiemi Suzukawa Patrícia Morais Lopes Pereira Mariana Luiza Silva Fernando Macedo Jr Magaly Girão Albuquerque Carlos Rangel Rodrigues Sueli Fumie Yamada-Ogatta Camilo Henrique da Silva Lima Marcelle de Lima Ferreira Bispo In vitro assays identified thiohydantoins with anti-trypanosomatid activity and molecular modelling studies indicated possible selective CYP51 inhibition Scientific Reports Trypanosoma Cruzi Molecular docking Molecular dynamics Cytochrome P450 |
| title | In vitro assays identified thiohydantoins with anti-trypanosomatid activity and molecular modelling studies indicated possible selective CYP51 inhibition |
| title_full | In vitro assays identified thiohydantoins with anti-trypanosomatid activity and molecular modelling studies indicated possible selective CYP51 inhibition |
| title_fullStr | In vitro assays identified thiohydantoins with anti-trypanosomatid activity and molecular modelling studies indicated possible selective CYP51 inhibition |
| title_full_unstemmed | In vitro assays identified thiohydantoins with anti-trypanosomatid activity and molecular modelling studies indicated possible selective CYP51 inhibition |
| title_short | In vitro assays identified thiohydantoins with anti-trypanosomatid activity and molecular modelling studies indicated possible selective CYP51 inhibition |
| title_sort | in vitro assays identified thiohydantoins with anti trypanosomatid activity and molecular modelling studies indicated possible selective cyp51 inhibition |
| topic | Trypanosoma Cruzi Molecular docking Molecular dynamics Cytochrome P450 |
| url | https://doi.org/10.1038/s41598-024-84697-2 |
| work_keys_str_mv | AT priscilagoescamargo invitroassaysidentifiedthiohydantoinswithantitrypanosomatidactivityandmolecularmodellingstudiesindicatedpossibleselectivecyp51inhibition AT helenatiemisuzukawa invitroassaysidentifiedthiohydantoinswithantitrypanosomatidactivityandmolecularmodellingstudiesindicatedpossibleselectivecyp51inhibition AT patriciamoraislopespereira invitroassaysidentifiedthiohydantoinswithantitrypanosomatidactivityandmolecularmodellingstudiesindicatedpossibleselectivecyp51inhibition AT marianaluizasilva invitroassaysidentifiedthiohydantoinswithantitrypanosomatidactivityandmolecularmodellingstudiesindicatedpossibleselectivecyp51inhibition AT fernandomacedojr invitroassaysidentifiedthiohydantoinswithantitrypanosomatidactivityandmolecularmodellingstudiesindicatedpossibleselectivecyp51inhibition AT magalygiraoalbuquerque invitroassaysidentifiedthiohydantoinswithantitrypanosomatidactivityandmolecularmodellingstudiesindicatedpossibleselectivecyp51inhibition AT carlosrangelrodrigues invitroassaysidentifiedthiohydantoinswithantitrypanosomatidactivityandmolecularmodellingstudiesindicatedpossibleselectivecyp51inhibition AT suelifumieyamadaogatta invitroassaysidentifiedthiohydantoinswithantitrypanosomatidactivityandmolecularmodellingstudiesindicatedpossibleselectivecyp51inhibition AT camilohenriquedasilvalima invitroassaysidentifiedthiohydantoinswithantitrypanosomatidactivityandmolecularmodellingstudiesindicatedpossibleselectivecyp51inhibition AT marcelledelimaferreirabispo invitroassaysidentifiedthiohydantoinswithantitrypanosomatidactivityandmolecularmodellingstudiesindicatedpossibleselectivecyp51inhibition |