Synthesis of thiosemicarbazone Schiff base derivatives as anti-leishmanial agents and molecular dynamics simulations insights
Abstract Leishmaniasis is one of the infectious diseases caused by protozoa and is considered the second most significant parasitic disease after malaria. In this research, thiosemicarbazone Schiff base derivatives were synthesized via a one-pot, two-step, three-component reaction. Then, the effecti...
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Nature Portfolio
2025-07-01
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| Online Access: | https://doi.org/10.1038/s41598-025-10545-6 |
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| author | Soheila Molaei Jafar Abbasi Shiran Neda Shakour Majid Baradaran Zahra Malihi Mohammad Reza Rahimi Yasamin Abedini Zal Saghi Sepehri |
| author_facet | Soheila Molaei Jafar Abbasi Shiran Neda Shakour Majid Baradaran Zahra Malihi Mohammad Reza Rahimi Yasamin Abedini Zal Saghi Sepehri |
| author_sort | Soheila Molaei |
| collection | DOAJ |
| description | Abstract Leishmaniasis is one of the infectious diseases caused by protozoa and is considered the second most significant parasitic disease after malaria. In this research, thiosemicarbazone Schiff base derivatives were synthesized via a one-pot, two-step, three-component reaction. Then, the effectiveness of the compounds against the two forms of Leishmania major and Leishmania tropica called amastigote and promastigote, was tested. All synthesized compounds displayed weak to good anti-amastigote and anti-promastigote activities. Notably, compounds 5g and 5p were the most potent compounds against amastigote and promastigote forms, respectively, of Leishmania major, with IC50 = 26.7 µM and 12.77 µM. Analogues 5e and 5g were the most potent compounds against amastigote and promastigote forms of Leishmania tropica, with IC50 = 92.3 µM and 12.77 µM, respectively. The cytotoxicity activity of the compounds was also evaluated using the J774.A1 cell lines. Some of the screened derivatives displayed low cytotoxicity to macrophage infection. Among compounds, 5p and 5e showed the highest SI (95.4 and 34.6) against L. major and L. tropica, respectively. In the next phase, the most effective thiosemicarbazone derivatives were examined for their ability to induce apoptosis in promastigotes. According to the results, these compounds displayed different early and late apoptosis as well as necrotic effects on promastigotes of Leishmania major and Leishmania tropica. Furthermore, the compounds’ drug-likeness and pharmacokinetic parameters were predicted in silico. All compounds showed acceptable drug-likeness and pharmacokinetic profiles. Furthermore, the most likely sites of the compounds metabolized by the major cytochromes were identified. Additionally, the in silico compounds’ cardiotoxicity potential was assessed. This investigation showed compounds 5m-p were cardiotoxic. Lastly, molecular docking and molecular dynamics simulations were performed to explore the potential mechanisms of anti-leishmanial activity in the LmPRT1 active site. |
| format | Article |
| id | doaj-art-e15bc1deaea345f184e6587c9259ea30 |
| institution | DOAJ |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj-art-e15bc1deaea345f184e6587c9259ea302025-08-20T03:04:25ZengNature PortfolioScientific Reports2045-23222025-07-0115113710.1038/s41598-025-10545-6Synthesis of thiosemicarbazone Schiff base derivatives as anti-leishmanial agents and molecular dynamics simulations insightsSoheila Molaei0Jafar Abbasi Shiran1Neda Shakour2Majid Baradaran3Zahra Malihi4Mohammad Reza Rahimi5Yasamin Abedini Zal6Saghi Sepehri7Zoonoses Research Center, Ardabil University of Medical SciencesPharmaceutical Sciences Research Center, Ardabil University of Medical SciencesDepartment of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical SciencesDepartment of Medicinal Chemistry, School of Pharmacy, Ardabil University of Medical SciencesDepartment of Medicinal Chemistry, School of Pharmacy, Ardabil University of Medical SciencesStudents Research Committee, School of Pharmacy, Ardabil University of Medical SciencesStudents Research Committee, School of Pharmacy, Ardabil University of Medical SciencesPharmaceutical Sciences Research Center, Ardabil University of Medical SciencesAbstract Leishmaniasis is one of the infectious diseases caused by protozoa and is considered the second most significant parasitic disease after malaria. In this research, thiosemicarbazone Schiff base derivatives were synthesized via a one-pot, two-step, three-component reaction. Then, the effectiveness of the compounds against the two forms of Leishmania major and Leishmania tropica called amastigote and promastigote, was tested. All synthesized compounds displayed weak to good anti-amastigote and anti-promastigote activities. Notably, compounds 5g and 5p were the most potent compounds against amastigote and promastigote forms, respectively, of Leishmania major, with IC50 = 26.7 µM and 12.77 µM. Analogues 5e and 5g were the most potent compounds against amastigote and promastigote forms of Leishmania tropica, with IC50 = 92.3 µM and 12.77 µM, respectively. The cytotoxicity activity of the compounds was also evaluated using the J774.A1 cell lines. Some of the screened derivatives displayed low cytotoxicity to macrophage infection. Among compounds, 5p and 5e showed the highest SI (95.4 and 34.6) against L. major and L. tropica, respectively. In the next phase, the most effective thiosemicarbazone derivatives were examined for their ability to induce apoptosis in promastigotes. According to the results, these compounds displayed different early and late apoptosis as well as necrotic effects on promastigotes of Leishmania major and Leishmania tropica. Furthermore, the compounds’ drug-likeness and pharmacokinetic parameters were predicted in silico. All compounds showed acceptable drug-likeness and pharmacokinetic profiles. Furthermore, the most likely sites of the compounds metabolized by the major cytochromes were identified. Additionally, the in silico compounds’ cardiotoxicity potential was assessed. This investigation showed compounds 5m-p were cardiotoxic. Lastly, molecular docking and molecular dynamics simulations were performed to explore the potential mechanisms of anti-leishmanial activity in the LmPRT1 active site.https://doi.org/10.1038/s41598-025-10545-6PromastigoteAmastigoteTropical diseaseApoptosisHydrazine-1-carbothioamide |
| spellingShingle | Soheila Molaei Jafar Abbasi Shiran Neda Shakour Majid Baradaran Zahra Malihi Mohammad Reza Rahimi Yasamin Abedini Zal Saghi Sepehri Synthesis of thiosemicarbazone Schiff base derivatives as anti-leishmanial agents and molecular dynamics simulations insights Scientific Reports Promastigote Amastigote Tropical disease Apoptosis Hydrazine-1-carbothioamide |
| title | Synthesis of thiosemicarbazone Schiff base derivatives as anti-leishmanial agents and molecular dynamics simulations insights |
| title_full | Synthesis of thiosemicarbazone Schiff base derivatives as anti-leishmanial agents and molecular dynamics simulations insights |
| title_fullStr | Synthesis of thiosemicarbazone Schiff base derivatives as anti-leishmanial agents and molecular dynamics simulations insights |
| title_full_unstemmed | Synthesis of thiosemicarbazone Schiff base derivatives as anti-leishmanial agents and molecular dynamics simulations insights |
| title_short | Synthesis of thiosemicarbazone Schiff base derivatives as anti-leishmanial agents and molecular dynamics simulations insights |
| title_sort | synthesis of thiosemicarbazone schiff base derivatives as anti leishmanial agents and molecular dynamics simulations insights |
| topic | Promastigote Amastigote Tropical disease Apoptosis Hydrazine-1-carbothioamide |
| url | https://doi.org/10.1038/s41598-025-10545-6 |
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