4-(1-Methylamino)ethylidene-1,5-disubstituted pyrrolidine-2,3-diones: synthesis, anti-inflammatory effect and in silico approaches
Pyrrolidine-2,3-diones are important intermediates in the synthesis of numerous nitrogen-containing heterocycles which possess a broad spectrum of biological and pharmacological activities. In this article, we report the synthesis of 4-(1-methylamino)ethylidene-1,5-disubstituted pyrrolidine-2,3-dion...
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Beilstein-Institut
2025-04-01
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| Series: | Beilstein Journal of Organic Chemistry |
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| Online Access: | https://doi.org/10.3762/bjoc.21.65 |
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| author | Nguyen Tran Nguyen Vo Viet Dai Luc Van Meervelt Do Thi Thao Nguyen Minh Thong |
| author_facet | Nguyen Tran Nguyen Vo Viet Dai Luc Van Meervelt Do Thi Thao Nguyen Minh Thong |
| author_sort | Nguyen Tran Nguyen |
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| description | Pyrrolidine-2,3-diones are important intermediates in the synthesis of numerous nitrogen-containing heterocycles which possess a broad spectrum of biological and pharmacological activities. In this article, we report the synthesis of 4-(1-methylamino)ethylidene-1,5-disubstituted pyrrolidine-2,3-diones via a reversible transimination reaction between Schiff’ base (C=N) linkage-containing pyrrolidine-2,3-dione derivatives and methylamine with yields of 80 to 92%. In addition to nuclear magnetic resonance spectroscopy, the structure of 4-(1-methylamino)ethylidene-1,5-diphenylpyrrolidine-2,3-dione (5a) was also verified through single-crystal X-ray diffraction. Furthermore, the synthesized molecules were evaluated for compliance with established drug-likeness rules (Lipinski, Veber, Ghose, Egan, and Muegge), as well as ADMET properties. All compounds satisfied these criteria, indicating favorable oral bioavailability. Molecular docking analysis showed that compounds 5a–e act as ligands for inducible nitric oxide synthase (iNOS), especially with Cys200 and Ser242 via hydrogen bonds. In addition, van der Waals interactions also contribute to the stabilization of the ligand–iNOS complexes. In particular, 4-(1-methylamino)ethylidene-5-phenyl-1-(3-nitrophenyl)pyrrolidine-2,3-dione (5e) exhibited the strongest binding affinity (−9.51 kcal/mol) and demonstrated significant inhibitory activity against nitric oxide (NO) production, with an IC50 value of 43.69 ± 5.26 µM. The presence of an electron-withdrawing group (-NO2 group) on the benzene ring at the 1-position of the pyrrolidine-2,3-dione subunit in compound 5e may be responsible for the observed high inhibition activity due to the enhancement and optimization of hydrogen bonding with Cys200. These results underscore the potential of 4-(1-methylamino)ethylidenepyrrolidine-2,3-diones, especially compound 5e, as promising scaffolds for the development of anti-inflammatory agents targeting iNOS-related pathologies. |
| format | Article |
| id | doaj-art-2f285e2eab914effb596501978652f5d |
| institution | OA Journals |
| issn | 1860-5397 |
| language | English |
| publishDate | 2025-04-01 |
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| series | Beilstein Journal of Organic Chemistry |
| spelling | doaj-art-2f285e2eab914effb596501978652f5d2025-08-20T02:11:12ZengBeilstein-InstitutBeilstein Journal of Organic Chemistry1860-53972025-04-0121181782910.3762/bjoc.21.651860-5397-21-654-(1-Methylamino)ethylidene-1,5-disubstituted pyrrolidine-2,3-diones: synthesis, anti-inflammatory effect and in silico approachesNguyen Tran Nguyen0Vo Viet Dai1Luc Van Meervelt2Do Thi Thao3Nguyen Minh Thong4The University of Danang-University of Science and Education, Danang 550000, Vietnam The University of Danang-University of Science and Education, Danang 550000, Vietnam Biomolecular Architecture, Department of Chemistry, KU Leuven, Celestijnenlaan 200F, B-3001 Leuven, Belgium Institute of Biotechnology, Vietnam Academy of Science and Technology (VAST), Hanoi 10072, Vietnam The University of Danang-University of Science and Education, Danang 550000, Vietnam Pyrrolidine-2,3-diones are important intermediates in the synthesis of numerous nitrogen-containing heterocycles which possess a broad spectrum of biological and pharmacological activities. In this article, we report the synthesis of 4-(1-methylamino)ethylidene-1,5-disubstituted pyrrolidine-2,3-diones via a reversible transimination reaction between Schiff’ base (C=N) linkage-containing pyrrolidine-2,3-dione derivatives and methylamine with yields of 80 to 92%. In addition to nuclear magnetic resonance spectroscopy, the structure of 4-(1-methylamino)ethylidene-1,5-diphenylpyrrolidine-2,3-dione (5a) was also verified through single-crystal X-ray diffraction. Furthermore, the synthesized molecules were evaluated for compliance with established drug-likeness rules (Lipinski, Veber, Ghose, Egan, and Muegge), as well as ADMET properties. All compounds satisfied these criteria, indicating favorable oral bioavailability. Molecular docking analysis showed that compounds 5a–e act as ligands for inducible nitric oxide synthase (iNOS), especially with Cys200 and Ser242 via hydrogen bonds. In addition, van der Waals interactions also contribute to the stabilization of the ligand–iNOS complexes. In particular, 4-(1-methylamino)ethylidene-5-phenyl-1-(3-nitrophenyl)pyrrolidine-2,3-dione (5e) exhibited the strongest binding affinity (−9.51 kcal/mol) and demonstrated significant inhibitory activity against nitric oxide (NO) production, with an IC50 value of 43.69 ± 5.26 µM. The presence of an electron-withdrawing group (-NO2 group) on the benzene ring at the 1-position of the pyrrolidine-2,3-dione subunit in compound 5e may be responsible for the observed high inhibition activity due to the enhancement and optimization of hydrogen bonding with Cys200. These results underscore the potential of 4-(1-methylamino)ethylidenepyrrolidine-2,3-diones, especially compound 5e, as promising scaffolds for the development of anti-inflammatory agents targeting iNOS-related pathologies.https://doi.org/10.3762/bjoc.21.65anti-inflammatory pyrrolidine-2,3-dione derivativesinospyrrolidine-2,3-dione derivativespyrrolidine-2,3-dionespyrrolidine-2,3-diones targeting reversible transimination reaction |
| spellingShingle | Nguyen Tran Nguyen Vo Viet Dai Luc Van Meervelt Do Thi Thao Nguyen Minh Thong 4-(1-Methylamino)ethylidene-1,5-disubstituted pyrrolidine-2,3-diones: synthesis, anti-inflammatory effect and in silico approaches Beilstein Journal of Organic Chemistry anti-inflammatory pyrrolidine-2,3-dione derivatives inos pyrrolidine-2,3-dione derivatives pyrrolidine-2,3-diones pyrrolidine-2,3-diones targeting reversible transimination reaction |
| title | 4-(1-Methylamino)ethylidene-1,5-disubstituted pyrrolidine-2,3-diones: synthesis, anti-inflammatory effect and in silico approaches |
| title_full | 4-(1-Methylamino)ethylidene-1,5-disubstituted pyrrolidine-2,3-diones: synthesis, anti-inflammatory effect and in silico approaches |
| title_fullStr | 4-(1-Methylamino)ethylidene-1,5-disubstituted pyrrolidine-2,3-diones: synthesis, anti-inflammatory effect and in silico approaches |
| title_full_unstemmed | 4-(1-Methylamino)ethylidene-1,5-disubstituted pyrrolidine-2,3-diones: synthesis, anti-inflammatory effect and in silico approaches |
| title_short | 4-(1-Methylamino)ethylidene-1,5-disubstituted pyrrolidine-2,3-diones: synthesis, anti-inflammatory effect and in silico approaches |
| title_sort | 4 1 methylamino ethylidene 1 5 disubstituted pyrrolidine 2 3 diones synthesis anti inflammatory effect and in silico approaches |
| topic | anti-inflammatory pyrrolidine-2,3-dione derivatives inos pyrrolidine-2,3-dione derivatives pyrrolidine-2,3-diones pyrrolidine-2,3-diones targeting reversible transimination reaction |
| url | https://doi.org/10.3762/bjoc.21.65 |
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