New Hybrid Tetrahydropyrrolo[3,2,1-<i>ij</i>]quinolin-1-ylidene-2-thioxothiazolidin-4-ones as New Inhibitors of Factor Xa and Factor XIa: Design, Synthesis, and In Silico and Experimental Evaluation
Despite extensive research in the field of thrombotic diseases, the prevention of blood clots remains an important area of study. Therefore, the development of new anticoagulant drugs with better therapeutic profiles and fewer side effects to combat thrombus formation is still needed. Herein, we rep...
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| Format: | Article |
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MDPI AG
2023-05-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/28/9/3851 |
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| author | Nadezhda P. Novichikhina Alexander S. Shestakov Svetlana M. Medvedeva Anna M. Lagutina Mikhail Yu. Krysin Nadezhda A. Podoplelova Mikhail A. Panteleev Ivan S. Ilin Alexey V. Sulimov Anna S. Tashchilova Vladimir B. Sulimov Athina Geronikaki Khidmet S. Shikhaliev |
| author_facet | Nadezhda P. Novichikhina Alexander S. Shestakov Svetlana M. Medvedeva Anna M. Lagutina Mikhail Yu. Krysin Nadezhda A. Podoplelova Mikhail A. Panteleev Ivan S. Ilin Alexey V. Sulimov Anna S. Tashchilova Vladimir B. Sulimov Athina Geronikaki Khidmet S. Shikhaliev |
| author_sort | Nadezhda P. Novichikhina |
| collection | DOAJ |
| description | Despite extensive research in the field of thrombotic diseases, the prevention of blood clots remains an important area of study. Therefore, the development of new anticoagulant drugs with better therapeutic profiles and fewer side effects to combat thrombus formation is still needed. Herein, we report the synthesis and evaluation of novel pyrroloquinolinedione-based rhodanine derivatives, which were chosen from 24 developed derivatives by docking as potential molecules to inhibit the clotting factors Xa and XIa. For the synthesis of new hybrid derivatives of pyrrolo[3,2,1-<i>ij</i>]quinoline-2-one, we used a convenient structural modification of the tetrahydroquinoline fragment by varying the substituents in positions 2, 4, and 6. In addition, the design of target molecules was achieved by alkylating the amino group of the rhodanine fragment with propargyl bromide or by replacing the rhodanine fragment with 2-thioxoimidazolidin-4-one. The in vitro testing showed that eight derivatives are capable of inhibiting both coagulation factors, two compounds are selective inhibitors of factor Xa, and two compounds are selective inhibitors of factor XIa. Overall, these data indicate the potential anticoagulant activity of these molecules through the inhibition of the coagulation factors Xa and XIa. |
| first_indexed | 2024-03-11T04:12:25Z |
| format | Article |
| id | doaj.art-ad401ca8260b4b42b6b1871b15ad1ad7 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-11T04:12:25Z |
| publishDate | 2023-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-ad401ca8260b4b42b6b1871b15ad1ad72023-11-17T23:24:19ZengMDPI AGMolecules1420-30492023-05-01289385110.3390/molecules28093851New Hybrid Tetrahydropyrrolo[3,2,1-<i>ij</i>]quinolin-1-ylidene-2-thioxothiazolidin-4-ones as New Inhibitors of Factor Xa and Factor XIa: Design, Synthesis, and In Silico and Experimental EvaluationNadezhda P. Novichikhina0Alexander S. Shestakov1Svetlana M. Medvedeva2Anna M. Lagutina3Mikhail Yu. Krysin4Nadezhda A. Podoplelova5Mikhail A. Panteleev6Ivan S. Ilin7Alexey V. Sulimov8Anna S. Tashchilova9Vladimir B. Sulimov10Athina Geronikaki11Khidmet S. Shikhaliev12Department of Organic Chemistry, Faculty of Chemistry, Voronezh State University, Universitetskaya pl. 1, 394018 Voronezh, RussiaDepartment of Organic Chemistry, Faculty of Chemistry, Voronezh State University, Universitetskaya pl. 1, 394018 Voronezh, RussiaDepartment of Organic Chemistry, Faculty of Chemistry, Voronezh State University, Universitetskaya pl. 1, 394018 Voronezh, RussiaDepartment of Organic Chemistry, Faculty of Chemistry, Voronezh State University, Universitetskaya pl. 1, 394018 Voronezh, RussiaDepartment of Organic Chemistry, Faculty of Chemistry, Voronezh State University, Universitetskaya pl. 1, 394018 Voronezh, RussiaDmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, 117997 Moscow, RussiaDmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, 117997 Moscow, RussiaDimonta, Ltd., 117186 Moscow, RussiaDimonta, Ltd., 117186 Moscow, RussiaDimonta, Ltd., 117186 Moscow, RussiaDimonta, Ltd., 117186 Moscow, RussiaSchool of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, GreeceDepartment of Organic Chemistry, Faculty of Chemistry, Voronezh State University, Universitetskaya pl. 1, 394018 Voronezh, RussiaDespite extensive research in the field of thrombotic diseases, the prevention of blood clots remains an important area of study. Therefore, the development of new anticoagulant drugs with better therapeutic profiles and fewer side effects to combat thrombus formation is still needed. Herein, we report the synthesis and evaluation of novel pyrroloquinolinedione-based rhodanine derivatives, which were chosen from 24 developed derivatives by docking as potential molecules to inhibit the clotting factors Xa and XIa. For the synthesis of new hybrid derivatives of pyrrolo[3,2,1-<i>ij</i>]quinoline-2-one, we used a convenient structural modification of the tetrahydroquinoline fragment by varying the substituents in positions 2, 4, and 6. In addition, the design of target molecules was achieved by alkylating the amino group of the rhodanine fragment with propargyl bromide or by replacing the rhodanine fragment with 2-thioxoimidazolidin-4-one. The in vitro testing showed that eight derivatives are capable of inhibiting both coagulation factors, two compounds are selective inhibitors of factor Xa, and two compounds are selective inhibitors of factor XIa. Overall, these data indicate the potential anticoagulant activity of these molecules through the inhibition of the coagulation factors Xa and XIa.https://www.mdpi.com/1420-3049/28/9/38515,6-dihydro-4<i>H</i>-pyrrolo[3,2,1-<i>ij</i>]quinoline-1,2-dionerhodaninesanticoagulant activitydocking studies |
| spellingShingle | Nadezhda P. Novichikhina Alexander S. Shestakov Svetlana M. Medvedeva Anna M. Lagutina Mikhail Yu. Krysin Nadezhda A. Podoplelova Mikhail A. Panteleev Ivan S. Ilin Alexey V. Sulimov Anna S. Tashchilova Vladimir B. Sulimov Athina Geronikaki Khidmet S. Shikhaliev New Hybrid Tetrahydropyrrolo[3,2,1-<i>ij</i>]quinolin-1-ylidene-2-thioxothiazolidin-4-ones as New Inhibitors of Factor Xa and Factor XIa: Design, Synthesis, and In Silico and Experimental Evaluation Molecules 5,6-dihydro-4<i>H</i>-pyrrolo[3,2,1-<i>ij</i>]quinoline-1,2-dione rhodanines anticoagulant activity docking studies |
| title | New Hybrid Tetrahydropyrrolo[3,2,1-<i>ij</i>]quinolin-1-ylidene-2-thioxothiazolidin-4-ones as New Inhibitors of Factor Xa and Factor XIa: Design, Synthesis, and In Silico and Experimental Evaluation |
| title_full | New Hybrid Tetrahydropyrrolo[3,2,1-<i>ij</i>]quinolin-1-ylidene-2-thioxothiazolidin-4-ones as New Inhibitors of Factor Xa and Factor XIa: Design, Synthesis, and In Silico and Experimental Evaluation |
| title_fullStr | New Hybrid Tetrahydropyrrolo[3,2,1-<i>ij</i>]quinolin-1-ylidene-2-thioxothiazolidin-4-ones as New Inhibitors of Factor Xa and Factor XIa: Design, Synthesis, and In Silico and Experimental Evaluation |
| title_full_unstemmed | New Hybrid Tetrahydropyrrolo[3,2,1-<i>ij</i>]quinolin-1-ylidene-2-thioxothiazolidin-4-ones as New Inhibitors of Factor Xa and Factor XIa: Design, Synthesis, and In Silico and Experimental Evaluation |
| title_short | New Hybrid Tetrahydropyrrolo[3,2,1-<i>ij</i>]quinolin-1-ylidene-2-thioxothiazolidin-4-ones as New Inhibitors of Factor Xa and Factor XIa: Design, Synthesis, and In Silico and Experimental Evaluation |
| title_sort | new hybrid tetrahydropyrrolo 3 2 1 i ij i quinolin 1 ylidene 2 thioxothiazolidin 4 ones as new inhibitors of factor xa and factor xia design synthesis and in silico and experimental evaluation |
| topic | 5,6-dihydro-4<i>H</i>-pyrrolo[3,2,1-<i>ij</i>]quinoline-1,2-dione rhodanines anticoagulant activity docking studies |
| url | https://www.mdpi.com/1420-3049/28/9/3851 |
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