1,2,3-Triazole Derivatives as Novel Antifibrinolytic Drugs
Fibrinolysis is a natural process that ensures blood fluidity through the removal of fibrin deposits. However, excessive fibrinolytic activity can lead to complications in different circumstances, such as general surgery or severe trauma. The current antifibrinolytic drugs in the market, aminocaproi...
| Main Authors: | , , , , , , , |
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| Format: | Article |
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Multidisciplinary Digital Publishing Institute
2022
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| Online Access: | https://hdl.handle.net/1721.1/146827 |
| _version_ | 1826207318711205888 |
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| author | Bosch-Sanz, Oriol Rabadà, Yvette Biarnés, Xevi Pedreño, Javier Caveda, Luis Balcells, Mercedes Martorell, Jordi Sánchez-García, David |
| author2 | Massachusetts Institute of Technology. Institute for Medical Engineering & Science |
| author_facet | Massachusetts Institute of Technology. Institute for Medical Engineering & Science Bosch-Sanz, Oriol Rabadà, Yvette Biarnés, Xevi Pedreño, Javier Caveda, Luis Balcells, Mercedes Martorell, Jordi Sánchez-García, David |
| author_sort | Bosch-Sanz, Oriol |
| collection | MIT |
| description | Fibrinolysis is a natural process that ensures blood fluidity through the removal of fibrin deposits. However, excessive fibrinolytic activity can lead to complications in different circumstances, such as general surgery or severe trauma. The current antifibrinolytic drugs in the market, aminocaproic acid (EACA) and tranexamic acid (TXA), require high doses repetitively to maintain their therapeutic effect. These high doses are related to a number of side effects such as headaches, nasal symptoms, or gastrointestinal discomfort and severely limit their use in patients with renal impairment. Therefore, the discovery of novel antifibrinolytics with a higher specificity and lower dosage could vastly improve the applicability of these drugs. Herein, we synthesized a total of ten compounds consisting of a combination of three key moieties: an oxadiazolone, a triazole, and a terminal amine. The IC<sub>50</sub> of each compound was calculated in our clot lysis assays, and the best candidate (<b>1</b>) provided approximately a 2.5-fold improvement over the current gold standard, TXA. Molecular docking and molecular dynamics were used to perform a structure–activity relationship (SAR) analysis with the lysine binding site in the Kringle 1 domain of plasminogen. This analysis revealed that 1,2,3-triazole was crucial for the activity, enhancing the binding affinity through pi–pi stacking and polar interactions with Tyr72. The results presented in this work open the door to further investigate this new family as potential antifibrinolytic drugs. |
| first_indexed | 2024-09-23T13:47:28Z |
| format | Article |
| id | mit-1721.1/146827 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T13:47:28Z |
| publishDate | 2022 |
| publisher | Multidisciplinary Digital Publishing Institute |
| record_format | dspace |
| spelling | mit-1721.1/1468272024-03-19T17:27:37Z 1,2,3-Triazole Derivatives as Novel Antifibrinolytic Drugs Bosch-Sanz, Oriol Rabadà, Yvette Biarnés, Xevi Pedreño, Javier Caveda, Luis Balcells, Mercedes Martorell, Jordi Sánchez-García, David Massachusetts Institute of Technology. Institute for Medical Engineering & Science Fibrinolysis is a natural process that ensures blood fluidity through the removal of fibrin deposits. However, excessive fibrinolytic activity can lead to complications in different circumstances, such as general surgery or severe trauma. The current antifibrinolytic drugs in the market, aminocaproic acid (EACA) and tranexamic acid (TXA), require high doses repetitively to maintain their therapeutic effect. These high doses are related to a number of side effects such as headaches, nasal symptoms, or gastrointestinal discomfort and severely limit their use in patients with renal impairment. Therefore, the discovery of novel antifibrinolytics with a higher specificity and lower dosage could vastly improve the applicability of these drugs. Herein, we synthesized a total of ten compounds consisting of a combination of three key moieties: an oxadiazolone, a triazole, and a terminal amine. The IC<sub>50</sub> of each compound was calculated in our clot lysis assays, and the best candidate (<b>1</b>) provided approximately a 2.5-fold improvement over the current gold standard, TXA. Molecular docking and molecular dynamics were used to perform a structure–activity relationship (SAR) analysis with the lysine binding site in the Kringle 1 domain of plasminogen. This analysis revealed that 1,2,3-triazole was crucial for the activity, enhancing the binding affinity through pi–pi stacking and polar interactions with Tyr72. The results presented in this work open the door to further investigate this new family as potential antifibrinolytic drugs. 2022-12-12T13:08:19Z 2022-12-12T13:08:19Z 2022-11-29 2022-12-09T20:23:02Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/146827 International Journal of Molecular Sciences 23 (23): 14942 (2022) PUBLISHER_CC http://dx.doi.org/10.3390/ijms232314942 Creative Commons Attribution https://creativecommons.org/licenses/by/4.0/ application/pdf Multidisciplinary Digital Publishing Institute Multidisciplinary Digital Publishing Institute |
| spellingShingle | Bosch-Sanz, Oriol Rabadà, Yvette Biarnés, Xevi Pedreño, Javier Caveda, Luis Balcells, Mercedes Martorell, Jordi Sánchez-García, David 1,2,3-Triazole Derivatives as Novel Antifibrinolytic Drugs |
| title | 1,2,3-Triazole Derivatives as Novel Antifibrinolytic Drugs |
| title_full | 1,2,3-Triazole Derivatives as Novel Antifibrinolytic Drugs |
| title_fullStr | 1,2,3-Triazole Derivatives as Novel Antifibrinolytic Drugs |
| title_full_unstemmed | 1,2,3-Triazole Derivatives as Novel Antifibrinolytic Drugs |
| title_short | 1,2,3-Triazole Derivatives as Novel Antifibrinolytic Drugs |
| title_sort | 1 2 3 triazole derivatives as novel antifibrinolytic drugs |
| url | https://hdl.handle.net/1721.1/146827 |
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