Human Cytotoxicity, Hemolytic Activity, Anti-Inflammatory Activity and Aqueous Solubility of Ibuprofen-Based Ionic Liquids
Ionic liquids (ILs) are a potential solution to the general problem of low solubility, polymorphism and low bioavailability of active pharmaceutical ingredients (APIs). In this work, we report on the synthesis of three pharmaceutically active ILs (API-ILs) based on ibuprofen, one of the most commonl...
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MDPI AG
2022-08-01
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| Series: | Sustainable Chemistry |
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| Online Access: | https://www.mdpi.com/2673-4079/3/3/23 |
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| author | Joana C. Bastos Nicole S. M. Vieira Maria Manuela Gaspar Ana B. Pereiro João M. M. Araújo |
| author_facet | Joana C. Bastos Nicole S. M. Vieira Maria Manuela Gaspar Ana B. Pereiro João M. M. Araújo |
| author_sort | Joana C. Bastos |
| collection | DOAJ |
| description | Ionic liquids (ILs) are a potential solution to the general problem of low solubility, polymorphism and low bioavailability of active pharmaceutical ingredients (APIs). In this work, we report on the synthesis of three pharmaceutically active ILs (API-ILs) based on ibuprofen, one of the most commonly available over-the-counter nonsteroidal anti-inflammatory drugs (NSAIDs), with imidazolium cations ([C<sub>2</sub>C<sub>1</sub>Im][Ibu] and [C<sub>2(OH)</sub>C1Im][Ibu]) and a cholinium cation ([N<sub>1112(OH)</sub>][Ibu]). An upgrade to the aqueous solubility (water and biological simulated fluids) for the ibuprofen-based ILs relative to the ibuprofen’s neutral and salt form (sodium ibuprofen) was verified. The cytotoxic profiles of the synthesized API-ILs were characterized using two human cells lines, Caco-2 colon carcinoma cells and HepG-2 hepatocellular carcinoma cells, up to ibuprofen’s maximum plasma concentration (C<sub>max</sub>) without impairing their cytotoxicity response. Additionally, the EC<sub>50</sub> in the Caco-2 cell line revealed similar results for both parent APIs and API-ILs. The biocompatibility of the ibuprofen-based ILs was also evaluated through a hemolytic activity assay, and the results showed that all the ILs were hemocompatible at concentrations higher than the ibuprofen C<sub>max</sub>. Moreover, the anti-inflammatory properties of the API-ILs were assessed through the inhibition of bovine serum albumin (BSA) denaturation and inhibition of cyclooxygenases (COX-1 and COX-2). The results showed that [C<sub>2</sub>C<sub>1</sub>Im][Ibu], [C<sub>2(OH)</sub>C1Im][Ibu] and [N<sub>1112(OH)</sub>][Ibu] maintained their anti-inflammatory response to ibuprofen, with improved selectivity towards COX-2, allowing the development of safer NSAIDs and the recognition of new avenues for selective COX-2 inhibitors in cancer chemotherapy and neurological diseases such as Alzheimer’s and Parkinson’s. |
| first_indexed | 2024-03-09T22:30:18Z |
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| institution | Directory Open Access Journal |
| issn | 2673-4079 |
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| last_indexed | 2024-03-09T22:30:18Z |
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| spelling | doaj.art-d9d6de2bcf0d4c4f9c62dcc3cf4a777d2023-11-23T18:58:33ZengMDPI AGSustainable Chemistry2673-40792022-08-013335837510.3390/suschem3030023Human Cytotoxicity, Hemolytic Activity, Anti-Inflammatory Activity and Aqueous Solubility of Ibuprofen-Based Ionic LiquidsJoana C. Bastos0Nicole S. M. Vieira1Maria Manuela Gaspar2Ana B. Pereiro3João M. M. Araújo4LAQV, REQUIMTE, Department of Chemistry, NOVA School of Science and Technology, Universidade NOVA de Lisboa, 2829-516 Caparica, PortugalLAQV, REQUIMTE, Department of Chemistry, NOVA School of Science and Technology, Universidade NOVA de Lisboa, 2829-516 Caparica, PortugalResearch Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, PortugalLAQV, REQUIMTE, Department of Chemistry, NOVA School of Science and Technology, Universidade NOVA de Lisboa, 2829-516 Caparica, PortugalLAQV, REQUIMTE, Department of Chemistry, NOVA School of Science and Technology, Universidade NOVA de Lisboa, 2829-516 Caparica, PortugalIonic liquids (ILs) are a potential solution to the general problem of low solubility, polymorphism and low bioavailability of active pharmaceutical ingredients (APIs). In this work, we report on the synthesis of three pharmaceutically active ILs (API-ILs) based on ibuprofen, one of the most commonly available over-the-counter nonsteroidal anti-inflammatory drugs (NSAIDs), with imidazolium cations ([C<sub>2</sub>C<sub>1</sub>Im][Ibu] and [C<sub>2(OH)</sub>C1Im][Ibu]) and a cholinium cation ([N<sub>1112(OH)</sub>][Ibu]). An upgrade to the aqueous solubility (water and biological simulated fluids) for the ibuprofen-based ILs relative to the ibuprofen’s neutral and salt form (sodium ibuprofen) was verified. The cytotoxic profiles of the synthesized API-ILs were characterized using two human cells lines, Caco-2 colon carcinoma cells and HepG-2 hepatocellular carcinoma cells, up to ibuprofen’s maximum plasma concentration (C<sub>max</sub>) without impairing their cytotoxicity response. Additionally, the EC<sub>50</sub> in the Caco-2 cell line revealed similar results for both parent APIs and API-ILs. The biocompatibility of the ibuprofen-based ILs was also evaluated through a hemolytic activity assay, and the results showed that all the ILs were hemocompatible at concentrations higher than the ibuprofen C<sub>max</sub>. Moreover, the anti-inflammatory properties of the API-ILs were assessed through the inhibition of bovine serum albumin (BSA) denaturation and inhibition of cyclooxygenases (COX-1 and COX-2). The results showed that [C<sub>2</sub>C<sub>1</sub>Im][Ibu], [C<sub>2(OH)</sub>C1Im][Ibu] and [N<sub>1112(OH)</sub>][Ibu] maintained their anti-inflammatory response to ibuprofen, with improved selectivity towards COX-2, allowing the development of safer NSAIDs and the recognition of new avenues for selective COX-2 inhibitors in cancer chemotherapy and neurological diseases such as Alzheimer’s and Parkinson’s.https://www.mdpi.com/2673-4079/3/3/23ionic liquidsibuprofenbioavailabilitycytotoxicityHepG2Caco-2 |
| spellingShingle | Joana C. Bastos Nicole S. M. Vieira Maria Manuela Gaspar Ana B. Pereiro João M. M. Araújo Human Cytotoxicity, Hemolytic Activity, Anti-Inflammatory Activity and Aqueous Solubility of Ibuprofen-Based Ionic Liquids Sustainable Chemistry ionic liquids ibuprofen bioavailability cytotoxicity HepG2 Caco-2 |
| title | Human Cytotoxicity, Hemolytic Activity, Anti-Inflammatory Activity and Aqueous Solubility of Ibuprofen-Based Ionic Liquids |
| title_full | Human Cytotoxicity, Hemolytic Activity, Anti-Inflammatory Activity and Aqueous Solubility of Ibuprofen-Based Ionic Liquids |
| title_fullStr | Human Cytotoxicity, Hemolytic Activity, Anti-Inflammatory Activity and Aqueous Solubility of Ibuprofen-Based Ionic Liquids |
| title_full_unstemmed | Human Cytotoxicity, Hemolytic Activity, Anti-Inflammatory Activity and Aqueous Solubility of Ibuprofen-Based Ionic Liquids |
| title_short | Human Cytotoxicity, Hemolytic Activity, Anti-Inflammatory Activity and Aqueous Solubility of Ibuprofen-Based Ionic Liquids |
| title_sort | human cytotoxicity hemolytic activity anti inflammatory activity and aqueous solubility of ibuprofen based ionic liquids |
| topic | ionic liquids ibuprofen bioavailability cytotoxicity HepG2 Caco-2 |
| url | https://www.mdpi.com/2673-4079/3/3/23 |
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