Functionalized 3-hydroxy-3-aminoquinoline-oxindole hybrids as promising dual-function anti-plasmodials
Malaria parasites continue to pose a concern. Drug resistance underlines the need for new structural cores that, when combined with existing antimalarial frameworks, can partially re-sensitize drug-resistant parasites to available antimalarial drugs, such as chloroquine (CQ). Herein, we used “covale...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-08-01
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| Series: | European Journal of Medicinal Chemistry Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2772417422000243 |
| _version_ | 1818029643457888256 |
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| author | Bharvi Sharma Jenny Legac Nosipho Cele Paul Awolade Philip J. Rosenthal Parvesh Singh Vipan Kumar |
| author_facet | Bharvi Sharma Jenny Legac Nosipho Cele Paul Awolade Philip J. Rosenthal Parvesh Singh Vipan Kumar |
| author_sort | Bharvi Sharma |
| collection | DOAJ |
| description | Malaria parasites continue to pose a concern. Drug resistance underlines the need for new structural cores that, when combined with existing antimalarial frameworks, can partially re-sensitize drug-resistant parasites to available antimalarial drugs, such as chloroquine (CQ). Herein, we used “covalent biotherapy” to design and synthesize a series of aminoquinoline-oxindoles. The most promising hybrid exhibited an IC50 value of 30.9 nM against the drug-resistant W2 strain of P. falciparum, and was seven-fold more active than CQ. To decipher the mode of action, UV–Vis spectral and molecular modelling studies were performed, demonstrating that the hybrid exerts antiplasmodial effects via hemozoin (aminoquinoline) and PfCRT inhibition (oxindole), demonstrating its dual-functionality. To the best of our knowledge, this is the first report of an oxindole core acting as a potential PfCRT inhibitor, which could be a key component in the development of CQ-based chemosensitizers in the near future. |
| first_indexed | 2024-12-10T05:22:57Z |
| format | Article |
| id | doaj.art-e40eef5a12da487e8527693137b24e2e |
| institution | Directory Open Access Journal |
| issn | 2772-4174 |
| language | English |
| last_indexed | 2024-12-10T05:22:57Z |
| publishDate | 2022-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | European Journal of Medicinal Chemistry Reports |
| spelling | doaj.art-e40eef5a12da487e8527693137b24e2e2022-12-22T02:00:46ZengElsevierEuropean Journal of Medicinal Chemistry Reports2772-41742022-08-015100052Functionalized 3-hydroxy-3-aminoquinoline-oxindole hybrids as promising dual-function anti-plasmodialsBharvi Sharma0Jenny Legac1Nosipho Cele2Paul Awolade3Philip J. Rosenthal4Parvesh Singh5Vipan Kumar6Department of Chemistry, Guru Nanak Dev University, Amritsar, 143005, Punjab, IndiaUniversity of California, San Francisco, CA, USASchool of Chemistry and Physics, University of KwaZulu-Natal, P/Bag X54001, Westville, Durban, South AfricaSchool of Chemistry and Physics, University of KwaZulu-Natal, P/Bag X54001, Westville, Durban, South AfricaUniversity of California, San Francisco, CA, USASchool of Chemistry and Physics, University of KwaZulu-Natal, P/Bag X54001, Westville, Durban, South Africa; Corresponding author.Department of Chemistry, Guru Nanak Dev University, Amritsar, 143005, Punjab, India; Corresponding author.Malaria parasites continue to pose a concern. Drug resistance underlines the need for new structural cores that, when combined with existing antimalarial frameworks, can partially re-sensitize drug-resistant parasites to available antimalarial drugs, such as chloroquine (CQ). Herein, we used “covalent biotherapy” to design and synthesize a series of aminoquinoline-oxindoles. The most promising hybrid exhibited an IC50 value of 30.9 nM against the drug-resistant W2 strain of P. falciparum, and was seven-fold more active than CQ. To decipher the mode of action, UV–Vis spectral and molecular modelling studies were performed, demonstrating that the hybrid exerts antiplasmodial effects via hemozoin (aminoquinoline) and PfCRT inhibition (oxindole), demonstrating its dual-functionality. To the best of our knowledge, this is the first report of an oxindole core acting as a potential PfCRT inhibitor, which could be a key component in the development of CQ-based chemosensitizers in the near future.http://www.sciencedirect.com/science/article/pii/S2772417422000243Oxindoles4-AminoquinolinesEpoxide-ring openingChloroquine resistanceHemozoin inhibitionPfCRT |
| spellingShingle | Bharvi Sharma Jenny Legac Nosipho Cele Paul Awolade Philip J. Rosenthal Parvesh Singh Vipan Kumar Functionalized 3-hydroxy-3-aminoquinoline-oxindole hybrids as promising dual-function anti-plasmodials European Journal of Medicinal Chemistry Reports Oxindoles 4-Aminoquinolines Epoxide-ring opening Chloroquine resistance Hemozoin inhibition PfCRT |
| title | Functionalized 3-hydroxy-3-aminoquinoline-oxindole hybrids as promising dual-function anti-plasmodials |
| title_full | Functionalized 3-hydroxy-3-aminoquinoline-oxindole hybrids as promising dual-function anti-plasmodials |
| title_fullStr | Functionalized 3-hydroxy-3-aminoquinoline-oxindole hybrids as promising dual-function anti-plasmodials |
| title_full_unstemmed | Functionalized 3-hydroxy-3-aminoquinoline-oxindole hybrids as promising dual-function anti-plasmodials |
| title_short | Functionalized 3-hydroxy-3-aminoquinoline-oxindole hybrids as promising dual-function anti-plasmodials |
| title_sort | functionalized 3 hydroxy 3 aminoquinoline oxindole hybrids as promising dual function anti plasmodials |
| topic | Oxindoles 4-Aminoquinolines Epoxide-ring opening Chloroquine resistance Hemozoin inhibition PfCRT |
| url | http://www.sciencedirect.com/science/article/pii/S2772417422000243 |
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