Ravindar, Lekkala and Hong, Ng yan and Bakar, Khairul Azreena and Hidayat, Ahmad Fadhlurrahman Ahmad and Feroz, Shevin Rizal and Raheem, Saki and Hasbullah, Siti Aishah and Hassan, Nurul Izzaty (2024) Synthesis, Molecular Docking and Heme Detoxification of Pyrano[2,3-c]pyrazole-aminoquinoline Hybrids as Potential Antimalarial Agents. Sains Malaysiana, 53 (8). pp. 1953-1968. ISSN 0126-6039, DOI https://doi.org/10.17576/jsm-2024-5308-18.
Full text not available from this repository.Abstract
Malaria, an infectious disease that spreads widely and can kill people, is still a problem for global health. This study adds to the list of possible solutions by making a group of new pyrano2,3-c]pyrazole-aminoquinoline hybrids. Here, five novel hybrids were synthesized by covalently linking the scaffolds of 4-aminoquinoline and pyrano2,3-c]pyrazoles via an ethyl linker. Molecular docking was used to study each hybrid's and standard chloroquine ability to bind to Plasmodium falciparum lactate dehydrogenase enzyme (PfLDH), an important enzyme in the parasite's glycolytic pathway. The hybrid compounds had a stronger binding affinity than the standard chloroquine. Compound 4c (-7.79 kcal/mol) and 4d (-7.73 kcal/mol) had strong interactions with PfLDH through hydrogen bonds, hydrophobic interactions, and Van der Waals interactions involving Val-26, Ile-54, Ala-98, Phe-100, Lys-118, Ile-119, and Glu-122. Additionally, the study explored the interaction between five hybrids and hemin, a pivotal component in the heme detoxification pathway of malaria parasites. The isothermal titration calorimetry (ITC) showed that the hybrids had different strengths when binding to hemin. This was because their structures were different. Hybrids 4a and 4b showed a strong affinity for hemin with Ka values of (1.43 f 0.60) x 106 M-1 and (1.64 f 0.97) x 106 M-1, respectively, indicating that they might be able to stop the disruption process. In contrast, hybrids 4c, 4d, and 4e interacted with hemin with markedly lower affinities. This study provides insights into the promising antimalarial properties of pyrano2,3-c]pyrazole-aminoquinoline hybrids. It details their interactions with PfLDH and hemin and offers potential avenues for developing novel therapeutic strategies against malaria.
| Item Type: | Article |
|---|---|
| Funders: | Universiti Kebangsaan Malaysia (UKM-T R2023-019) |
| Uncontrolled Keywords: | Isothermal titration calorimetry; Malaria; molecular docking; pyrano2; 3-c]pyrazole-aminoquinoline hybrids |
| Subjects: | Q Science > Q Science (General) Q Science > QH Natural history |
| Divisions: | Faculty of Science > Institute of Biological Sciences |
| Depositing User: | Ms. Juhaida Abd Rahim |
| Date Deposited: | 07 Apr 2025 08:03 |
| Last Modified: | 07 Apr 2025 08:03 |
| URI: | http://eprints.um.edu.my/id/eprint/46741 |
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