Synthesis, Molecular Docking and Heme Detoxification of Pyrano[2,3-c]pyrazole-aminoquinoline Hybrids as Potential Antimalarial Agents
Document Type
Article
Publication Date
8-1-2024
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.
Keywords
Isothermal titration calorimetry, Malaria, molecular docking, pyrano2, 3-c]pyrazole-aminoquinoline hybrids
Divisions
InstituteofBiologicalSciences
Funders
Universiti Kebangsaan Malaysia (UKM-T R2023-019)
Publication Title
Sains Malaysiana
Volume
53
Issue
8
Publisher
Penerbit Universiti Kebangsaan Malaysia
Publisher Location
-, BANGI, SELANGOR 43600, MALAYSIA