Potent antiplasmodial alkaloids from the rhizobacterium Pantoea agglomerans as hemozoin modulators
Document Type
Article
Publication Title
Bioorganic Chemistry
Abstract
Global health concern regarding malaria has increased since the first report of artemisinin-resistant Plasmodium falciparum (Pf) two decades ago. The current therapies suffer various drawbacks such as low efficacy and significant side effects, alarming for an urgent need of more effective and less toxic drugs with higher patient compliance. Chemical entities with natural origins become progressively attractive as new drug leads due to their structural diversity and bio-compatibility. This study initially aimed at the targeted isolation of hydroxyquinoline derivatives following our published genomics and metabolomics study of Pantoea agglomerans (Pa). Fermentation of Pa on a pre-selected medium followed by chromatographic isolation, NMR and HRMS analyses led to the characterisation of one new hydroxyquinoline alkaloid together with another six known congeners and two known hydroxyquinolone derivatives. When screened for their antimalarial activity by high throughput screening against asexual blood-stage parasites, almost all compounds showed potent and selective sub-micromolar activities. Computational investigation was performed to identify the antiplasmodial potential targets. Ligand-based similarity search predicted the tested compounds to act as hemozoin inhibitors. Computational target identification results were further validated by competitive hemozoin inhibitory properties of hydroxyquinoline and hydroxyquinolone derivatives in vitro. The overall results suggest this natural scaffold is of potential to be developed as antimalarial drug lead.
DOI
10.1016/j.bioorg.2021.105215
Publication Date
10-1-2021
Recommended Citation
Thissera, Bathini; Hallyburton, Irene; Ngwa, Che Julius; Cherif-Silini, Hafsa; Hassane, Ahmed S.I.; Anderson, Mark; Campbell, Lorna A.; Mutter, Nicole; Eshelli, Manal; Abdelmohsen, Usama R.; Yaseen, Mohammed; Pradel, Gabriele; Belbahri, Lassaad; Elgendy, Bahaa; Hegazy, Lamees; and Rateb, Mostafa E., "Potent antiplasmodial alkaloids from the rhizobacterium Pantoea agglomerans as hemozoin modulators" (2021). Pharmaceutical and Administrative Sciences Faculty Publications. 88.
https://doi.org/10.1016/j.bioorg.2021.105215
https://collections.uhsp.edu/pharm-admin-sciences_pubs/88