Hydrazonophenol, a Food Vacuole-Targeted and Ferriprotoporphyrin IX-Interacting Chemotype Prevents Drug-Resistant Malaria
| Autor: | Shubhra Jyoti Saha, Chinmoy Banerjee, Uday Bandyopadhyay, Subhashis Debsharma, Shiladitya Nag, Somnath Mazumder, Rudranil De, Saikat Pramanik, Debanjan Saha, Asim Azhar Siddiqui |
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| Rok vydání: | 2018 |
| Předmět: |
Hemeproteins
0301 basic medicine Plasmodium berghei Plasmodium falciparum 030106 microbiology Drug Resistance Antimalarials Mice 03 medical and health sciences Phenols In vivo parasitic diseases Food vacuole Animals Moiety Bioassay Malaria Falciparum Microscopy Confocal biology Chemistry Hemozoin Hydrazones Plasmodium yoelii Hydrogen-Ion Concentration biology.organism_classification In vitro 030104 developmental biology Infectious Diseases Biochemistry Cerebral Malaria Vacuoles Hemin Biological Assay Protein Binding |
| Zdroj: | ACS Infectious Diseases. 5:63-73 |
| ISSN: | 2373-8227 |
| DOI: | 10.1021/acsinfecdis.8b00178 |
| Popis: | The rapid emergence of resistance against frontline antimalarial drugs essentially warrants the identification of new-generation antimalarials. Here, we describe the synthesis of ( E)-2-isopropyl-5-methyl-4-((2-(pyridin-4-yl)hydrazono)methyl)phenol (18), which binds ferriprotoporphyrin-IX (FeIII-PPIX) ( Kd = 33 nM) and offers antimalarial activity against chloroquine-resistant and sensitive strains of Plasmodium falciparum in vitro. Structure-function analysis reveals that compound 18 binds FeIII-PPIX through the -C═N-NH- moiety and 2-pyridyl substitution at the hydrazine counterpart plays a critical role in antimalarial efficacy. Live cell confocal imaging using a fluorophore-tagged compound confirms its accumulation inside the acidic food vacuole (FV) of P. falciparum. Furthermore, this compound concentration-dependently elevates the pH in FV, implicating a plausible interference with FeIII-PPIX crystallization (hemozoin formation) by a dual function: increasing the pH and binding free FeIII-PPIX. Different off-target bioassays reduce the possibility of the promiscuous nature of compound 18. Compound 18 also exhibits potent in vivo antimalarial activity against chloroquine-resistant P. yoelii and P. berghei ANKA (causing cerebral malaria) in mice with negligible toxicity. |
| Databáze: | OpenAIRE |
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