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Antimalarial Mannoxanes: Hybrid Antimalarial Drugs with Outstanding Oral Activity Profiles and A Potential Dual Mechanism of Action
Author(s) -
Chadwick James,
Amewu Richard K.,
Marti Francesc,
Garah Fatima BousejraEl,
Sharma Raman,
Berry Neil G.,
Stocks Paul A.,
BurrellSaward Hollie,
Wittlin Sergio,
Rottmann Matthias,
Brun Reto,
Taramelli Donatella,
Parapini Silvia,
Ward Stephen A.,
O'Neill Paul M.
Publication year - 2011
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201100196
Subject(s) - amodiaquine , mechanism of action , mechanism (biology) , pharmacology , artemisinin , chemistry , artesunate , drug , plasmodium falciparum , computational biology , computer science , malaria , medicine , biochemistry , biology , philosophy , in vitro , immunology , epistemology
A double‐edged sword ! A series of drug hybrids (mannoxanes) have been designed that have the capacity to target Plasmodium falciparum by two distinctive mechanisms. Selected compounds are active at low nanomolar concentrations and outperform artesunate, RKA 182 and a peroxide/amodiaquine combination in terms of curative effects in mice at 10 mg kg −1 . Proof of dual mechanism potential is provided by studies on hematin (Fe III PPIX) dimerisation inhibition and ferrous‐mediated, C‐centred radical production.