1338604-84-4Relevant articles and documents
Comparison of the reactivity of antimalarial 1,2,4,5-tetraoxanes with 1,2,4-trioxolanes in the presence of ferrous iron salts, heme, and ferrous iron salts/phosphatidylcholine
Bousejra-El Garah, Fatima,Wong, Michael He-Long,Amewu, Richard K.,Muangnoicharoen, Sant,Maggs, James L.,Stigliani, Jean-Luc,Park, B. Kevin,Chadwick, James,Ward, Stephen A.,O'Neill, Paul M.
supporting information; scheme or table, p. 6443 - 6455 (2011/12/04)
Dispiro-1,2,4,5-tetraoxanes and 1,2,4-trioxolanes represent attractive classes of synthetic antimalarial peroxides due to their structural simplicity, good stability, and impressive antimalarial activity. We investigated the reactivity of a series of potent amide functionalized tetraoxanes with Fe(II)gluconate, FeSO4, FeSO4/TEMPO, FeSO 4/phosphatidylcholine, and heme to gain knowledge of their potential mechanism of bioactivation and to compare the results with the corresponding 1,2,4-trioxolanes. Spin-trapping experiments demonstrate that Fe(II)-mediated peroxide activation of tetraoxanes produces primary and secondary C-radical intermediates. Reaction of tetraoxanes and trioxolanes with phosphatidylcholine, a predominant unsaturated lipid present in the parasite digestive vacuole membrane, under Fenton reaction conditions showed that both endoperoxides share a common reactivity in terms of phospholipid oxidation that differs with that of artemisinin. Significantly, when tetraoxanes undergo bioactivation in the presence of heme, only the secondary C-centered radical is observed, which smoothly produces regioisomeric drug derived-heme adducts. The ability of these tetraoxanes to alkylate the porphyrin ring was also confirmed with Fe IITPP and MnIITPP, and docking studies were performed to rationalize the regioselectivity observed in the alkylation process. The efficient process of heme alkylation and extensive lipid peroxidation observed here may play a role in the mechanism of action of these two important classes of synthetic endoperoxide antimalarial.
Identification of a 1,2,4,5-tetraoxane antimalarial drug-development candidate (RKA 182) with superior properties to the semisynthetic artemisinins
O'Neill, Paul M.,Amewu, Richard K.,Nixon, Gemma L.,ElGarah, Fatima Bousejra,Mungthin, Mathirut,Chadwick, James,Shone, Alison E.,Vivas, Livia,Lander, Hollie,Barton, Victoria,Muangnoicharoen, Sant,Bray, Patrick G.,Davies, Jill,Park, B. Kevin,Wittlin, Sergio,Brun, Reto,Preschel, Michael,Zhang, Kesheng,Ward, Stephen A.
scheme or table, p. 5693 - 5697 (2010/11/04)
(Figure Presented) Fighting drug resistence: From a library of over 150 1,2,4,5-tetraoxanes, the candidate RKA182 was selected for preclinical development as an antimalarial agent. RKA182 has outstanding in vitro activity against resistant strains of P. falciparum and retains this level of activity against southeast asian isolates that failed artemisinin-based combination therapy.
