Second generation antimalarial tetraoxanes N205 and E209

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Synthetic endoperoxide antimalarials are promising successors for current front-line antimalarials, semisynthetic artemisinin derivatives. E209 and N205 are reported to possess potent fast killing of P.falciparum and 66% cure rate in the P.berghei mouse model after a single dose of 30 mg/kg. These compounds are amphiphilic but poorly water soluble, particularly in fasted state simulated intestinal fluid (FaSSIF).
Introducing nonlinearity to the tetraoxane scaffold through the 3″ position of the cyclohexyl ring successfully decreased melting point and improved FaSSIF solubility. A chiral center formed in the 3″ position so the analogues were synthesised and evaluated as both individual enantiomers and racemic mixtures. R was varied and their pharmacokinetic profiles were investigated. Using conjugate addition with Rh(acac)(C₂H₄)₂ with BINAP as the chiral ligand, antimalarial potency was preserved compared to chloroquine-sensitive strains and all the analogues maintained a low nanomolar potency against P.falciparum . The pharmacokinetics such as oral bioavailability had overall improved, which supported the potential use of these analogues in malaria treatment.

C. M. Woodley, G. L. Nixon, N. Basilico, S. Parapini, W. D. Hong, S. A. Ward, G. A. Biagini, S. C. Leung, D. Taramelli, K. Onuma, T. Hasebe and P. M. O’Neill, ACS Medicinal Chemistry Letters, 2021, 12, 1077-1085.