Hydroxyl mechanism of the antimalarial action of dimeric analogues of artemisinin

Abstract

Kinetic schemes of intramolecular oxidation have been constructed for four model compounds containing two artemisinin residues. Each step of the kinetic scheme has been characterized by an enthalpy of reaction. The activation energy and rate constant have been calculated using the intersecting-parabolas model. The competition between unimolecular and bimolecular reactions has been taken into account in constructing the kinetic scheme. In the case of H atom abstraction from the C-H bond in the α-position with respect to the hydroperoxyl group, the fragmentation of the molecule concerted with H abstraction has been taken into consideration. The intramolecular oxidation of the model compounds yields hydroperoxide groups, which, reacting with Fe(II), generate free radicals. Among the latter, hydroxyl radicals play the key role, as in the case of artemisinin. It is the number of hydroxyl radicals generated by the artemisinin analogues (n OH) that correlates with their antimalarial activity. The relationship between the effectiveness of the dimeric analogues, which is characterized by IC 50, and n OH is linear and, in the n OH = 3–7 range, is given by the formula IC 50(artemisinin)/IC 50(analogue) = 1 + 0.27/(n OH − 3.17).