Electron affinity and dipole moment of 1,2,4,5-tetraoxanes antimalarials and correlation with activity against Plasmodium falciparum

Antimalarial activity of 1,2,4,5-tetraoxanes is believed to be related to oxidation of heme by the peroxide group. This observation suggests that electron affinity of tetraoxanes is related to its activity. We have investigated the electron affinity of 20 tetraoxanes using quantum chemistry calculations at X3LYP/6-31(+)G(d) level and analyzed its correlation with activity. Other two parameters, dipole moment and logP, were also investigated. Using multi-linear regression, we have found that the electron affinity and the dipole moment have meaningful correlation with pIC(50) for K1 strain of Plasmodium falciparum, while logP is less important. Molecule 16 is out of the correlation. Docking studies suggest that the high activity of molecule 16 could be due to the intermolecular interaction between the amine group of molecule 16 and the carboxylic acid group of heme.