Methemoglobin Generation by 8-Aminoquinolines: Effect of Substitution at 5-Position of Primaquine

Abstract

Currently, the only clinically approved antimalarial drug to treat relapsing malaria is primaquine (PQ), yet PQ administration can cause life-threatening hemolytic anemia in some patients. In our efforts to understand the connection between PQ and methemoglobin formation, the effect of 5-substituted primaquine derivatives on the basicity of hemoglobin-bound O2 was investigated using various computational methods, including quantum mechanics/molecular mechanics (QM/MM) calculations, molecular dynamics simulations and density functional theory calculations, to determine the geometries, relative energies, spin densities, proton affinities and ionization potentials of various PQ derivatives and PQ···hemoglobin complexes. We found that the protein environment and solvent do not change our previously proposed methemoglobin formation mechanism that 5-hydroxyprimaquine donates an electron to O2, facilitating its conversion to H2O2 and generating methemoglobin. Because of 5-hydroxyprimaquine's ability to lose an electron by this mechanism, we then used different substituents at primaquine's 5-position and found that an electron-withdrawing group (EWG) increases the ionization potential of the corresponding derivative. As a result, the EWG-substituted derivatives make the hemoglobin-bound O2 less basic, because of their weaker electron-donating ability. These derivatives hence are predicted to have a lower propensity to generate methemoglobin, which can inform future design of less hemotoxic antimalarial drugs. We also carried out experimental measurement of methemoglobin formation for some of the 5-substituted derivatives.