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

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• 作者：Haining Liu ; Babu L. Tekwani ; N. P. Dhammika Nanayakkara ; Larry A. Walker ; Robert J. Doerksen
• 刊名：Chemical Research in Toxicology
• 出版年：2013
• 出版时间：December 16, 2013
• 年：2013
• 卷：26
• 期：12
• 页码：1801-1809
• 全文大小：380K
• 年卷期：v.26,no.12(December 16, 2013)
• ISSN：1520-5010

文摘

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路路路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鈥檚 ability to lose an electron by this mechanism, we then used different substituents at primaquine鈥檚 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.