title: Methemoglobinemia Hemotoxicity of Some Antimalarial 8-Aminoquinoline Analogues and Their Hydroxylated Derivatives: Density Functional Theory Computation of Ionization Potentials.
abstract: The administration of primaquine (PQ), an essential drug for the treatment and radical cure of malaria, can lead to methemoglobin formation and life-threatening hemolysis for glucose-6-phosphate dehydrogenase deficient patients. The ionization potential (IP, a quantitative measure of the ability to lose an electron) of the metabolites generated by antimalarial 8-aminoquinoline (8-AQ) drugs like PQ has been believed to be correlated in part to this methemoglobinemia hemotoxicity: the lower the IP of an 8-AQ derivative, the higher the concentration of methemoglobin generated. In this work, demethoxylated primaquine (AQ02) was employed as a model, by intensive computation at the B3LYP-SCRF(PCM)/6-311++G**//B3LYP/6-31G** level in water, to study the effects of hydroxylation at various positions on the ionization potential. Compared to the parent AQ02, the IPs of AQ02's metabolites hydroxylated at N1', C5, and C7 were lower by 61, 30, and 19 kJ/mol, respectively, while differences in the IP relative to PQ were small for hydroxylation at all other positions. The C6 position, at which the IP of the hydroxylated metabolite was greater than that of AQ02, by 2 kJ/mol, was found to be unique. Several literature and proposed 8-AQ analogues were studied to evaluate substituent effects on their potential to generate methemoglobin, with the finding that hydroxylations at N1' and C5 contribute the most to the potential hemotoxicity of PQ-based antimalarials, whereas hydroxylation at C7 has little effect. Phenoxylation at C5 in PQ-based 8-AQs can block the hydroxylation at C5 and reduce the potential for methemoglobin generation, while -CF3 and chlorines attached to the phenolic ring can further reduce the risk. The H-shift at N1' during the cationization of hydroxylated metabolites of 8-AQs sharply decreased their IPs, but this effect can be significantly reduced by the introduction of an electron-withdrawing group to the quinoline core. The results and this approach may be utilized for the design of safer antimalarial 8-AQ analogues.
authors.affiliation: National Center for Natural Products Research, Research Institute of Pharmaceutical Science, and ‡Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi , University, Mississippi 38677, United States.
authors.forename: Yuanqing
authors.initials: Y
authors.lastname: Ding
authors.affiliation: National Center for Natural Products Research, Research Institute of Pharmaceutical Science, and ‡Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi , University, Mississippi 38677, United States.
authors.forename: Haining
authors.initials: H
authors.lastname: Liu
authors.affiliation: National Center for Natural Products Research, Research Institute of Pharmaceutical Science, and ‡Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi , University, Mississippi 38677, United States.
authors.forename: Babu L
authors.initials: BL
authors.lastname: Tekwani
authors.affiliation: National Center for Natural Products Research, Research Institute of Pharmaceutical Science, and ‡Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi , University, Mississippi 38677, United States.
authors.forename: N P Dhammika
authors.initials: NP
authors.lastname: Nanayakkara
authors.affiliation: National Center for Natural Products Research, Research Institute of Pharmaceutical Science, and ‡Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi , University, Mississippi 38677, United States.
authors.forename: Ikhlas A
authors.initials: IA
authors.lastname: Khan
authors.affiliation: National Center for Natural Products Research, Research Institute of Pharmaceutical Science, and ‡Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi , University, Mississippi 38677, United States.
authors.forename: Larry A
authors.initials: LA
authors.lastname: Walker
authors.affiliation: National Center for Natural Products Research, Research Institute of Pharmaceutical Science, and ‡Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi , University, Mississippi 38677, United States.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Doerksen
mesh_terms: D000634:Aminoquinolines / Q000633:toxicity*; D000962:Antimalarials / Q000633:toxicity*; D004563:Electrochemistry; D006900:Hydroxylation; D008708:Methemoglobinemia / Q000139:chemically induced*
chemical_list: D000634:Aminoquinolines; D000962:Antimalarials; C080436:8-aminoquinoline