Methemoglobinemia hemotoxicity of some antimalarial 8-aminoquinoline analogues and their hydroxylated derivatives: density functional theory computation of ionization potentials

Authors: DING, YUANQING - University Of Mississippi; LIU, HAINING - University Of Mississippi; TEKWANI, BABU - University Of Mississippi; NANAYAKKARA, N.P. DHAMMIKA - University Of Mississippi; KHAN, IKHLAS - University Of Mississippi; WALKER, LARRY - University Of Mississippi; DOERKSEN, ROBERT - University Of Mississippi

Submitted to: Chemical Research in Toxicology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/25/2016
Publication Date: 5/26/2016
Citation: Ding, Y., Liu, H., Tekwani, B.L., Nanayakkara, N., Khan, I.A., Walker, L.A., Doerksen, R.J. 2016. Methemoglobinemia hemotoxicity of some antimalarial 8-aminoquinoline analogues and their hydroxylated derivatives: density functional theory computation of ionization potentials. Chemical Research in Toxicology. http://dx.doi.org/acs.orglett.6b00063.

Interpretive Summary: Demethoxylated primaquine (AQ02) was employed as a model to study potential hemotoxicity of PQ-based antimalarials by calculating the ionization potentials of their hydroxylated metabolites. Hydroxylation at N1', C5, and C7 was found to contribute the most to the methemoglobin generation. Phenoxylation at C5 in PQ-based 8-AQs can reduce this risk. The introduction of an electron-withdrawing group to the core can significantly reduce this risk. The hydroxylation at C7 has little effect.

Technical Abstract: The administration of primaquine (PQ), an essential drug for 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 more methemoglobin will be 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 analogs 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 design of safer antimalarial 8- AQ analogs.