title: Computational Study on the Effect of Exocyclic Substituents on the Ionization Potential of Primaquine: Insights into the Design of Primaquine-Based Antimalarial Drugs with Less Methemoglobin Generation.
abstract: The effect of an exocyclic substituent on the ionization potential of primaquine, an important antimalarial drug, was investigated using density functional theory methods. It was found that an electron-donating group (EDG) makes the ionization potential decrease. In contrast, an electron-withdrawing group (EWG) makes the ionization potential increase. Among all the exocyclic positions, a substituent at the 5- or 7-position has the largest effect. This can be explained by the contribution of the atomic orbitals at those positions to the highest occupied molecular orbital (HOMO). In addition, a substituent at the N8-position has a considerably large effect on the ionization potential because this atom makes the second largest contribution to the HOMO. These findings have potential implications for the design of less hemotoxic antimalarial drugs. We suggest that it is worth considering placement of an EWG at the 5-, 7-, or N8-positions of primaquine in future drug discovery attempts.
authors.affiliation: Department of BioMolecular Sciences and ‡the National Center for Natural Products Research, School of Pharmacy, University of Mississippi , University, Mississippi 38677, United States.
authors.forename: Haining
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of BioMolecular Sciences and ‡the National Center for Natural Products Research, School of Pharmacy, University of Mississippi , University, Mississippi 38677, United States.
authors.forename: Yuanqing
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Department of BioMolecular Sciences and ‡the National Center for Natural Products Research, School of Pharmacy, University of Mississippi , University, Mississippi 38677, United States.
authors.forename: Larry A
authors.initials: LA
authors.lastname: Walker
authors.affiliation: Department of BioMolecular Sciences and ‡the National Center for Natural Products Research, School of Pharmacy, University of Mississippi , University, Mississippi 38677, United States.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Doerksen
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D008706:Methemoglobin / Q000096:biosynthesis*; D015394:Molecular Structure; D011319:Primaquine / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011789:Quantum Theory
chemical_list: D000962:Antimalarials; D008706:Methemoglobin; D011319:Primaquine