{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T12:40:01Z","timestamp":1788871201404,"version":"build-2803163510"},"reference-count":38,"publisher":"American Chemical Society (ACS)","issue":"29","license":[{"start":{"date-parts":[[2015,6,23]],"date-time":"2015-06-23T00:00:00Z","timestamp":1435017600000},"content-version":"vor","delay-in-days":365,"URL":"https:\/\/pubs.acs.org\/page\/policy\/authorchoice_termsofuse.html"}],"funder":[{"DOI":"10.13039\/100000199","name":"U.S. Department of Agriculture","doi-asserted-by":"publisher","award":["58-6408-2-0009"],"award-info":[{"award-number":["58-6408-2-0009"]}],"id":[{"id":"10.13039\/100000199","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,7,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>For antimalarial 8-aminoquinoline (8-AQ) drugs, the ionization potential (energy required to remove an electron) of their putative metabolites has been proposed to be correlated in part to their hemotoxicity potential. NPC1161 is a developmental candidate as an 8-AQ antimalarial drug. In this work, the ionization potentials (IPs) of the S-NPC1161 (NPC1161a) hydroxylated derivatives, which are possible metabolites derived from action of endogenous cytochrome P450 (CYP450) enzymes, were calculated at the B3LYP-SCRF(PCM)\/6-311++G**\/\/B3LYP\/6-31G** level in water. The derivative hydroxylated at N1\u2032 (8-amino) was found to have the smallest IP of \u223c430 kJ\/mol, predicting that it would be the most hemotoxic. The calculated IPs of the derivatives hydroxylated at the C2 and C7 positions were \u223c475 and \u223c478 kJ\/mol, respectively, whereas the calculated IPs of those hydroxylated at all other possible positions were between 480 and 490 kJ\/mol. The homolytic bond dissociation energies (HBDEs) of all C\u2013H\/N\u2013H bonds in NPC1161a were also calculated. The smaller HBDEs of the C\u2013H\/N\u2013H bonds on the 8-amino side chain suggest that these positions are more easily hydroxylated compared to other sites. Molecular orbital analysis implies that the N1\u2032 position should be the most reactive center when NPC1161 approaches the heme in CYP450.<\/jats:p>","DOI":"10.1021\/jp502612t","type":"journal-article","created":{"date-parts":[[2014,6,23]],"date-time":"2014-06-23T18:53:31Z","timestamp":1403549611000},"page":"5501-5507","source":"Crossref","is-referenced-by-count":4,"title":["Hydroxylated\nDerivatives of NPC1161: Theoretical\nInsights into Their Potential\nToxicity and the Feasibility and Regioselectivity of Their Formation"],"prefix":"10.1021","volume":"118","author":[{"given":"Yuanqing","family":"Ding","sequence":"first","affiliation":[{"name":"University of Mississippi , , School of Pharmacy, , , ,","place":["University, Mississippi, United States, 38677"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haining","family":"Liu","sequence":"additional","affiliation":[{"name":"University of Mississippi , , School of Pharmacy, , , ,","place":["University, Mississippi, United States, 38677"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N. P. Dhammika","family":"Nanayakkara","sequence":"additional","affiliation":[{"name":"University of Mississippi , , School of Pharmacy, , , ,","place":["University, Mississippi, United States, 38677"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ikhlas A.","family":"Khan","sequence":"additional","affiliation":[{"name":"University of Mississippi , , School of Pharmacy, , , ,","place":["University, Mississippi, United States, 38677"]},{"name":"University of Mississippi , , School of Pharmacy, , , ,","place":["University, Mississippi, United States, 38677"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Babu L.","family":"Tekwani","sequence":"additional","affiliation":[{"name":"University of Mississippi , , School of Pharmacy, , , ,","place":["University, Mississippi, United States, 38677"]},{"name":"University of Mississippi , , School of Pharmacy, , , ,","place":["University, Mississippi, United States, 38677"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Larry A.","family":"Walker","sequence":"additional","affiliation":[{"name":"University of Mississippi , , School of Pharmacy, , , ,","place":["University, Mississippi, United States, 38677"]},{"name":"University of Mississippi , , School of Pharmacy, , , ,","place":["University, Mississippi, United States, 38677"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert J.","family":"Doerksen","sequence":"additional","affiliation":[{"name":"University of Mississippi , , School of Pharmacy, , , ,","place":["University, Mississippi, United States, 38677"]},{"name":"University of Mississippi , , School of Pharmacy, , , ,","place":["University, Mississippi, United States, 38677"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2014,6,23]]},"reference":[{"key":"2026090306161921600_cit1","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/S0140-6736(12)60034-8","article-title":"Global\nMalaria Mortality between 1980 and 2010: A Systematic\nAnalysis","volume":"379","author":"Murray","year":"2012","journal-title":"Lancet"},{"key":"2026090306161921600_cit2","doi-asserted-by":"crossref","first-page":"1524","DOI":"10.1021\/ja01212a040","article-title":"Alkylaminoalkyl Derivatives\nof 8-Aminoquinoline","volume":"68","author":"Elderfield","year":"1946","journal-title":"J. Am. Chem. Soc."},{"key":"2026090306161921600_cit3","doi-asserted-by":"crossref","first-page":"160","DOI":"10.2165\/00003495-199039020-00002","article-title":"Treatment of Malaria\u25001990","volume":"39","author":"Panisko","year":"1990","journal-title":"Drugs"},{"key":"2026090306161921600_cit4","doi-asserted-by":"crossref","first-page":"1336","DOI":"10.1086\/424663","article-title":"Primaquine Therapy\nfor Malaria","volume":"39","author":"Baird","year":"2004","journal-title":"Clin. Infect. Dis."},{"key":"2026090306161921600_cit5","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1093\/milmed\/134.9.802","article-title":"Gametocytocidal\nand Sporontocidal\nEffects of Primaquine upon Two Strains of Plasmodium Falciparum","volume":"134","author":"Rieckmann","year":"1969","journal-title":"Military Med."},{"key":"2026090306161921600_cit6","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1056\/NEJM196811212792102","article-title":"Methemoglobinemia\nProvoked by Malarial Chemoprophylaxis in Vietnam","volume":"279","author":"Cohen","year":"1968","journal-title":"N. Engl. J. Med."},{"key":"2026090306161921600_cit7","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1001\/archinte.1962.03620140081013","article-title":"Primaquine Sensitivity:\nGlucose-6-Phosphate Dehydrogenase Deficiency: An Inborn Error of Metabolism\nof Medical and Biological Significance","volume":"109","author":"Tarlov","year":"1962","journal-title":"Arch.\nInt. Med."},{"key":"2026090306161921600_cit8","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.taap.2009.07.012","article-title":"Cytochrome\nP450-Dependent Toxic Effects of Primaquine on Human Erythrocytes","volume":"241","author":"Ganesan","year":"2009","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"2026090306161921600_cit9","doi-asserted-by":"crossref","first-page":"2130","DOI":"10.1128\/AAC.00645-07","article-title":"Antiparasitic Activities and Toxicities of Individual\nEnantiomers of the 8-Aminoquinoline 8-[(4-Amino-1-methylbutyl)amino]-6-methoxy-4-methyl-5-[3,4-dichlorophenoxy]quinoline\nSuccinate","volume":"52","author":"Nanayakkara","year":"2008","journal-title":"Antimicrob. Agents Chemother."},{"key":"2026090306161921600_cit10","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1186\/1475-2875-12-212","article-title":"The Metabolism\nof Primaquine to Its Active Metabolite Is Dependent on CYP 2D6","volume":"12","author":"Pybus","year":"2013","journal-title":"Malar. J."},{"key":"2026090306161921600_cit11","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1006\/eesa.1999.1868","article-title":"Toxicology\nof the 8-Aminoquinolines and Genetic Factors Associated with Their\nToxicity in Man","volume":"45","author":"Srivastava","year":"2000","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"2026090306161921600_cit12","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1002\/med.20062","article-title":"Recent Advances\nin Antimalarial Drug\nDevelopment","volume":"27","author":"Suryanaryana","year":"2007","journal-title":"Med. Res. Rev."},{"key":"2026090306161921600_cit13","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1016\/j.ejmech.2008.08.011","article-title":"Primaquine Revisited\nSix Decades\nafter Its Discovery","volume":"44","author":"Vale","year":"2009","journal-title":"Eur. J. Med. Chem."},{"key":"2026090306161921600_cit14","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1016\/S0022-3565(24)29564-1","article-title":"Primaquine-Induced\nHemolytic Anemia: Formation and Hemotoxicity of the Arylhydroxylamine\nMetabolite 6-Methoxy-8-hydroxylaminoquinoline","volume":"297","author":"Bolchoz","year":"2001","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"2026090306161921600_cit15","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1124\/jpet.102.041459","article-title":"Primaquine-Induced\nHemolytic Anemia: Formation of Free Radicals in Rat Erythrocytes Exposed\nto 6-Methoxy-8-hydroxylaminoquinoline","volume":"303","author":"Bolchoz","year":"2002","journal-title":"J. Pharmacol.\nExp. Ther."},{"key":"2026090306161921600_cit16","doi-asserted-by":"crossref","first-page":"980","DOI":"10.1124\/jpet.105.090407","article-title":"Primaquine-Induced Hemolytic Anemia:\nRole of Splenic Macrophages in the Fate of 5-Hydroxyprimaquine-Treated\nRat Erythrocytes","volume":"315","author":"Bowman","year":"2005","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"2026090306161921600_cit17","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1124\/jpet.103.062984","article-title":"Primaquine-Induced\nHemolytic Anemia: Susceptibility of Normal Versus Glutathione-Depleted\nRat Erythrocytes to 5-Hydroxyprimaquine","volume":"309","author":"Bowman","year":"2004","journal-title":"J.\nPharmacol. Exp. Ther."},{"key":"2026090306161921600_cit18","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/S0940-2993(99)80010-4","article-title":"Metabolism of Primaquine by Liver Homogenate Fractions. Evidence\nfor Monoamine Oxidase and Cytochrome P450 Involvement in the Oxidative\nDeamination of Primaquine to Carboxyprimaquine","volume":"51","author":"Constantino","year":"1999","journal-title":"Exp. Toxic. Pathol."},{"key":"2026090306161921600_cit19","first-page":"468","article-title":"The Conversion of\nPrimaquine into Primaquine-Aldehyde, Primaquine-Alcohol, and Carboxyprimaquine,\na Major Plasma Metabolite","volume":"117","author":"Frischer","year":"1991","journal-title":"J. Lab. Clin. Med."},{"key":"2026090306161921600_cit20","doi-asserted-by":"crossref","first-page":"6848","DOI":"10.1016\/S0021-9258(19)50504-X","article-title":"Hydroxylated\nMetabolites of the Antimalarial Drug Primaquine.\nOxidation and Redox Cycling","volume":"267","author":"Va\u0301squez-Vivar","year":"1992","journal-title":"J. Biol. Chem."},{"key":"2026090306161921600_cit21","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/0006-2952(94)90022-1","article-title":"Oxidative\nActivity of Primaquine Metabolites on Rat\nErythrocytes in Vitro and in Vivo","volume":"47","author":"Va\u0301squez-Vivar","year":"1994","journal-title":"Biochem.\nPharmacol."},{"key":"2026090306161921600_cit22","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1016\/0041-008X(85)90155-3","article-title":"Structure\u2013Activity\nRelationships of Putative Primaquine Metabolites Causing Methemoglobin\nFormation in Canine Hemolysates","volume":"81","author":"Link","year":"1985","journal-title":"Toxicol. Appl.\nPharmacol."},{"key":"2026090306161921600_cit23","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/1475-2875-13-2","article-title":"Tafenoquine\nand NPC-1161b Require CYP 2D Metabolism for Anti-Malarial Activity:\nImplications for the 8-Aminoquinoline Class of Anti-Malarial Compounds","volume":"13","author":"Marcsisin","year":"2014","journal-title":"Malar. J."},{"key":"2026090306161921600_cit24","unstructured":"McChesney, J.; Nanayakkara, D. N.; Bartlett, M.; Ager, A. L.\n          8-Aminoquinolines. U.S. Patent 6,376,511, 2002."},{"key":"2026090306161921600_cit25","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.jconrel.2003.09.012","article-title":"Targetable\nWater-Soluble Polymer\u2013Drug Conjugates for the Treatment of\nVisceral Leishmaniasis","volume":"94","author":"Nan","year":"2004","journal-title":"J. Controlled Release"},{"key":"2026090306161921600_cit26","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/S0168-3659(01)00514-4","article-title":"N-(2-Hydroxypropyl)methacrylamide\n(HPMA) Copolymers for Targeted Delivery of 8-Aminoquinoline Antileishmanial\nDrugs","volume":"77","author":"Nan","year":"2001","journal-title":"J. Controlled Release"},{"key":"2026090306161921600_cit27","doi-asserted-by":"crossref","first-page":"1372","DOI":"10.1063\/1.464304","article-title":"A New Mixing\nof Hartree-Fock and Local Density-Functional Theories","volume":"98","author":"Becke","year":"1993","journal-title":"J. Chem. Phys."},{"key":"2026090306161921600_cit28","doi-asserted-by":"crossref","first-page":"5648","DOI":"10.1063\/1.464913","article-title":"Density-Functional\nThermochemistry. III. The Role of Exact Exchange","volume":"98","author":"Becke","year":"1993","journal-title":"J. Chem. Phys."},{"key":"2026090306161921600_cit29","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1103\/PhysRevB.37.785","article-title":"Development of the Colle\u2013Salvetti\nCorrelation-Energy Formula into a Functional of the Electron Density","volume":"37","author":"Lee","year":"1988","journal-title":"Phys. Rev. B"},{"key":"2026090306161921600_cit30","volume-title":"Gaussian 09","author":"Frisch","year":"2009"},{"key":"2026090306161921600_cit31","doi-asserted-by":"crossref","first-page":"1801","DOI":"10.1021\/tx400067a","article-title":"Methemoglobin\nGeneration by 8-Aminoquinolines: Effect of Substitution at 5-Position\nof Primaquine","volume":"26","author":"Liu","year":"2013","journal-title":"Chem. Res. Toxicol."},{"key":"2026090306161921600_cit32","doi-asserted-by":"crossref","first-page":"1476","DOI":"10.1021\/tx200094v","article-title":"DFT Study\non the Radical Anions Formed\nby Primaquine and Its Derivatives","volume":"24","author":"Liu","year":"2011","journal-title":"Chem. Res.\nToxicol."},{"key":"2026090306161921600_cit33","doi-asserted-by":"crossref","first-page":"1172","DOI":"10.1021\/ja107472c","article-title":"Methemoglobinemia\nCaused by 8-Aminoquinoline Drugs: DFT Calculations Suggest an Analogy\nto H4B\u2019s Role in Nitric Oxide Synthase","volume":"133","author":"Liu","year":"2011","journal-title":"J. Am. Chem. Soc."},{"key":"2026090306161921600_cit34","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1039\/c3md00045a","article-title":"Effect of Antimalarial\nDrug Primaquine and Its Derivatives on the Ionization Potential of\nHemoglobin: A QM\/MM Study","volume":"4","author":"Liu","year":"2013","journal-title":"Med. Chem. Commun."},{"key":"2026090306161921600_cit35","unstructured":"MacroModel, version 9.9; Schro\u0308dinger\nLLC: New York, 2011."},{"key":"2026090306161921600_cit36","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1021\/tx700079z","article-title":"Cytochrome\nP450 and Chemical Toxicology","volume":"21","author":"Guengerich","year":"2008","journal-title":"Chem. Res. Toxicol."},{"key":"2026090306161921600_cit37","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1021\/ar970171h","article-title":"Hydrogen\nAtom Abstraction by Metal-Oxo Complexes: Understanding the Analogy\nwith Organic Radical Reactions","volume":"31","author":"Mayer","year":"1998","journal-title":"Acc. Chem. Res."},{"key":"2026090306161921600_cit38","doi-asserted-by":"crossref","first-page":"8362","DOI":"10.1021\/ja048528h","article-title":"A Predictive Pattern of Computed Barriers for C\u2013H Hydroxylation\nby Compound I of Cytochrome P450","volume":"126","author":"de Visser","year":"2004","journal-title":"J. Am. Chem.\nSoc."}],"container-title":["The Journal of Physical Chemistry A"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/jp502612t","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/jpcafh\/article-pdf\/118\/29\/5501\/14280781\/jp502612t.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/jpcafh\/article-pdf\/118\/29\/5501\/14280781\/jp502612t.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T10:16:26Z","timestamp":1788430586000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/jpcafh\/article\/118\/29\/5501\/1373768\/Hydroxylated-Derivatives-of-NPC1161-Theoretical"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,6,23]]},"references-count":38,"journal-issue":{"issue":"29","published-online":{"date-parts":[[2014,6,23]]},"published-print":{"date-parts":[[2014,7,24]]}},"URL":"https:\/\/doi.org\/10.1021\/jp502612t","relation":{},"ISSN":["1089-5639","1520-5215"],"issn-type":[{"value":"1089-5639","type":"print"},{"value":"1520-5215","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,6,23]]}}}