{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T14:25:01Z","timestamp":1780583101804,"version":"3.54.1"},"reference-count":70,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,2,27]],"date-time":"2025-02-27T00:00:00Z","timestamp":1740614400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Malaria remains a major global health problem that has been exacerbated by the impact of the COVID-19 pandemic on health systems. To combat this, the World Health Organization (WHO) has set a target of driving forward research into innovative treatment methods such as new drugs and vaccines. Quinones, particularly 1,4-naphthoquinones, have been identified as promising candidates for the development of antiprotozoal drugs. Herein, we report several methods for the preparation of 2-benzyl-1,4-naphthoquinones. In particular, the silver-catalyzed Kochi\u2013Anderson radical decarboxylation is well suited for the preparation of these compounds. The antiprotozoal activity of all synthesized compounds was evaluated against Plasmodium falciparum NF54 and Trypanosoma brucei rhodesiense STIB900. Cytotoxicity towards L6 cells was also determined, and the respective selectivity indices (SI) were calculated. The synthesized compounds exhibited good antiplasmodial activity against the P. falciparum (NF54) strain, particularly (2-fluoro-5-trifluoromethylbenzyl)-menadione 2e, which showed strong efficacy and high selectivity (IC50 = 0.006 \u00b5M, SI = 7495). In addition, these compounds also displayed favorable physicochemical properties, suggesting that the benzylnaphthoquinone scaffold may be a viable option for new antiplasmodial drugs.<\/jats:p>","DOI":"10.3390\/ijms26052114","type":"journal-article","created":{"date-parts":[[2025,2,27]],"date-time":"2025-02-27T08:04:44Z","timestamp":1740643484000},"page":"2114","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Pharmacomodulation of the Redox-Active Lead Plasmodione: Synthesis of Substituted 2-Benzylnaphthoquinone Derivatives, Antiplasmodial Activities, and Physicochemical Properties"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0845-750X","authenticated-orcid":false,"given":"Armin","family":"Presser","sequence":"first","affiliation":[{"name":"Institute of Pharmaceutical Sciences, Pharmaceutical Chemistry, University of Graz, Schubertstrasse 1, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregor","family":"Blaser","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Sciences, Pharmaceutical Chemistry, University of Graz, Schubertstrasse 1, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8327-0732","authenticated-orcid":false,"given":"Eva-Maria","family":"Pferschy-Wenzig","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Sciences, Pharmacognosy, University of Graz, Beethovenstrasse 8, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcel","family":"Kaiser","sequence":"additional","affiliation":[{"name":"Swiss Tropical and Public Health Institute, Kreuzstrasse 2, 4123 Allschwil, Switzerland"},{"name":"Faculty of Philosophy and Natural Sciences, University of Basel, Petersplatz 1, 4003 Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pascal","family":"M\u00e4ser","sequence":"additional","affiliation":[{"name":"Swiss Tropical and Public Health Institute, Kreuzstrasse 2, 4123 Allschwil, Switzerland"},{"name":"Faculty of Philosophy and Natural Sciences, University of Basel, Petersplatz 1, 4003 Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang","family":"Schuehly","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Sciences, Pharmacognosy, University of Graz, Beethovenstrasse 8, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,27]]},"reference":[{"key":"ref_1","unstructured":"WHO Global Malaria Programme (2024, October 08). World Malaria Report 2023. World Health Organization [Online]. Available online: https:\/\/www.who.int\/publications\/i\/item\/9789240086173."},{"key":"ref_2","unstructured":"WHO Global Malaria Programme (2024, October 08). Global Technical Strategy for Malaria 2016\u20132030, 2021 Update. World Health Organization [Online]. Available online: https:\/\/www.who.int\/publications\/i\/item\/9789240031357."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e939357","DOI":"10.12659\/MSM.939357","article-title":"Editorial: Current Status of Two Adjuvanted Malaria Vaccines and the World Health Organization (WHO) Strategy to Eradicate Malaria by 2030","volume":"29","author":"Parums","year":"2023","journal-title":"Med. Sci. Monit."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2328","DOI":"10.1016\/S0140-6736(23)01249-7","article-title":"Malaria","volume":"402","author":"Poespoprodjo","year":"2023","journal-title":"Lancet"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.ijpddr.2019.10.004","article-title":"Antileishmanial activity of terpenylquinones on Leishmania infantum and their effects on Leishmania topoisomerase IB","volume":"11","author":"Reguera","year":"2019","journal-title":"Int. J. Parasitol. Drugs Drug Resist."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e1900597","DOI":"10.1002\/cbdv.201900597","article-title":"New Antiparasitic Bis-Naphthoquinone Derivatives","volume":"17","author":"Jentzsch","year":"2020","journal-title":"Chem. Biodivers."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Rivera, G., Patel, N.B., and Bandyopadhyay, D. (2021). Editorial: Discovery and Development of Drugs for Neglected Diseases: Chagas Disease, Human African Trypanosomiasis, and Leishmaniasis. Front. Chem., 9.","DOI":"10.3389\/fchem.2021.775327"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Prieto Cardenas, L.S., Arias Soler, K.A., Nossa Gonzalez, D.L., Rozo Nunez, W.E., Cardenas-Chaparro, A., Duchowicz, P.R., and Gomez Castano, J.A. (2022). In Silico Antiprotozoal Evaluation of 1,4-Naphthoquinone Derivatives against Chagas and Leishmaniasis Diseases Using QSAR, Molecular Docking, and ADME Approaches. Pharmaceuticals, 15.","DOI":"10.3390\/ph15060687"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"357","DOI":"10.2174\/187152106778520451","article-title":"Quinones and malaria","volume":"5","author":"Fotie","year":"2006","journal-title":"Anti-Infect. Agents Med. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"4570","DOI":"10.3390\/molecules14114570","article-title":"The trypanocidal activity of naphthoquinones: A review","volume":"14","year":"2009","journal-title":"Molecules"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.1055\/s-0033-1350934","article-title":"Pharmacological properties of shikonin\u2014A review of literature since 2002","volume":"79","author":"Andujar","year":"2013","journal-title":"Planta Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1590\/0001-3765201820170815","article-title":"The Antifungal Activity of Naphthoquinones: An Integrative Review","volume":"90","author":"Futuro","year":"2018","journal-title":"An. Acad. Bras. Cienc."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"113084","DOI":"10.1016\/j.ejmech.2020.113084","article-title":"Antimalarial application of quinones: A recent update","volume":"210","author":"Patel","year":"2021","journal-title":"Eur. J. Med. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1002\/cbdv.200590009","article-title":"Antiplasmodial activity of naphthoquinones related to lapachol and \u03b2-lapachone","volume":"2","author":"Ravelo","year":"2005","journal-title":"Chem. Biodivers."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.abb.2009.11.012","article-title":"Antiplasmodial activity of quinones: Roles of aziridinyl substituents and the inhibition of Plasmodium falciparum glutathione reductase","volume":"494","author":"Grellier","year":"2010","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.molbiopara.2011.01.002","article-title":"Design of antiparasitic and antifungal hydroxy-naphthoquinones that are less susceptible to drug resistance","volume":"177","author":"Hughes","year":"2011","journal-title":"Mol. Biochem. Parasitol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Sumsakul, W., Plengsuriyakarn, T., Chaijaroenkul, W., Viyanant, V., Karbwang, J., and Na-Bangchang, K. (2014). Antimalarial activity of plumbagin in vitro and in animal models. BMC Complement. Altern. Med., 14.","DOI":"10.1186\/1472-6882-14-15"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"11557","DOI":"10.1021\/ja201729z","article-title":"Glutathione Reductase-Catalyzed Cascade of Redox Reactions to Bioactivate Potent Antimalarial 1,4-Naphthoquinones\u2014A New Strategy to Combat Malarial Parasites","volume":"133","author":"Muller","year":"2011","journal-title":"J. Am. Chem. Soc."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1337","DOI":"10.1089\/ars.2014.6047","article-title":"Antimalarial NADPH-Consuming Redox-Cyclers As Superior Glucose-6-Phosphate Dehydrogenase Deficiency Copycats","volume":"22","author":"Bielitza","year":"2015","journal-title":"Antioxid. Redox Signal."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1002\/cmdc.201600009","article-title":"Redox Polypharmacology as an Emerging Strategy to Combat Malarial Parasites","volume":"11","author":"Sidorov","year":"2016","journal-title":"ChemMedChem"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"5146","DOI":"10.1128\/AAC.02975-15","article-title":"The redox cycler plasmodione is a fast-acting antimalarial lead compound with pronounced activity against sexual and early asexual blood-stage parasites","volume":"60","author":"Ehrhardt","year":"2016","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e202400187","DOI":"10.1002\/cbic.202400187","article-title":"Proteomic Profiling of Antimalarial Plasmodione Using 3-Benz(o)ylmenadione Affinity-Based Probes","volume":"25","author":"Iacobucci","year":"2024","journal-title":"ChemBioChem"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1016\/j.freeradbiomed.2020.11.010","article-title":"A role for the succinate dehydrogenase in the mode of action of the redox-active antimalarial drug, plasmodione","volume":"162","author":"Mounkoro","year":"2021","journal-title":"Free Radic. Biol. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e202400535","DOI":"10.1002\/ejoc.202400535","article-title":"Direct Functionalization of para-Quinones: A Historical Review and New Perspectives","volume":"27","author":"Kumar","year":"2024","journal-title":"Eur. J. Org. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3622","DOI":"10.1002\/ejoc.202100452","article-title":"Direct C-H Radical Alkylation of 1,4-Quinones","volume":"2021","author":"Donzel","year":"2021","journal-title":"Eur. J. Org. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1982","DOI":"10.1002\/ejoc.201600144","article-title":"A Platform of Regioselective Methodologies to Access Polysubstituted 2-Methyl-1,4-naphthoquinone Derivatives: Scope and Limitations","volume":"2016","author":"Rodo","year":"2016","journal-title":"Eur. J. Org. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1039\/C9OB02289A","article-title":"Iron-catalyzed regioselective alkylation of 1,4-quinones and coumarins with functionalized alkyl bromides","volume":"18","author":"Li","year":"2020","journal-title":"Org. Biomol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"10055","DOI":"10.1021\/acs.joc.1c00814","article-title":"Bioinspired Photoredox Benzylation of Quinones","volume":"86","author":"Donzel","year":"2021","journal-title":"J. Org. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2647","DOI":"10.1039\/C8OB00227D","article-title":"Synthesis of plasmodione metabolites and 13C-enriched plasmodione as chemical tools for drug metabolism investigation","volume":"16","author":"Feng","year":"2018","journal-title":"Org. Biomol. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1651","DOI":"10.1021\/ja00709a039","article-title":"Silver(I)-catalyzed oxidative decarboxylation of acids by peroxydisulfate. Role of silver(II)","volume":"92","author":"Anderson","year":"1970","journal-title":"J. Am. Chem. Soc."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4795","DOI":"10.1039\/c2ob25229e","article-title":"Exploring the trifluoromenadione core as a template to design antimalarial redox-active agents interacting with glutathione reductase","volume":"10","author":"Lanfranchi","year":"2012","journal-title":"Org. Biomol. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"6614","DOI":"10.1039\/c3cc43357a","article-title":"Copper-mediated C-H trifluoromethylation of quinones","volume":"49","author":"Ilchenko","year":"2013","journal-title":"Chem. Commun."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3730","DOI":"10.1021\/ol4016095","article-title":"Copper-Catalyzed Direct C-H Trifluoromethylation of Quinones","volume":"15","author":"Wang","year":"2013","journal-title":"Org. Lett."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1522","DOI":"10.1021\/ol5004498","article-title":"Catalytic C-H \u03b1-Trifluoromethylation of \u03b1,\u03b2-Unsaturated Carbonyl Compounds","volume":"16","author":"Fang","year":"2014","journal-title":"Org. Lett."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Urgin, K., Jida, M., Ehrhardt, K., Muller, T., Lanzer, M., Maes, L., Elhabiri, M., and Davioud-Charvet, E. (2017). Pharmacomodulation of the antimalarial plasmodione: Synthesis of biaryl- and N-arylalkylamine analogues, antimalarial activities and physicochemical properties. Molecules, 22.","DOI":"10.3390\/molecules22010161"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Nwaka, S., Ramirez, B., Brun, R., Maes, L., Douglas, F., and Ridley, R. (2009). Advancing drug innovation for neglected diseases-criteria for lead progression. PLoS Negl. Trop. Dis., 3.","DOI":"10.1371\/journal.pntd.0000440"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1038\/nrd4683","article-title":"Hit and lead criteria in drug discovery for infectious diseases of the developing world","volume":"14","author":"Katsuno","year":"2015","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Samby, K., Willis, P.a., Burrows, J.n., Laleu, B., and Webborn, P.j.h. (2021). Actives from MMV Open Access Boxes? A suggested way forward. PLoS Pathog., 17.","DOI":"10.1371\/journal.ppat.1009384"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"W513","DOI":"10.1093\/nar\/gkae303","article-title":"ProTox 3.0: A webserver for the prediction of toxicity of chemicals","volume":"52","author":"Banerjee","year":"2024","journal-title":"Nucleic Acids Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1016\/j.toxrep.2016.09.007","article-title":"Cytotoxicity, hemolysis and in vivo acute toxicity of 2-hydroxy-3-anilino-1,4-naphthoquinone derivatives","volume":"3","author":"Fumagalli","year":"2016","journal-title":"Toxicol. Rep."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1038\/nrd3367","article-title":"Probing the links between in vitro potency, ADMET and physicochemical parameters","volume":"10","author":"Gleeson","year":"2011","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1420","DOI":"10.1021\/tx200211v","article-title":"Improving Drug Candidates by Design: A Focus on Physicochemical Properties As a Means of Improving Compound Disposition and Safety","volume":"24","author":"Meanwell","year":"2011","journal-title":"Chem. Res. Toxicol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"10091","DOI":"10.1021\/acs.jmedchem.9b01596","article-title":"Facts, Patterns, and Principles in Drug Discovery: Appraising the Rule of 5 with Measured Physicochemical Data","volume":"63","author":"Tinworth","year":"2020","journal-title":"J. Med. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S0169-409X(96)00423-1","article-title":"Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings","volume":"23","author":"Lipinski","year":"1997","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S0169-409X(00)00129-0","article-title":"Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings","volume":"46","author":"Lipinski","year":"2001","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2615","DOI":"10.1021\/jm020017n","article-title":"Molecular Properties That Influence the Oral Bioavailability of Drug Candidates","volume":"45","author":"Veber","year":"2002","journal-title":"J. Med. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1039\/C1MD00017A","article-title":"Molecular obesity, potency and other addictions in drug discovery","volume":"2","author":"Hann","year":"2011","journal-title":"MedChemComm"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1789","DOI":"10.1021\/jm301514n","article-title":"Contributions of Molecular Properties to Drug Promiscuity","volume":"56","author":"Tarcsay","year":"2013","journal-title":"J. Med. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1016\/j.drudis.2018.01.010","article-title":"Present drug-likeness filters in medicinal chemistry during the hit and lead optimization process: How far can they be simplified?","volume":"23","author":"Mignani","year":"2018","journal-title":"Drug Discov. Today"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2400","DOI":"10.1021\/jacsau.2c00415","article-title":"The Time and Place for Nature in Drug Discovery","volume":"2","author":"Young","year":"2022","journal-title":"JACS Au"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1038\/nrd4163","article-title":"The role of ligand efficiency metrics in drug discovery","volume":"13","author":"Hopkins","year":"2014","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"6401","DOI":"10.1021\/acs.jmedchem.8b00077","article-title":"Lipophilic efficiency as an important metric in drug design","volume":"61","author":"Johnson","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"3006","DOI":"10.1016\/j.bmc.2018.04.004","article-title":"Practical application of ligand efficiency metrics in lead optimisation","volume":"26","author":"Scott","year":"2018","journal-title":"Bioorg. Med. Chem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"7210","DOI":"10.1021\/acs.jmedchem.1c00416","article-title":"Target-Based Evaluation of \u201cDrug-Like\u201d Properties and Ligand Efficiencies","volume":"64","author":"Leeson","year":"2021","journal-title":"J. Med. Chem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1080\/17460441.2021.1884065","article-title":"Ligand efficiency indices for effective drug discovery: A unifying vector formulation","volume":"16","year":"2021","journal-title":"Expert. Opin. Drug Discov."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1617","DOI":"10.1021\/ci900094m","article-title":"Simple Size-Independent Measure of Ligand Efficiency","volume":"49","author":"Nissink","year":"2009","journal-title":"J. Chem. Inf. Model."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.1080\/17460441.2017.1365056","article-title":"Ligand efficiency metrics in drug discovery: The pros and cons from a practical perspective","volume":"12","author":"Cavalluzzi","year":"2017","journal-title":"Expert. Opin. Drug Discov."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1016\/j.chembiol.2014.08.013","article-title":"Oral Druggable Space beyond the Rule of 5: Insights from Drugs and Clinical Candidates","volume":"21","author":"Doak","year":"2014","journal-title":"Chem. Biol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"5683","DOI":"10.1021\/acs.jmedchem.3c02332","article-title":"Beyond Rule of Five and PROTACs in Modern Drug Discovery: Polarity Reducers, Chameleonicity, and the Evolving Physicochemical Landscape","volume":"67","author":"Price","year":"2024","journal-title":"J. Med. Chem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"2636","DOI":"10.1021\/acs.jmedchem.7b00717","article-title":"Beyond the Rule of 5: Lessons Learned from AbbVie\u2019s Drugs and Compound Collection","volume":"61","author":"DeGoey","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1016\/j.drudis.2011.06.001","article-title":"Getting physical in drug discovery II: The impact of chromatographic hydrophobicity measurements and aromaticity","volume":"16","author":"Young","year":"2011","journal-title":"Drug Discov. Today"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1021\/acschemneuro.6b00029","article-title":"Central Nervous System Multiparameter Optimization Desirability: Application in Drug Discovery","volume":"7","author":"Wager","year":"2016","journal-title":"ACS Chem. Neurosci."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1021\/cn100008c","article-title":"Moving beyond Rules: The Development of a Central Nervous System Multiparameter Optimization (CNS MPO) Approach to Enable Alignment of Druglike Properties","volume":"1","author":"Wager","year":"2010","journal-title":"ACS Chem. Neurosci."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1038\/nchem.1243","article-title":"Quantifying the chemical beauty of drugs","volume":"4","author":"Bickerton","year":"2012","journal-title":"Nat. Chem."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1111\/cbdd.14137","article-title":"Computational prediction of Lee retention indices of polycyclic aromatic hydrocarbons by using machine learning","volume":"101","author":"Sun","year":"2023","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1007\/s10822-011-9435-z","article-title":"Assessing the lipophilicity of fragments and early hits","volume":"25","author":"Mortenson","year":"2011","journal-title":"J. Comput.-Aided Mol. Des."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"6421","DOI":"10.1021\/acs.jmedchem.8b00180","article-title":"Mapping the Efficiency and Physicochemical Trajectories of Successful Optimizations","volume":"61","author":"Young","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1002\/minf.201000161","article-title":"Ligand Efficiency Indices (LEIs): More than a Simple Efficiency Yardstick","volume":"30","author":"Blasi","year":"2011","journal-title":"Mol. Inform."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1016\/j.drudis.2010.08.004","article-title":"Ligand efficiency indices for an effective mapping of chemico-biological space: The concept of an atlas-like representation","volume":"15","author":"Perisic","year":"2010","journal-title":"Drug Discov. Today"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"5019","DOI":"10.1021\/acs.joc.8b00170","article-title":"The Application of 2-Benzyl-1,4-naphthoquinones as Pronucleophiles in Aminocatalytic Synthesis of Tricyclic Derivatives","volume":"83","author":"Skrzynska","year":"2018","journal-title":"J. Org. Chem."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/5\/2114\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:43:39Z","timestamp":1760028219000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/5\/2114"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,27]]},"references-count":70,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2025,3]]}},"alternative-id":["ijms26052114"],"URL":"https:\/\/doi.org\/10.3390\/ijms26052114","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,27]]}}}