{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T17:16:58Z","timestamp":1780334218454,"version":"3.54.1"},"reference-count":107,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2021,9,21]],"date-time":"2021-09-21T00:00:00Z","timestamp":1632182400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Despite many efforts, malaria remains among the most problematic infectious diseases worldwide, mainly due to the development of drug resistance by P. falciparum. Over the past decade, new essential pathways have been emerged to fight against malaria. Among them, epigenetic processes and mitochondrial metabolism appear to be important targets. This review will focus on recent evolutions concerning worldwide efforts to conceive, synthesize and evaluate new drug candidates interfering selectively and efficiently with these two targets and pathways. The focus will be on compounds\/scaffolds that possess biological\/pharmacophoric properties on DNA methyltransferases and HDAC\u2019s for epigenetics, and on cytochrome bc1 and dihydroorotate dehydrogenase for mitochondrion.<\/jats:p>","DOI":"10.3390\/molecules26185711","type":"journal-article","created":{"date-parts":[[2021,9,21]],"date-time":"2021-09-21T22:34:01Z","timestamp":1632263641000},"page":"5711","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Antimalarial Inhibitors Targeting Epigenetics or Mitochondria in Plasmodium falciparum: Recent Survey upon Synthesis and Biological Evaluation of Potential Drugs against Malaria"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6819-7266","authenticated-orcid":false,"given":"Christina L.","family":"Koumpoura","sequence":"first","affiliation":[{"name":"CNRS, LCC (Laboratoire de Chimie de Coordination), Universit\u00e9 de Toulouse, UPS, INPT, Inserm ERL 1289, 205 Route de Narbonne, BP 44099, CEDEX 4, F-31077 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9092-6776","authenticated-orcid":false,"given":"Anne","family":"Robert","sequence":"additional","affiliation":[{"name":"CNRS, LCC (Laboratoire de Chimie de Coordination), Universit\u00e9 de Toulouse, UPS, INPT, Inserm ERL 1289, 205 Route de Narbonne, BP 44099, CEDEX 4, F-31077 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7549-1911","authenticated-orcid":false,"given":"Constantinos M.","family":"Athanassopoulos","sequence":"additional","affiliation":[{"name":"Synthetic Organic Chemistry Laboratory, Department of Chemistry, University of Patras, GR-26504 Patras, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michel","family":"Baltas","sequence":"additional","affiliation":[{"name":"CNRS, LCC (Laboratoire de Chimie de Coordination), Universit\u00e9 de Toulouse, UPS, INPT, Inserm ERL 1289, 205 Route de Narbonne, BP 44099, CEDEX 4, F-31077 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,21]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2020). World Malaria Report 2020, World Health Organization."},{"key":"ref_2","unstructured":"(2021, June 03). Centers for Disease Control and Prevention, Available online: https:\/\/www.cdc.gov\/."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1038\/d41586-021-01096-7","article-title":"Malaria vaccine shows promise\u2014Now come tougher trials","volume":"593","author":"Ledford","year":"2021","journal-title":"Nature"},{"key":"ref_4","unstructured":"World Health Organization (2015). Guidelines for the treatment of Malaria, World Health Organization. [3rd ed.]."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1038\/nm.4381","article-title":"Antimalarial drug resistance: Linking Plasmodium falciparum parasite biology to the clinic","volume":"23","author":"Blasco","year":"2017","journal-title":"Nat. Med."},{"key":"ref_6","unstructured":"World Health Organization (2019). Status Report on Artemisinin Resistance and ACT Efficacy, World Health Organization."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Cort\u00e9s, A., Crowley, V.M., Vaquero, A., Voss, T.S., and Rall, G.F. (2012). A View on the Role of Epigenetics in the Biology of Malaria Parasites. PLoS Pathog., 8.","DOI":"10.1371\/journal.ppat.1002943"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1017\/S0031182004005888","article-title":"The multiple roles of the mitochondrion of the malarial parasite","volume":"129","author":"Krungkrai","year":"2004","journal-title":"Parasitology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1146\/annurev.micro.091208.073424","article-title":"Mitochondrial Evolution and Functions in Malaria Parasites","volume":"63","author":"Vaidya","year":"2009","journal-title":"Annu. Rev. Microbiol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Gupta, A.P., Chin, W.H., Zhu, L., Mok, S., Luah, Y.H., Lim, E.H., and Bozdech, Z. (2013). Dynamic Epigenetic Regulation of Gene Expression during the Life Cycle of Malaria Parasite Plasmodium falciparum. PLoS Pathog., 9.","DOI":"10.1371\/journal.ppat.1003170"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"950","DOI":"10.1128\/AAC.04419-14","article-title":"Histone Methyltransferase Inhibitors Are Orally Bioavailable, Fast-Acting Molecules with Activity against Different Species Causing Malaria in Humans","volume":"59","author":"Malmquist","year":"2015","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1016\/j.chom.2013.11.007","article-title":"Genome-wide mapping of DNA methylation in the human malaria parasite Plasmodium falciparum","volume":"14","author":"Ponts","year":"2013","journal-title":"Cell Host Microbe."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1093\/nar\/gkz1093","article-title":"Discovery of a new predominant cytosine DNA modification that is linked to gene expression in malaria parasites","volume":"48","author":"Hammam","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2355","DOI":"10.1038\/s41598-020-59298-4","article-title":"Epigenetic inhibitors target multiple stages of Plasmodium falciparum parasites","volume":"10","author":"Coetzee","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e01217-20","DOI":"10.1128\/mSphere.01217-20","article-title":"The Role of The Histone Methyltransferase PfSET10 in Antigenic Variation by Malaria Parasites: A Cautionary Tale","volume":"6","author":"Ngwa","year":"2021","journal-title":"mSphere"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e02021-19","DOI":"10.1128\/AAC.02021-19","article-title":"A histone methyltransferase inhibitor can reverse epigenetically acquired drug resistance in the malaria parasite Plasmodium falciparum","volume":"64","author":"Chan","year":"2020","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.cbpa.2020.05.008","article-title":"Targeting histone acetylation\/deacetylation in parasites: An update (2017\u20132020)","volume":"57","author":"Fioravanti","year":"2020","journal-title":"Curr. Opin. Chem. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/j.ejmech.2018.10.041","article-title":"Identification of novel quinazoline derivatives as potent antiplasmodial agents","volume":"161","author":"Bouchut","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4665","DOI":"10.1021\/acs.jmedchem.7b00176","article-title":"Rational Design of Bisubstrate-Type Analogs as Inhibitors of DNA Methyltransferases in Cancer Cells","volume":"60","author":"Halby","year":"2017","journal-title":"J. Med. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1021\/acscentsci.9b00874","article-title":"DNA Methylation Bisubstrate Inhibitors Are Fast-Acting Drugs Active against Artemisinin-Resistant Plasmodium falciparum Parasites","volume":"6","author":"Nardella","year":"2020","journal-title":"ACS Cent. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Buchini, S., and Leumann, C. (2006). 2-O\u2019-Aminoethyl Oligoribonucleotides Containing Novel Base Analogs: Synthesis and Triple-Helix Formation at Pyrimidine\/Purine Inversion Sites. Eur. J. Org. Chem., 3152\u20133168.","DOI":"10.1002\/ejoc.200600182"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1042\/bj0870258","article-title":"The presence of acetyl groups of histones","volume":"87","author":"Philips","year":"1963","journal-title":"Biochem. J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1073\/pnas.51.5.786","article-title":"Acetylation and Methylation of Histones and Their Possible Role in the Regulation of RNA Synthesis","volume":"51","author":"Allfrey","year":"1964","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1089\/ars.2013.5776","article-title":"Targeting histone deacetylases in diseases: Where are we?","volume":"23","author":"Benedetti","year":"2015","journal-title":"Antioxid. Redox. Signal."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1634\/theoncologist.12-10-1247","article-title":"FDA approval summary: Vorinostat for treatment of advanced primary cutaneous T-cell lymphoma","volume":"12","author":"Mann","year":"2007","journal-title":"Oncologist"},{"key":"ref_26","first-page":"296","article-title":"Panobinostat (Farydak): A novel option for the treatment of relapsed or relapsed and refractory multiple myeloma","volume":"41","author":"Moore","year":"2016","journal-title":"Pharm. Ther."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2666","DOI":"10.1158\/1078-0432.CCR-14-3119","article-title":"FDA approval: Belinostat for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma","volume":"21","author":"Lee","year":"2015","journal-title":"Clin. Cancer. Res."},{"key":"ref_28","first-page":"22","article-title":"Romidepsin for the treatment of peripheral T-cell lymphoma","volume":"6","author":"Barbarotta","year":"2015","journal-title":"J. Adv. Pract. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1186\/s13148-019-0776-0","article-title":"The Timeline of Epigenetic Drug Discovery: From Reality to Dreams","volume":"11","author":"Ganesan","year":"2019","journal-title":"Clin. Epigenet."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1792","DOI":"10.1038\/s41467-020-15615-z","article-title":"Selective inhibition of cancer cell self-renewal through a Quisinostat-histone H1.0 axis","volume":"11","author":"Wu","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.ijpddr.2015.05.004","article-title":"Profiling the anti-protozoal activity of anti-cancer HDAC inhibitors against Plasmodium and Trypanosoma parasites","volume":"5","author":"Engel","year":"2015","journal-title":"Int. J. Parasitol. Drug. Resist."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Andrews, K.T., Gupta, A.P., Tran, T.N., Fairlie, D.P., Gobert, G.N., and Bozdhek, Z. (2012). Comparative gene expression profiling of P. falciparum malaria parasites exposed to three different histone deacetylase inhibitors. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0031847"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"292","DOI":"10.2174\/156802609788085313","article-title":"Targeting Histone Deacetylase Inhibitors for Anti-Malarial Therapy","volume":"9","author":"Andrews","year":"2009","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"13143","DOI":"10.1073\/pnas.93.23.13143","article-title":"Apicidin: A Novel Antiprotozoal Agent that Inhibits Parasite Histone Deacetylase","volume":"93","author":"Gurnett","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_35","first-page":"3467","article-title":"Towards Histone Deacetylase Inhibitors as New Antimalarial Drugs","volume":"18","author":"Andrews","year":"2012","journal-title":"Curr. Pharm. Des."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1021\/acsmedchemlett.5b00468","article-title":"Discovery of a Selective Series of Inhibitors of Plasmodium falciparum HDACs","volume":"7","author":"Ontoria","year":"2016","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_37","unstructured":"Atenni, B., Ferrigno, F., Jones, P., Ingenito, R., Kinzel, O., Llauger-Bufi, L., Ontoria, J.M., Pescatore, G., Rowley, M., and Scarpelli, R. (2006). Heterocycles Derivatives as Histone Deacetylase (HDAC) Inhibitors. (WO\/2006\/061638)."},{"key":"ref_38","unstructured":"Deziel, R., Rahil, J., Wahhab, A., Allan, M., and Nguyen, N. (2009). Sirtuin Inhibitors. (WO\/2009\/026701)."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1002\/cmdc.201800808","article-title":"Structure-Activity and Structure-Toxicity Relationships of Peptoid-Based Histone Deacetylase Inhibitors with Dual-Stage Antiplasmodial Activity","volume":"14","author":"Mackwitz","year":"2019","journal-title":"Chem. Med. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1454","DOI":"10.1128\/AAC.00757-07","article-title":"Potent antimalarial activity of histone deacetylase inhibitor analogs","volume":"52","author":"Andrews","year":"2008","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.ijpddr.2016.12.005","article-title":"Effect of clinically approved HDAC inhibitors on Plasmodium, Leishmania and Schistosoma parasite growth","volume":"7","author":"Chua","year":"2017","journal-title":"Int. J. Parasitol. Drugs Drug Resist."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1016\/j.jmgm.2015.10.006","article-title":"Homology modeling of parasite histone deacetylases to guide the structure-based design of selective inhibitors","volume":"62","author":"Melesina","year":"2015","journal-title":"J. Mol. Graphics Modell."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"4780","DOI":"10.1021\/acs.jmedchem.6b01595","article-title":"Lysine Deacetylase Inhibitors in Parasites: Past, Present, and Future Perspectives","volume":"60","author":"Hailu","year":"2017","journal-title":"J. Med. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1016\/j.ejmech.2018.09.018","article-title":"One-pot, multi-component synthesis and structure-activity relationships of peptoid-based histone deacetylase (HDAC) inhibitors targeting malaria parasites","volume":"158","author":"Diedrich","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2254","DOI":"10.1021\/acs.jmedchem.0c02104","article-title":"Discovery of Novel Plasmodium falciparum HDAC1 Inhibitors with Dual-Stage Antimalarial Potency and Improved Safety Based on the Clinical Anticancer Drug Candidate Quisinostat","volume":"64","author":"Li","year":"2021","journal-title":"J. Med. Chem."},{"key":"ref_46","unstructured":"Jiang, L., and Haung, Z. (2017). Novel High-Efficiency Antimalarial Drug, Quisinostat. (WO\/2017\/143964)."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3673","DOI":"10.1016\/j.bmcl.2014.06.081","article-title":"The Use of Spirocyclic Scaffolds in Drug Discovery","volume":"24","author":"Zheng","year":"2014","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_48","unstructured":"Dickens, J.W.J., Houpis, I.N., Lang, Y.L., Leys, C., Stokbroekx, S.C.M., and Weerts, J.E.E. (2008). Mono-Hydrochloric Salts of an Inhibitor of Histone Deacetylase. (WO2008138918A1)."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"10403","DOI":"10.1021\/acs.jmedchem.1c00821","article-title":"Procainamide\u2013SAHA Fused Inhibitors of hHDAC6 Tackle Multidrug-Resistant Malaria Parasites","volume":"64","author":"Nardella","year":"2021","journal-title":"J. Med. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"40749","DOI":"10.1074\/jbc.M505593200","article-title":"Procainamide Is a Specific Inhibitor of DNA Methyltransferase 1","volume":"280","author":"Lee","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1007\/s00894-018-3761-1","article-title":"In silico identification of inhibitors against Plasmodium falciparum histone deacetylase 1 (PfHDAC-1)","volume":"24","author":"Kumar","year":"2018","journal-title":"J. Mol. Model."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/978-1-4939-0366-5_1","article-title":"Protein structure modeling with MODELLER","volume":"1137","author":"Webb","year":"2014","journal-title":"Methods Mol. Biol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1016\/j.ejmech.2016.09.085","article-title":"Dihydroorotate dehydrogenase: An inevitable drug target for the development of antimalarials","volume":"125","author":"Singh","year":"2017","journal-title":"Eur. J. Med. Chem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1038\/nrd.2018.174","article-title":"Mitochondria as a therapeutic target for common pathologies","volume":"12","author":"Murphy","year":"2018","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1023\/B:PRES.0000036888.18223.0e","article-title":"X-ray structure of Rhodobacter capsulatus cytochrome bc1: Comparison with its mitochondrial and chloroplast counterparts","volume":"81","author":"Berry","year":"2004","journal-title":"Photosynth. Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1016\/S0969-2126(00)00152-0","article-title":"Structure at 2.3 A resolution of the cytochrome bc1 complex from the yeast Saccharomyces cerevisiae co-crystallized with an antibody Fv fragment","volume":"8","author":"Hunte","year":"2000","journal-title":"Structure"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1126\/science.277.5322.60","article-title":"Crystal Structure of the Cytochrome bc1 Complex from Bovine Heart Mitochondria","volume":"277","author":"Xia","year":"1997","journal-title":"Science"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1038\/33612","article-title":"Electron transfer by domain movement in cytochrome bc1","volume":"392","author":"Zhang","year":"1998","journal-title":"Nature"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"12282","DOI":"10.1016\/S0021-9258(18)67236-9","article-title":"Purification of a three-subunit ubiquinol-cytochrome c oxidoreductase complex from Paracoccus denitrificans","volume":"261","author":"Yang","year":"1986","journal-title":"J. Biol. Chem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/0022-5193(76)90124-7","article-title":"Possible molecular mechanisms of the protonmotive function of cytochrome systems","volume":"62","author":"Mitchell","year":"1976","journal-title":"J. Theor. Biol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1073\/pnas.69.1.50","article-title":"Aerobic Reduction of Cytochrome b566 in Pigeon-Heart Mitochondria","volume":"69","author":"Chance","year":"1972","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/j.jmb.2005.05.053","article-title":"Binding of the Respiratory Chain Inhibitor Antimycin to the Mitochondrial bc1 Complex: A New Crystal Structure Reveals an Altered Intramolecular Hydrogen-bonding Pattern","volume":"351","author":"Huang","year":"2005","journal-title":"J. Mol. Biol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"11168","DOI":"10.1021\/ja3001908","article-title":"Computational Discovery of Picomolar Qo Site Inhibitors of Cytochrome bc1 Complex","volume":"134","author":"Hao","year":"2012","journal-title":"J. Am. Chem. Soc."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"17542","DOI":"10.1074\/jbc.M710126200","article-title":"Structure of complex III with bound cytochrome c in reduced state and definition of a minimal core interface for electron transfer","volume":"283","author":"Solmaz","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2846","DOI":"10.1074\/jbc.M708608200","article-title":"Inhibitor-complexed Structures of the Cytochrome bc1 from the Photosynthetic Bacterium Rhodobacter sphaeroides","volume":"283","author":"Esser","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1038\/nature05572","article-title":"Specific role of mitochondrial electron transport in blood-stage Plasmodium falciparum","volume":"446","author":"Painter","year":"2007","journal-title":"Nature"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"14926","DOI":"10.1021\/bi060919g","article-title":"Mechanism of Flavin Reduction in Class 2 Dihydroorotate Dehydrogenases","volume":"45","author":"Fagan","year":"2006","journal-title":"Biochemistry"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"226","DOI":"10.2174\/187152610791163336","article-title":"Plasmodium dihydroorotate dehydrogenase: A promising target for novel anti-malarial chemotherapy","volume":"10","author":"Phillips","year":"2010","journal-title":"Infect. Disord. Drug Targets"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"5540","DOI":"10.1021\/jm200592f","article-title":"Structure-Guided Lead Optimization of Triazolopyrimidine-Ring Substituents Identifies Potent Plasmodium falciparum Dihydroorotate Dehydrogenase Inhibitors with Clinical Candidate Potential","volume":"54","author":"Coteron","year":"2011","journal-title":"J. Med. Chem."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.1016\/0006-2952(92)90213-3","article-title":"Site of action of the antimalarial hydroxynaphthoquinone, 2-[trans-4-(4\u2032-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone (566C80)","volume":"43","author":"Fry","year":"1992","journal-title":"Biochem. Pharmacol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1086\/514710","article-title":"Efficacy and Safety of Atovaquone\/Proguanil as Suppressive Prophylaxis for Plasmodium falciparum Malaria","volume":"27","author":"Shanks","year":"1998","journal-title":"Clin. Infect. Dis."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1046\/j.1365-2958.1999.01515.x","article-title":"Resistance mutations reveal the atovaquone-binding domain of cytochrome b in malaria parasites","volume":"33","author":"Srivastava","year":"1999","journal-title":"Mol. Microbiol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1334","DOI":"10.1128\/AAC.43.6.1334","article-title":"A mechanism for the Synergistic Antimalarial Action of Atovaquone and Proguanil","volume":"43","author":"Srivastava","year":"1999","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"4029","DOI":"10.1038\/ncomms5029","article-title":"Structural analysis of atovaquone-inhibited cytochrome bc1 complex reveals the molecular basis of antimalarial drug action","volume":"5","author":"Birth","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_75","unstructured":"Hudson, A.T., and Randall, A.W. (1991). Naphthoquinone derivatives. (U.S. Patent 5053432A)."},{"key":"ref_76","unstructured":"Hudson, A.T., and Latter, V. (1994). Medicaments. (EP0580185A1)."},{"key":"ref_77","first-page":"576277","article-title":"Process for the preparation of trans-2,3-disubstituted naphthoquinones. U.S. Patent 7,842,840 B2. 2010","volume":"149","author":"Antonio","year":"2008","journal-title":"Chem. Abstr."},{"key":"ref_78","unstructured":"Saralya, S.S., Shasikumar, S.H., Shashipraba, S., Kanakamajalu, S., Koottungalamadhom, R.R., Ananathalakshmi, V., Govindarajalu, J., Rao, K.S., and Nagarajan, K. (2009). Preparation of naphthoquinone compounds using 2,3-dihalonaphthoquinone. (WO 2009122432A2)."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"7629","DOI":"10.1016\/S0040-4039(98)01691-8","article-title":"Synthesis of atovaquone","volume":"39","author":"Williams","year":"1998","journal-title":"Tetrahedron Lett."},{"key":"ref_80","unstructured":"Dwyer, A.N., Gordon, A., and Urquhart, M. (2012). Novel process. (WO\/2012\/080243 A2)."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1607","DOI":"10.1021\/op300165q","article-title":"Discovery and Development of an Efficient Process to Atovaquone","volume":"16","author":"Britton","year":"2012","journal-title":"Org. Process Res. Dev."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1021\/op500032w","article-title":"A Single-Pot Synthesis of Atovaquone: An Antiparasitic Drug of Choice","volume":"18","author":"Dike","year":"2014","journal-title":"Org. Process Res. Dev."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"7496934","DOI":"10.1155\/2017\/7496934","article-title":"Synthesis, SAR, and Docking Studies Disclose 2-Arylfuran-1,4-naphthoquinones as In Vitro Antiplasmodial Hits","volume":"2017","author":"Borgati","year":"2017","journal-title":"J. Trop. Med."},{"key":"ref_84","first-page":"109","article-title":"Methods for assessment of antimalarial activity in the different phases of the Plasmodium life cycle","volume":"3","author":"Nogueira","year":"2010","journal-title":"Rev. Pan-Amaz. Saude"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1016\/S0169-4758(98)01284-8","article-title":"Lactate dehydrogenase and the diagnosis of malaria","volume":"9","author":"Makler","year":"1998","journal-title":"Parasitol. Today"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1006\/phrs.2000.0791","article-title":"Amino-naphthoquinones\u2014a novel class of compounds with potent antimalarial activity against Plasmodium falciparum","volume":"4","author":"Kapadia","year":"2001","journal-title":"Pharmacol. Res."},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Oramas-Royo, S., L\u00f3pez-Rojas, P., Amesty, A., Guti\u00e9rrez, D., Flores, N., Mart\u00edn-Rodr\u00edguez, P., Fern\u00e1ndez-P\u00e9rez, L., and Est\u00e9vez-Braun, A. (2019). Synthesis and Antiplasmodial Activity of 1,2,3-Triazole-Naphthoquinone Conjugates. Molecules, 24.","DOI":"10.3390\/molecules24213917"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"2596","DOI":"10.1002\/1521-3773(20020715)41:14<2596::AID-ANIE2596>3.0.CO;2-4","article-title":"A Stepwise Huisgen Cycloaddition Process: Copper(I)-Catalyzed Regioselective \u201cLigation\u201d of Azides and Terminal Alkynes","volume":"41","author":"Rostovtsev","year":"2002","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_89","first-page":"312","article-title":"Structure of Plasmodium falciparum dihydroorotate dehydrogenase with a bound inhibitor","volume":"62","author":"Hurt","year":"2006","journal-title":"Acta Cryst."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1107\/S2053230X15000989","article-title":"The X-ray structure of Plasmodium falciparum dihydroorotate dehydrogenase bound to a potent and selective N-phenylbenzamide inhibitor reveals novel binding-site interactions","volume":"71","author":"Deng","year":"2015","journal-title":"Acta Cryst. Sect. F Struct. Biol. Commun."},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Xu, L., Li, W., Diao, Y., Sun, H., Li, H., Zhu, L., Zhou, H., and Zhao, Z. (2018). Synthesis, Design, and Structure\u2013Activity Relationship of the Pyrimidone Derivatives as Novel Selective Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase. Molecules, 23.","DOI":"10.3390\/molecules23061254"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"7911","DOI":"10.1021\/jm400938g","article-title":"Novel selective and potent inhibitors of malaria parasite dihydroorotate dehydrogenase: Discovery and optimization of dihydrothiophenone derivatives","volume":"56","author":"Xu","year":"2013","journal-title":"J. Med. Chem."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/S0009-2797(99)00144-1","article-title":"Kinetics of Inhibition of Human and Rat Dihydroorotate Dehydrogenase by Atovaquone, Lawsone Derivatives, Brequinar Sodium and Polyporic Acid","volume":"124","author":"Knecht","year":"2000","journal-title":"Chem. Biol. Interact."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1021\/jm050540c","article-title":"Novel Procedure for Modeling Ligand\/Receptor Induced Fit Effects","volume":"49","author":"Woody","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.ejmech.2016.09.073","article-title":"Evaluation of 7-arylaminopyrazolo[1,5-a]pyrimidines as anti-Plasmodium falciparum, antimalarial, and Pf-dihydroorotate dehydrogenase inhibitors","volume":"126","author":"Azeredo","year":"2017","journal-title":"Eur. J. Med. Chem."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"8285","DOI":"10.3390\/molecules17078285","article-title":"New trifluoromethyl triazolopyrimidines as anti-Plasmodium falciparum agents","volume":"17","author":"Boechat","year":"2012","journal-title":"Molecules"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1021\/jm00137a023","article-title":"Synthesis and Antischistosomal activity of certain Pyrazolo[1,5-a]pyrimidines","volume":"24","author":"Senga","year":"1981","journal-title":"J. Med. Chem."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1639","DOI":"10.1002\/(SICI)1096-987X(19981115)19:14<1639::AID-JCC10>3.0.CO;2-B","article-title":"Automated docking using a Lamarckian genetic algorithm and empirical binding free energy function","volume":"19","author":"Morris","year":"1998","journal-title":"J. Comput. Chem."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1021\/acsmedchemlett.7b00030","article-title":"Discovery of Antimalarial Azetidine-2-carbonitriles That Inhibit P. falciparum Dihydroorotate Dehydrogenase","volume":"8","author":"Maetani","year":"2017","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1038\/nature19804","article-title":"Diversity-oriented synthesis yields novel multistage antimalarial inhibitors","volume":"538","author":"Kato","year":"2016","journal-title":"Nature"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"9259","DOI":"10.1021\/ja102798t","article-title":"Distinct biological network properties between the targets of natural products and disease genes","volume":"132","author":"Seiler","year":"2010","journal-title":"J. Am. Chem. Soc."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"9424","DOI":"10.1021\/acsomega.8b01062","article-title":"Phthalimide Derivatives with Bioactivity against Plasmodium falciparum: Synthesis, Evaluation, and Computational Studies Involving bc1 Cytochrome Inhibition","volume":"3","author":"Monteiro","year":"2018","journal-title":"ACS Omega"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1021\/acsmedchemlett.8b00371","article-title":"Potent Antimalarial 2-Pyrazolyl Quinolone bc1 (Qi) Inhibitors with Improved Drug-like Properties","volume":"9","author":"Hong","year":"2018","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1831","DOI":"10.1021\/jm201179h","article-title":"Identification, Design and Biological Evaluation of Bisaryl Quinolones Targeting Plasmodium falciparum Type II NADH: Quinone Oxidoreductase (PfNDH2)","volume":"55","author":"Pidathala","year":"2012","journal-title":"J. Med. Chem."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1124\/mol.108.045120","article-title":"Acridinediones: Selective and potent inhibitors of the malaria parasite mitochondrial bc(1) complex","volume":"73","author":"Biagini","year":"2008","journal-title":"Mol. Pharmacol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1073\/pnas.1416611112","article-title":"Antimalarial 4(1H)-pyridones bind to the Qi site of cytochrome bc1","volume":"112","author":"Capper","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1093\/nar\/gku340","article-title":"SWISS-MODEL: Modelling protein tertiary and quaternary structure using evolutionary information","volume":"42","author":"Biasini","year":"2014","journal-title":"Nucleic Acids Res."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/18\/5711\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:02:51Z","timestamp":1760166171000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/18\/5711"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,21]]},"references-count":107,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2021,9]]}},"alternative-id":["molecules26185711"],"URL":"https:\/\/doi.org\/10.3390\/molecules26185711","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,21]]}}}