{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T05:13:38Z","timestamp":1790745218476,"version":"4.1.0"},"reference-count":132,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2021,7,30]],"date-time":"2021-07-30T00:00:00Z","timestamp":1627603200000},"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>The protozoan diseases Human African Trypanosomiasis (HAT), Chagas disease (CD), and leishmaniases span worldwide and therefore their impact is a universal concern. The present regimen against kinetoplastid protozoan infections is poor and insufficient. Target-based design expands the horizon of drug design and development and offers novel chemical entities and potential drug candidates to the therapeutic arsenal against the aforementioned neglected diseases. In this review, we report the most promising targets of the main kinetoplastid parasites, as well as their corresponding inhibitors. This overview is part of the Special Issue, entitled \u201cAdvances of Medicinal Chemistry against Kinetoplastid Protozoa (Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp.) Infections: Drug Design, Synthesis and Pharmacology\u201d.<\/jats:p>","DOI":"10.3390\/molecules26154629","type":"journal-article","created":{"date-parts":[[2021,8,1]],"date-time":"2021-08-01T21:44:32Z","timestamp":1627854272000},"page":"4629","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":88,"title":["An Overview on Target-Based Drug Design against Kinetoplastid Protozoan Infections: Human African Trypanosomiasis, Chagas Disease and Leishmaniases"],"prefix":"10.3390","volume":"26","author":[{"given":"Violeta","family":"Kourbeli","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Division of Pharmaceutical Chemistry, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimioupoli-Zografou, 157 84 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleni","family":"Chontzopoulou","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry, Faculty of Chemistry, National and Kapodistrian University of Athens, Panepistimioupoli-Zografou, 157 71 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kalliopi","family":"Moschovou","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry, Faculty of Chemistry, National and Kapodistrian University of Athens, Panepistimioupoli-Zografou, 157 71 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimitrios","family":"Pavlos","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry, Faculty of Chemistry, National and Kapodistrian University of Athens, Panepistimioupoli-Zografou, 157 71 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5309-992X","authenticated-orcid":false,"given":"Thomas","family":"Mavromoustakos","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry, Faculty of Chemistry, National and Kapodistrian University of Athens, Panepistimioupoli-Zografou, 157 71 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6974-2561","authenticated-orcid":false,"given":"Ioannis P.","family":"Papanastasiou","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Division of Pharmaceutical Chemistry, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimioupoli-Zografou, 157 84 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2126","DOI":"10.1016\/S0140-6736(19)33070-3","article-title":"2020: A crucial year for neglected tropical diseases","volume":"394","author":"Lancet","year":"2019","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1038\/nature05775","article-title":"Origins of major human infectious diseases","volume":"447","author":"Wolfe","year":"2007","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/s40249-020-0630-9","article-title":"Neglected tropical diseases: An effective global response to local poverty-related disease priorities","volume":"9","author":"Engels","year":"2020","journal-title":"Infect. Dis. Poverty"},{"key":"ref_4","first-page":"4","article-title":"Ten failings in global neglected tropical diseases control","volume":"11","author":"Hotez","year":"2017","journal-title":"PLoS Negl. Trop. Dis."},{"key":"ref_5","unstructured":"Foodborne, D.E., African, H., Lymphatic, L.L., Scabies, O.R., Soil-transmitted, S., and Yaws, T. (2020). Chagas Disease Echinococcosis Foodborne Trematodiases Human African Trypanosomiasis Leishmaniasis Leprosy Rabies Yaws Ending the Neglect to Attain the Sustainable Development Goals a Sustainability Framework for Action against Neglected Tropical Diseases, World Health Organization."},{"key":"ref_6","unstructured":"(2021, June 16). About US|Uniting to Combat NTDs. Available online: https:\/\/test-unitingtocombatntds.pantheonsite.io\/about-us\/."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1186\/s40249-018-0444-1","article-title":"Innovation in neglected tropical disease drug discovery and development","volume":"7","author":"Weng","year":"2018","journal-title":"Infect. Dis. Poverty"},{"key":"ref_8","first-page":"175","article-title":"Drug discovery and development for neglected diseases: The DNDi model","volume":"5","author":"Chatelain","year":"2011","journal-title":"Drug Des. Devel. Ther."},{"key":"ref_9","unstructured":"(2021, June 16). Who We Are|DNDi. Available online: https:\/\/dndi.org\/about\/who-we-are\/."},{"key":"ref_10","unstructured":"(2021, June 16). About the Open Lab\u2014Tres Cantos Open Lab Foundation. Available online: https:\/\/www.openlabfoundation.org\/AboutTheOpenLab."},{"key":"ref_11","unstructured":"(2021, June 16). Novartis Institute for Tropical Diseases|Novartis. Available online: https:\/\/www.novartis.com\/our-science\/novartis-institutes-biomedical-research\/research-locations\/novartis-institute-tropical."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1021\/acsinfecdis.9b00371","article-title":"Setting Our Sights on Infectious Diseases","volume":"6","author":"Horn","year":"2020","journal-title":"ACS Infect. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1021\/acsinfecdis.8b00298","article-title":"Drug Discovery for Kinetoplastid Diseases: Future Directions","volume":"5","author":"Rao","year":"2019","journal-title":"ACS Infect. Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1038\/nrmicro.2016.193","article-title":"Anti-trypanosomatid drug discovery: An ongoing challenge and a continuing need","volume":"15","author":"Field","year":"2017","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1038\/s41586-018-0327-4","article-title":"Challenges and recent progress in drug discovery for tropical diseases","volume":"559","author":"Duce","year":"2018","journal-title":"Nature"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"9375","DOI":"10.1021\/acs.jmedchem.9b00359","article-title":"Overview of Recent Strategic Advances in Medicinal Chemistry","volume":"62","author":"Wu","year":"2019","journal-title":"J. Med. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1493","DOI":"10.3389\/fimmu.2018.01493","article-title":"Human Kinetoplastid Protozoan Infections: Where Are We Going Next?","volume":"9","author":"Filardy","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"F\u00e8vre, E.M., Wissmann, B.V., Welburn, S.C., and Lutumba, P. (2008). The burden of human African Trypanosomiasis. PLoS Negl. Trop. Dis., 2.","DOI":"10.1371\/journal.pntd.0000333"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.2174\/156802611795429167","article-title":"State of the Art in African Trypanosome Drug Discovery","volume":"11","author":"Jacobs","year":"2011","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_20","unstructured":"(2021, May 25). Human African trypanosomiasis (Sleeping Sickness), Available online: https:\/\/www.cdc.gov\/parasites\/sleepingsickness\/index.html."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Spaulding, A., Gallerstein, M.F., and Ferrins, L. (2019). Drug discovery and development for human African trypanosomiasis. Negl. Trop. Dis. Drug Discov. Dev., 115\u2013137.","DOI":"10.1002\/9783527808656.ch5"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1407","DOI":"10.1586\/14787210.2014.959496","article-title":"Treatment options for second-stage gambiense human African trypanosomiasis","volume":"12","author":"Eperon","year":"2014","journal-title":"Expert Rev. Anti. Infect. Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.ebiom.2017.10.032","article-title":"A Phase III Diagnostic Accuracy Study of a Rapid Diagnostic Test for Diagnosis of Second-Stage Human African Trypanosomiasis in the Democratic Republic of the Congo","volume":"27","author":"Boelaert","year":"2018","journal-title":"EBioMedicine"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.ijpddr.2019.11.004","article-title":"Current trends in the pharmacological management of Chagas disease","volume":"12","author":"Ribeiro","year":"2020","journal-title":"Int. J. Parasitol. Drugs Drug Resist."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/S0140-6736(17)31612-4","article-title":"Chagas disease","volume":"391","author":"Molina","year":"2018","journal-title":"Lancet"},{"key":"ref_26","unstructured":"(2021, July 20). Chagas Disease (American Trypanosomiasis). Available online: https:\/\/www.who.int\/health-topics\/chagas-disease#tab=tab_1."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"105906","DOI":"10.1016\/j.ijantimicag.2020.105906","article-title":"Searching for drugs for Chagas disease, leishmaniasis and schistosomiasis: A review","volume":"55","author":"Santos","year":"2020","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_28","first-page":"277","article-title":"The main sceneries of Chagas disease transmission. The vectors, blood and oral transmissions-A comprehensive review","volume":"110","year":"2015","journal-title":"Mem. Inst. Oswaldo Cruz. Rio Janeiro"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"389","DOI":"10.3389\/fvets.2021.653999","article-title":"Trends in the Epidemiology of Leishmaniasis in the City of Barcelona (1996\u20132019)","volume":"8","author":"Palma","year":"2021","journal-title":"Front. Vet. Sci."},{"key":"ref_30","unstructured":"(2021, July 20). Leishmaniasis. Available online: https:\/\/www.who.int\/health-topics\/leishmaniasis#tab=tab_1."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1590\/S0074-02762007000900018","article-title":"Chagas disease: What is known and what is needed\u2014A background article","volume":"102","author":"Coura","year":"2007","journal-title":"Mem. Inst. Oswaldo Cruz"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e02851","DOI":"10.7554\/eLife.02851","article-title":"Global distribution maps of the leishmaniases","volume":"3","author":"Pigott","year":"2014","journal-title":"Elife"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1007\/s40257-015-0114-z","article-title":"Cutaneous Leishmaniasis: Recent Developments in Diagnosis and Management","volume":"16","author":"Reedijk","year":"2015","journal-title":"Am. J. Clin. Dermatol."},{"key":"ref_34","first-page":"37","article-title":"An Overview on the Therapeutics of Neglected Infectious Diseases\u2014Leishmaniasis and Chagas Diseases","volume":"9","author":"Brindha","year":"2021","journal-title":"Front. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1793","DOI":"10.1056\/NEJMe020133","article-title":"Kala-Azar\u2014Progress against a Neglected Disease","volume":"347","author":"Murray","year":"2002","journal-title":"N. Engl. J. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1709","DOI":"10.4155\/fmc.13.161","article-title":"Ask the Experts: Drug discovery for the treatment of leishmaniasis, African sleeping sickness and Chagas disease","volume":"5","author":"Avery","year":"2013","journal-title":"Future Med. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1017\/S0031182012000169","article-title":"Update on field use of the available drugs for the chemotherapy of human African trypanosomiasis","volume":"139","author":"Simarro","year":"2012","journal-title":"Parasitology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1128\/AAC.01168-19","article-title":"100 Years of Suramin","volume":"64","author":"Wiedemar","year":"2020","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1046\/j.1365-3156.2001.00710.x","article-title":"Clinical description of encephalopathic syndromes and risk factors for their occurrence and outcome during melarsoprol treatment of human African trypanosomiasis","volume":"6","author":"Blum","year":"2001","journal-title":"Trop. Med. Int. Health"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Seixas, J., Atouguia, J., Josenando, T., Vatunga, G., Bilenge, C.M.M., Lutumba, P., and Burri, C. (2020). Clinical study on the melarsoprol-related encephalopathic syndrome: Risk factors and HLA association. Trop. Med. Infect. Dis., 5.","DOI":"10.3390\/tropicalmed5010005"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1046\/j.1365-3156.2001.00714.x","article-title":"Re-emergence of epidemic sleeping sickness in southern Sudan","volume":"6","author":"Moore","year":"2001","journal-title":"Trop. Med. Int. Health"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Priotto, G., Fogg, C., Balasegaram, M., Erphas, O., Louga, A., Checchi, F., Ghabri, S., and Piola, P. (2006). Three Drug Combinations for Late-Stage Trypanosoma brucei gambiense Sleeping Sickness: A Randomized Clinical Trial in Uganda. PLoS Clin. Trials, 1.","DOI":"10.1371\/journal.pctr.0010039"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"11855","DOI":"10.1021\/ja9033473","article-title":"Direct interaction between amphotericin B and ergosterol in lipid bilayers as revealed by 2H NMR spectroscopy","volume":"131","author":"Matsumori","year":"2009","journal-title":"J. Am. Chem. Soc."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.2174\/1389450121666200422083735","article-title":"An Insight into the Current Perspective and Potential Drug Targets for Visceral Leishmaniasis (VL)","volume":"21","author":"Mansuri","year":"2020","journal-title":"Curr. Drug Targets"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Altamura, F., Rajesh, R., Catta-Preta, C.M.C., Moretti, N.S., and Cestari, I. (2020). The current drug discovery landscape for trypanosomiasis and leishmaniasis: Challenges and strategies to identify drug targets. Drug Dev. Res.","DOI":"10.1002\/ddr.21664"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1017\/S0031182016002523","article-title":"Chemotherapy of leishmaniasis: Present challenges","volume":"145","author":"Uliana","year":"2018","journal-title":"Parasitology"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1038\/s41420-018-0092-z","article-title":"Different apoptosis pathways in Leishmania parasites","volume":"4","author":"Basmaciyan","year":"2018","journal-title":"Cell Death Discov."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1080\/14728222.2019.1685981","article-title":"The proteasome as a target for protozoan parasites","volume":"23","author":"Xie","year":"2019","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1038\/nature19339","article-title":"Proteasome inhibition for treatment of leishmaniasis, Chagas disease and sleeping sickness","volume":"537","author":"Khare","year":"2016","journal-title":"Nature"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1208\/s12249-017-0849-3","article-title":"Commentary: Why Pharmaceutical Scientists in Early Drug Discovery Are Critical for Influencing the Design and Selection of Optimal Drug Candidates","volume":"19","author":"Landis","year":"2018","journal-title":"AAPS PharmSciTech"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"10773","DOI":"10.1021\/acs.jmedchem.0c00499","article-title":"Discovery and Characterization of Clinical Candidate LXE408 as a Kinetoplastid-Selective Proteasome Inhibitor for the Treatment of Leishmaniases","volume":"63","author":"Nagle","year":"2020","journal-title":"J. Med. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1007\/s10822-007-9159-2","article-title":"An improved relaxed complex scheme for receptor flexibility in computer-aided drug design","volume":"22","author":"Amaro","year":"2008","journal-title":"J. Comput. Aided. Mol. Des."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"17278","DOI":"10.1073\/pnas.0805820105","article-title":"Discovery of drug-like inhibitors of an essential RNA-editing ligase in Trypanosoma brucei","volume":"105","author":"Amaro","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"5025","DOI":"10.1021\/jm100456a","article-title":"Computer-aided identification of trypanosoma brucei uridine diphosphate galactose 4\u2019-epimerase inhibitors: Toward the development of novel therapies for African sleeping sickness","volume":"53","author":"Durrant","year":"2010","journal-title":"J. Med. Chem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1111\/j.1365-2958.2010.07236.x","article-title":"Trypanosoma brucei pteridine reductase 1 is essential for survival in vitro and for virulence in mice","volume":"77","author":"Sienkiewicz","year":"2010","journal-title":"Mol. Microbiol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"4454","DOI":"10.1021\/jm900414x","article-title":"One scaffold, three binding modes: Novel and selective pteridine reductase 1 inhibitors derived from fragment hits discovered by virtual screening","volume":"52","author":"Mpamhanga","year":"2009","journal-title":"J. Med. Chem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"4153","DOI":"10.4049\/jimmunol.161.8.4153","article-title":"Blockade of CTLA-4 enhances host resistance to the intracellular pathogen, Leishmania donovani","volume":"161","author":"Murphy","year":"1998","journal-title":"J. Immunol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"e00019-18","DOI":"10.1128\/IAI.00019-18","article-title":"PDL-1 Blockade Prevents T Cell Exhaustion, Inhibits Autophagy, and Promotes Clearance of Leishmania donovani","volume":"86","author":"Habib","year":"2018","journal-title":"Infect. Immun."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"FSO325","DOI":"10.4155\/fsoa-2018-0037","article-title":"Histone deacetylases as targets for antitrypanosomal drugs","volume":"4","author":"Zuma","year":"2018","journal-title":"Futur. Sci. OA"},{"key":"ref_60","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. Drugs Drug Resist."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.actatropica.2008.07.006","article-title":"Efficacy of the diamidine DB75 and its prodrug DB289, against murine models of human African trypanosomiasis","volume":"108","author":"Thuita","year":"2008","journal-title":"Acta Trop."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1016\/j.cell.2007.08.046","article-title":"Hydrodynamic Flow-Mediated Protein Sorting on the Cell Surface of Trypanosomes","volume":"131","author":"Engstler","year":"2007","journal-title":"Cell"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.1002\/cmdc.200900098","article-title":"Synthesis and evaluation of 1-(1-(benzo[b]thiophen-2-yl)cyclohexyl) piperidine (BTCP) analogues as inhibitors of trypanothione reductase","volume":"4","author":"Patterson","year":"2009","journal-title":"ChemMedChem"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1038\/nature08893","article-title":"N-myristoyltransferase inhibitors as new leads to treat sleeping sickness","volume":"464","author":"Frearson","year":"2010","journal-title":"Nature"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1146\/annurev.mi.46.100192.003403","article-title":"Metabolism and Functions of Trypanothione in the Kinetoplastida","volume":"46","author":"Fairlamb","year":"1992","journal-title":"Annu. Rev. Microbiol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1002\/pro.5560050107","article-title":"The crystal structure of trypanothione reductase from the human pathogen Trypanosoma cruzi at 2.3 \u00c5 resolution","volume":"5","author":"Zhang","year":"1996","journal-title":"Protein Sci."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/0014-5793(93)81501-P","article-title":"Crystallization and preliminary crystallographic analysis of trypanothione reductase from Trypanosoma cruzi, the causative agent of Chagas\u2019 disease","volume":"317","author":"Sticherling","year":"1993","journal-title":"FEBS Lett."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"29493","DOI":"10.1074\/jbc.M403187200","article-title":"Two interacting binding sites for quinacrine derivatives in the active site of trypanothione reductase: A template for drug design","volume":"279","author":"Saravanamuthu","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_69","first-page":"539","article-title":"The Parasite-Specific Trypanothione Metabolism of Trypanosoma and Leishmania","volume":"384","author":"Meiering","year":"2003","journal-title":"Biol. Chem."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1880","DOI":"10.1002\/cmdc.201402032","article-title":"Binding to large enzyme pockets: Small-molecule inhibitors of trypanothione reductase","volume":"9","author":"Persch","year":"2014","journal-title":"ChemMedChem"},{"key":"ref_71","first-page":"642502","article-title":"Sterol Biosynthesis Pathway as Target for Anti-trypanosomatid Drugs","volume":"2009","author":"Cola","year":"2009","journal-title":"Interdiscip. Perspect. Infect. Dis."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1017\/S0031182013000103","article-title":"Use of clomipramine as chemotherapy of the chronic phase of Chagas disease","volume":"140","author":"Fauro","year":"2013","journal-title":"Parasitology"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"2027","DOI":"10.1007\/s00436-014-3850-8","article-title":"Anti-Trypanosoma cruzi and anti-leishmanial activity by quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives","volume":"113","author":"Palos","year":"2014","journal-title":"Parasitol. Res."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/0035-9203(76)90169-3","article-title":"Chemotherapy of Chagas\u2019 disease","volume":"70","author":"Gutteridge","year":"1976","journal-title":"Trans. R. Soc. Trop. Med. Hyg."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Kaiser, M., M\u00e4ser, P., Tadoori, L.P., Ioset, J.R., Brun, R., and Sullivan, D.J. (2015). Antiprotozoal activity profiling of approved drugs: A starting point toward drug repositioning. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0135556"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.1007\/s00436-019-06206-z","article-title":"In vitro evaluation of arylsubstituted imidazoles derivatives as antiprotozoal agents and docking studies on sterol 14\u03b1-demethylase (CYP51) from Trypanosoma cruzi, Leishmania infantum, and Trypanosoma brucei","volume":"118","author":"Cos","year":"2019","journal-title":"Parasitol. Res."},{"key":"ref_77","first-page":"1934578X1601100","article-title":"Molecular Docking and Binding Mode Analysis of Plant Alkaloids as in Vitro and in silico Inhibitors of Trypanothione Reductase from Trypanosoma cruzi","volume":"11","author":"Cordell","year":"2016","journal-title":"Nat. Prod. Commun."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.1002\/pmic.200300637","article-title":"Proteomic analysis of the human pathogen Trypanosoma cruzi","volume":"4","author":"Paba","year":"2004","journal-title":"Proteomics"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"107506","DOI":"10.1016\/j.jmgm.2019.107506","article-title":"In silico repositioning of etidronate as a potential inhibitor of the Trypanosoma cruzi enolase: T. cruzi enolase inhibitors","volume":"95","author":"Reigada","year":"2020","journal-title":"J. Mol. Graph. Model."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.jmgm.2017.08.007","article-title":"In silico identification of inhibitors of ribose 5-phosphate isomerase from Trypanosoma cruzi using ligand and structure based approaches","volume":"77","author":"Luiz","year":"2017","journal-title":"J. Mol. Graph. Model."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1016\/j.tetasy.2016.07.009","article-title":"Update: Biological and chemical aspects of Nectandra genus (Lauraceae)","volume":"27","author":"Grecco","year":"2016","journal-title":"Tetrahedron Asymmetry"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1016\/j.phymed.2018.09.236","article-title":"Butenolides from Nectandra oppositifolia (Lauraceae) displayed anti-Trypanosoma cruzi activity via deregulation of mitochondria","volume":"54","author":"Conserva","year":"2019","journal-title":"Phytomedicine"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1007\/978-1-4419-8414-2_7","article-title":"Cruzain: The path from target validation to the clinic","volume":"712","author":"Sajid","year":"2011","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.2174\/1381612013397528","article-title":"The Major Cysteine Proteinase of Trypanosoma cruzi: A Valid Target for Chemotherapy of Chagas Disease","volume":"7","author":"Cazzulo","year":"2001","journal-title":"Curr. Pharm. Des."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1590\/S0074-02762009000900034","article-title":"Two approaches to discovering and developing new drugs for Chagas disease","volume":"104","author":"McKerrow","year":"2009","journal-title":"Mem. Inst. Oswaldo Cruz"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"15","DOI":"10.3762\/bjoc.9.3","article-title":"Chemical-biological characterization of a cruzain inhibitor reveals a second target and a mammalian off-target","volume":"9","author":"Choy","year":"2013","journal-title":"Beilstein J. Org. Chem."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.ejmech.2017.01.027","article-title":"Synthesis and antitrypanosomal activities of novel pyridylchalcones","volume":"128","author":"Bhambra","year":"2017","journal-title":"Eur. J. Med. Chem."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"7104","DOI":"10.1002\/slct.202000777","article-title":"Chalcone-Quinoline Conjugates as Potential T. cruzi Cruzipain Inhibitors: Docking Studies, Molecular Dynamics and Evaluation of Drug-Likeness","volume":"5","author":"Yepes","year":"2020","journal-title":"ChemistrySelect"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"4228","DOI":"10.1016\/j.bmc.2016.07.013","article-title":"Design, synthesis, molecular docking and biological evaluation of thiophen-2-iminothiazolidine derivatives for use against Trypanosoma cruzi","volume":"24","author":"Silva","year":"2016","journal-title":"Bioorg. Med. Chem."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1111\/j.1574-6968.2004.tb09522.x","article-title":"The pentose phosphate pathway in Trypanosoma cruzi","volume":"234","author":"Maugeri","year":"2004","journal-title":"FEMS Microbiol. Lett."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.molbiopara.2011.01.010","article-title":"Functional characterization of NADP-dependent isocitrate dehydrogenase isozymes from Trypanosoma cruzi","volume":"177","author":"Leroux","year":"2011","journal-title":"Mol. Biochem. Parasitol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/s40409-018-0165-8","article-title":"Efficacy of sertraline against Trypanosoma cruzi: An in vitro and in silico study","volume":"24","author":"Ferreira","year":"2018","journal-title":"J. Venom. Anim. Toxins Incl. Trop. Dis."},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Brandan, C.P., Padilla, A.M., Xu, D., Tarleton, R.L., and Basombrio, M.A. (2011). Knockout of the dhfr-ts gene in trypanosoma cruzi generates attenuated parasites able to confer protection against a virulent challenge. PLoS Negl. Trop. Dis., 5.","DOI":"10.1371\/journal.pntd.0001418"},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Ju\u00e1rez-Saldivar, A., Schroeder, M., Salentin, S., Joachim Haupt, V., Saavedra, E., V\u00e1zquez, C., Reyes-Espinosa, F., Herrera-Mayorga, V., Villalobos-Rocha, J.C., and Garc\u00eda-P\u00e9rez, C.A. (2020). Computational drug repositioning for chagas disease using protein-ligand interaction profiling. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21124270"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1002\/prot.22115","article-title":"Structure-based approach to pharmacophore identification, in silico screening, and three-dimensional quantitative structure-activity relationship studies for inhibitors of Trypanosoma cruzi dihydrofolate reductase function","volume":"73","author":"Schormann","year":"2008","journal-title":"Proteins Struct. Funct. Genet."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"58","DOI":"10.3389\/fchem.2021.634663","article-title":"QSAR Modeling for Multi-Target Drug Discovery: Designing Simultaneous Inhibitors of Proteins in Diverse Pathogenic Parasites","volume":"9","author":"Kleandrova","year":"2021","journal-title":"Front. Chem."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/j.ejmech.2015.04.028","article-title":"Design, synthesis and biological evaluation of quinazoline derivatives as anti-trypanosomatid and anti-plasmodial agents","volume":"96","year":"2015","journal-title":"Eur. J. Med. Chem."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"6468","DOI":"10.1039\/c2dt12179d","article-title":"Bisphosphonate metal complexes as selective inhibitors of Trypanosoma cruzi farnesyl diphosphate synthase","volume":"41","author":"Demoro","year":"2012","journal-title":"Dalt. Trans."},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Bastos, T.M., Soares, M.B.P., Franco, C.H., Alc\u00e2ntara, L., Antonini, L., Sabatino, M., Mautone, N., Freitas-Junior, L.H., Moraes, C.B., and Ragno, R. (2020). Identification of inhibitors to trypanosoma cruzi sirtuins based on compounds developed to human enzymes. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21103659"},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Matutino Bastos, T., Mannochio Russo, H., Silvio Moretti, N., Schenkman, S., Marcourt, L., Gupta, M.P., Wolfender, J.L., Ferreira Queiroz, E., and Botelho Pereira Soares, M. (2019). Chemical Constituents of Anacardium occidentale as Inhibitors of Trypanosoma cruzi Sirtuins. Molecules, 24.","DOI":"10.3390\/molecules24071299"},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Freitas, E.O., Nico, D., Alves-Silva, M.V., Morrot, A., Clinch, K., Evans, G.B., Tyler, P.C., Schramm, V.L., and Palatnik-de-Sousa, C.B. (2015). Immucillins ImmA and ImmH Are Effective and Non-toxic in the Treatment of Experimental Visceral Leishmaniasis. PLoS Negl. Trop. Dis., 9.","DOI":"10.1371\/journal.pntd.0004297"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1016\/j.bbrc.2017.05.048","article-title":"Pyrrole-indolinone SU11652 targets the nucleoside diphosphate kinase from Leishmania parasites","volume":"488","author":"Vieira","year":"2017","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1515\/ap-2017-0070","article-title":"In vitro effects of purine and pyrimidine analogues on Leishmania donovani and Leishmania infantum promastigotes and intracellular amastigotes","volume":"62","author":"Azzouz","year":"2017","journal-title":"Acta Parasitol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"681","DOI":"10.2174\/1389450121666200128112948","article-title":"Unveiling the Targets Involved in the Quest of Antileishmanial Leads Using In silico Methods","volume":"21","author":"Boniface","year":"2020","journal-title":"Curr. Drug Targets"},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Stevanovi\u0107, S., Perdih, A., Sen\u0107anski, M., Gli i\u0107, S., Duarte, M., Tom\u00e1s, A.M., Sena, F.V., Sousa, F.M., Pereira, M.M., and Solmajer, T. (2018). In Silico Discovery of a Substituted 6-Methoxy-quinalidine with Leishmanicidal Activity in Leishmania infantum. Molecules, 23.","DOI":"10.3390\/molecules23040772"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.parint.2016.01.001","article-title":"Oleanolic acid (OA) as an antileishmanial agent: Biological evaluation and in silico mechanistic insights","volume":"65","author":"Melo","year":"2016","journal-title":"Parasitol. Int."},{"key":"ref_107","doi-asserted-by":"crossref","unstructured":"Battista, T., Colotti, G., Ilari, A., and Fiorillo, A. (2020). Targeting trypanothione reductase, a key enzyme in the redox trypanosomatid metabolism, to develop new drugs against leishmaniasis and trypanosomiases. Molecules, 25.","DOI":"10.3390\/molecules25081924"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1002\/ardp.201500312","article-title":"Antileishmanial, DNA Interaction, and Docking Studies of Some Ferrocene-Based Heteroleptic Pentavalent Antimonials","volume":"349","author":"Rauf","year":"2016","journal-title":"Arch. Pharm."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1021\/jm901059x","article-title":"Structure-based design of pteridine reductase inhibitors targeting African sleeping sickness and the leishmaniases","volume":"53","author":"Tulloch","year":"2010","journal-title":"J. Med. Chem."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1016\/j.bioorg.2017.02.005","article-title":"Molecular hybridization conceded exceptionally potent quinolinyl-oxadiazole hybrids through phenyl linked thiosemicarbazide antileishmanial scaffolds: In silico validation and SAR studies","volume":"71","author":"Taha","year":"2017","journal-title":"Bioorg. Chem."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1016\/j.ejmech.2016.12.019","article-title":"Synthesis and molecular modelling studies of phenyl linked oxadiazole-phenylhydrazone hybrids as potent antileishmanial agents","volume":"126","author":"Taha","year":"2017","journal-title":"Eur. J. Med. Chem."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1016\/j.bmcl.2015.12.085","article-title":"Antileishmanial activity of novel indolyl-coumarin hybrids: Design, synthesis, biological evaluation, molecular docking study and in silico ADME prediction","volume":"26","author":"Sangshetti","year":"2016","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"3845","DOI":"10.1016\/j.bmcl.2017.06.053","article-title":"Antileishmanial potential of fused 5-(pyrazin-2-yl)-4H-1,2,4-triazole-3-thiols: Synthesis, biological evaluations and computational studies","volume":"27","author":"Patil","year":"2017","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"3033","DOI":"10.1128\/AAC.48.8.3033-3042.2004","article-title":"Inhibitors of Leishmania mexicana CRK3 cyclin-dependent kinase: Chemical library screen and antileishmanial activity","volume":"48","author":"Grant","year":"2004","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-019-52774-6","article-title":"Biochemical characterization and chemical validation of Leishmania MAP Kinase-3 as a potential drug target","volume":"9","author":"Raj","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_116","first-page":"1","article-title":"Genistein and ascorbic acid reduce oxidative stress-derived DNA damage induced by the antileishmanial meglumine antimoniate","volume":"62","author":"Soares","year":"2018","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1016\/j.ejmech.2016.08.048","article-title":"Synthesis and evaluation against Leishmania amazonensis of novel pyrazolo[3,4-d]pyridazinone-N-acylhydrazone-(bi)thiophene hybrids","volume":"124","author":"Jacomini","year":"2016","journal-title":"Eur. J. Med. Chem."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1016\/j.ejmech.2018.04.057","article-title":"Identification of chalcone-based antileishmanial agents targeting trypanothione reductase","volume":"152","author":"Ortalli","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.bcp.2016.12.012","article-title":"Novel \u03b2-carboline-quinazolinone hybrids disrupt Leishmania donovani redox homeostasis and show promising antileishmanial activity","volume":"129","author":"Ramu","year":"2017","journal-title":"Biochem. Pharmacol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1186\/1756-3305-3-107","article-title":"Targeting essential pathways in trypanosomatids gives insights into protozoan mechanisms of cell death","volume":"3","author":"Smirlis","year":"2010","journal-title":"Parasit. Vectors"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1038\/s41422-019-0164-5","article-title":"The molecular machinery of regulated cell death","volume":"29","author":"Tang","year":"2019","journal-title":"Cell Res."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1111\/j.1365-2958.2006.05274.x","article-title":"Cysteine peptidases CPA and CPB are vital for autophagy and differentiation in Leishmania mexicana","volume":"61","author":"Williams","year":"2006","journal-title":"Mol. Microbiol."},{"key":"ref_123","first-page":"1","article-title":"Cell death pathways in pathogenic trypanosomatids: Lessons of (over)kill","volume":"10","year":"2019","journal-title":"Cell Death Dis."},{"key":"ref_124","doi-asserted-by":"crossref","unstructured":"Pe\u00f1a-Guerrero, J., Nguewa, P.A., and Garc\u00eda-Sosa, A.T. (2021). Machine learning, artificial intelligence, and data science breaking into drug design and neglected diseases. Wiley Interdiscip. Rev. Comput. Mol. Sci., e1513.","DOI":"10.1002\/wcms.1513"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1038\/s41563-019-0338-z","article-title":"Exploiting machine learning for end-to-end drug discovery and development","volume":"18","author":"Ekins","year":"2019","journal-title":"Nat. Mater."},{"key":"ref_126","unstructured":"Mitchell, T.M. (1997). Machine Learning, McGraw-Hill Science."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"S55","DOI":"10.1038\/d41586-018-05267-x","article-title":"How artificial intelligence is changing drug discovery","volume":"557","author":"Fleming","year":"2018","journal-title":"Nature"},{"key":"ref_128","unstructured":"(2021, June 22). DNDi and Atomwise Collaborate to Advance Drug Development Using AI for Neglected Diseases|DNDi. Available online: https:\/\/dndi.org\/press-releases\/2019\/dndi-and-atomwise-collaborate-to-advance-drug-development-using-ai-for-neglected-diseases\/."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1471-2105-14-329","article-title":"Cheminformatic models based on machine learning for pyruvate kinase inhibitors of Leishmania mexicana","volume":"14","author":"Jamal","year":"2013","journal-title":"BMC Bioinform."},{"key":"ref_130","first-page":"351","article-title":"New Approaches to Overcome Transport Related Drug Resistance in Trypanosomatid Parasites","volume":"7","author":"Soriano","year":"2016","journal-title":"Front. Pharmacol."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"2007","DOI":"10.1042\/BCJ20200176","article-title":"Computationally designed synthetic peptides for transporter proteins imparts allostericity in Miltefosine resistant L. major","volume":"447","author":"Kabra","year":"2020","journal-title":"Biochem. J."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.1093\/cid\/ciaa933","article-title":"Predicted Impact of COVID-19 on Neglected Tropical Disease Programs and the Opportunity for Innovation","volume":"72","author":"Toor","year":"2021","journal-title":"Clin. Infect. Dis."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/15\/4629\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:37:23Z","timestamp":1760164643000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/15\/4629"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,30]]},"references-count":132,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2021,8]]}},"alternative-id":["molecules26154629"],"URL":"https:\/\/doi.org\/10.3390\/molecules26154629","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,30]]}}}