{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:59:01Z","timestamp":1787029141987,"version":"build-2736575974"},"reference-count":98,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2024,9,30]],"date-time":"2024-09-30T00:00:00Z","timestamp":1727654400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior-Brasil (CAPES)","award":["001"],"award-info":[{"award-number":["001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Visceral leishmaniasis (VL), caused by protozoa of the genus Leishmania, remains a significant public health concern due to its potentially lethal nature if untreated. Current chemotherapy options are limited by severe toxicity and drug resistance. Derivatives of 1,2,4-oxadiazole have emerged as promising drug candidates due to their broad biological activity. This study investigated the effects of novel 1,2,4-oxadiazole derivatives (Ox1\u2013Ox7) on Leishmania infantum, the etiological agent of VL. In silico predictions using SwissADME suggest that these compounds have high oral absorption and good bioavailability. Among them, Ox1 showed the most promise, with higher selectivity against promastigotes and lower cytotoxicity towards L929 fibroblasts and J774.G8 macrophages. Ox1 exhibited selectivity indices of 18.7 and 61.7 against L. infantum promastigotes and amastigotes, respectively, compared to peritoneal macrophages. Ultrastructural analyses revealed severe morphological damage in both parasite forms, leading to cell death. Additionally, Ox1 decreased the mitochondrial membrane potential in promastigotes, as shown by flow cytometry. Molecular docking and dynamic simulations indicated a strong affinity of Ox1 for the L. infantum CYP51 enzyme. Overall, Ox1 is a promising and effective compound against L. infantum.<\/jats:p>","DOI":"10.3390\/molecules29194654","type":"journal-article","created":{"date-parts":[[2024,9,30]],"date-time":"2024-09-30T06:39:35Z","timestamp":1727678375000},"page":"4654","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["1,2,4-Oxadiazole Derivatives: Physicochemical Properties, Antileishmanial Potential, Docking and Molecular Dynamic Simulations of Leishmania infantum Target Proteins"],"prefix":"10.3390","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9026-6528","authenticated-orcid":false,"given":"Deyzi C. S.","family":"Barbosa","sequence":"first","affiliation":[{"name":"Department of Microbiology, Aggeu Magalh\u00e3es Institute (IAM-FIOCRUZ), Recife 50740-465, PE, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5309-0036","authenticated-orcid":false,"given":"Vanderlan N.","family":"Holanda","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, University Center of Vit\u00f3ria de Santo Ant\u00e3o (UNIVISA), Vit\u00f3ria de Santo Ant\u00e3o 55610-050, PE, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0545-2447","authenticated-orcid":false,"given":"Elton M. A.","family":"Lima","sequence":"additional","affiliation":[{"name":"Center for Exact and Natural Sciences, Federal University of Pernambuco (UFPE), Recife 50740-560, PE, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9995-7352","authenticated-orcid":false,"given":"Marton K. A.","family":"Cavalcante","sequence":"additional","affiliation":[{"name":"Parasitology Laboratory, Academic Center of Vit\u00f3ria, Federal University of Pernambuco (UFPE), Recife 50670-420, PE, Brazil"},{"name":"Department of Immunology, Aggeu Magalh\u00e3es Institute (IAM-FIOCRUZ), Recife 50740-465, PE, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2205-0618","authenticated-orcid":false,"given":"Maria Carolina A.","family":"Brelaz-de-Castro","sequence":"additional","affiliation":[{"name":"Parasitology Laboratory, Academic Center of Vit\u00f3ria, Federal University of Pernambuco (UFPE), Recife 50670-420, PE, Brazil"},{"name":"Department of Immunology, Aggeu Magalh\u00e3es Institute (IAM-FIOCRUZ), Recife 50740-465, PE, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8573-2216","authenticated-orcid":false,"given":"Elton J. F.","family":"Chaves","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Federal University of Para\u00edba (UFPB), Jo\u00e3o Pessoa 58051-900, PB, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9805-9497","authenticated-orcid":false,"given":"Gerd B.","family":"Rocha","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Federal University of Para\u00edba (UFPB), Jo\u00e3o Pessoa 58051-900, PB, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0215-755X","authenticated-orcid":false,"given":"Carla J. O.","family":"Silva","sequence":"additional","affiliation":[{"name":"Department of Fundamental Chemistry, Federal University of Pernambuco (UFPE), Recife 50740-540, PE, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6111-2351","authenticated-orcid":false,"given":"Ronaldo N.","family":"Oliveira","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Federal Rural University of Pernambuco (UFRPE), Recife 52171-900, PE, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5806-0944","authenticated-orcid":false,"given":"Regina C. B. 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Advances in Pharmaceutical Product Development and Research."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1007\/s40475-021-00232-7","article-title":"A Review of Leishmaniasis: Current Knowledge and Future Directions","volume":"8","author":"Mann","year":"2021","journal-title":"Curr. Trop. Med. Rep."},{"key":"ref_5","unstructured":"(2024, June 29). WHO Leishmaniasis. Available online: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/leishmaniasis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"218","DOI":"10.3390\/immuno2010015","article-title":"Host\u2013Pathogen Interaction in Leishmaniasis: Immune Response and Vaccination Strategies","volume":"2","author":"Yasmin","year":"2022","journal-title":"Immuno"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"151","DOI":"10.4103\/0974-777X.62883","article-title":"Treatment of Visceral Leishmaniasis","volume":"2","author":"Moore","year":"2010","journal-title":"J. Glob. Infect. Dis."},{"key":"ref_8","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_9","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_10","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/j.ejmech.2018.08.012","article-title":"An Update on Small Molecule Strategies Targeting Leishmaniasis","volume":"157","author":"Kapil","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2967","DOI":"10.1007\/s11030-021-10375-4","article-title":"A Review on Synthetic Account of 1,2,4-Oxadiazoles as Anti-Infective Agents","volume":"26","author":"Dhameliya","year":"2022","journal-title":"Mol. Divers."},{"key":"ref_12","unstructured":"Shukla, P., Verma, A., and Mishra, P. (2017). Significance of Nitrogen Heterocyclic Nuclei in the Search of Pharmacological Active Compounds. New Perspective in Agricultural and Human Health, Bharti Publishers."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e04245","DOI":"10.1016\/j.heliyon.2020.e04245","article-title":"Synthesis, Characterization and Biological Investigations of Potentially Bioactive Heterocyclic Compounds Containing 4-Hydroxy Coumarin","volume":"6","author":"Nagaraja","year":"2020","journal-title":"Heliyon"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Barbuceanu, S.-F., Rosca, E.-V., Apostol, T.-V., Socea, L.-I., Draghici, C., Farcasanu, I.C., Ruta, L.L., Nitulescu, G.M., Iscrulescu, L., and Pahontu, E.-M. (2023). New Heterocyclic Compounds from Oxazol-5(4H)-One and 1,2,4-Triazin-6(5H)-One Classes: Synthesis, Characterization and Toxicity Evaluation. Molecules, 28.","DOI":"10.3390\/molecules28124834"},{"key":"ref_15","unstructured":"(2024, September 14). Biological Activity of Oxadiazole and Thiadiazole Derivatives|Applied Microbiology and Biotechnology. Available online: https:\/\/link.springer.com\/article\/10.1007\/s00253-022-11969-0."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Biernacki, K., Da\u015bko, M., Ciupak, O., Kubi\u0144ski, K., Rachon, J., and Demkowicz, S. (2020). Novel 1,2,4-Oxadiazole Derivatives in Drug Discovery. Pharmaceuticals, 13.","DOI":"10.3390\/ph13060111"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2516","DOI":"10.1021\/ol200234r","article-title":"Structure and Cytotoxicity of Phidianidines A and B: First Finding of 1,2,4-Oxadiazole System in a Marine Natural Product","volume":"13","author":"Carbone","year":"2011","journal-title":"Org. Lett."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Zhou, M., Boulos, J.C., Omer, E.A., Klauck, S.M., and Efferth, T. (2023). Modes of Action of a Novel C-MYC Inhibiting 1,2,4-Oxadiazole Derivative in Leukemia and Breast Cancer Cells. Molecules, 28.","DOI":"10.3390\/molecules28155658"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1016\/j.bioorg.2019.01.054","article-title":"Design, Synthesis and Biological Evaluation of (E)-5-Styryl-1,2,4-Oxadiazoles as Anti-Tubercular Agents","volume":"86","author":"Gadekar","year":"2019","journal-title":"Bioorgan. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"113472","DOI":"10.1016\/j.ejmech.2021.113472","article-title":"Synthesis of Alkynylated 1,2,4-Oxadiazole\/1,2,3-1H-Triazole Glycoconjugates: Discovering New Compounds for Use in Chemotherapy against Lung Carcinoma and Mycobacterium tuberculosis","volume":"220","author":"Ferreira","year":"2021","journal-title":"Eur. J. Med. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Mohamed, M.F.A., Marzouk, A.A., Nafady, A., El-Gamal, D.A., Allam, R.M., Abuo-Rahma, G.E.-D.A., El Subbagh, H.I., and Moustafa, A.H. (2020). Design, Synthesis and Molecular Modeling of Novel Aryl Carboximidamides and 3-Aryl-1,2,4-Oxadiazoles Derived from Indomethacin as Potent Anti-Inflammatory iNOS\/PGE2 Inhibitors. Bioorgan. Chem., 105.","DOI":"10.1016\/j.bioorg.2020.104439"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1007\/s00044-020-02505-8","article-title":"Design, Synthesis, and Characterization of Novel Substituted 1,2,4-Oxadiazole and Their Biological Broadcast","volume":"29","author":"Parikh","year":"2020","journal-title":"Med. Chem. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2815","DOI":"10.1016\/j.bmc.2004.03.054","article-title":"Antikinetoplastid Activity of 3-Aryl-5-Thiocyanatomethyl-1,2,4-Oxadiazoles","volume":"12","author":"Cottrell","year":"2004","journal-title":"Bioorgan. Med. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"112418","DOI":"10.1016\/j.ejmech.2020.112418","article-title":"Discovery of Highly Potent and Selective Antiparasitic New Oxadiazole and Hydroxy-Oxindole Small Molecule Hybrids","volume":"201","author":"Fernandes","year":"2020","journal-title":"Eur. J. Med. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"950","DOI":"10.1016\/j.bmcl.2016.12.083","article-title":"Design, Synthesis, and Bioactivities of Novel Oxadiazole-Substituted Pyrazole Oximes","volume":"27","author":"Dai","year":"2017","journal-title":"Bioorgan. Med. Chem. Lett."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.22271\/phyto.2020.v9.i6s.13132","article-title":"Synthesis, Evaluation & Pharmacological Action of Oxadiazole Derivatives","volume":"9","author":"Meher","year":"2020","journal-title":"J. Pharmacogn. Phytochem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1007\/s12639-021-01455-1","article-title":"Anti-Leishmania infantum in Vitro Effect of n-Cyclohexyl-1,2,4-Oxadiazole and Its ADME\/TOX Parameters","volume":"46","author":"Pinheiro","year":"2022","journal-title":"J. Parasit. Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2522","DOI":"10.1080\/00397911.2018.1509350","article-title":"Focused Microwave Irradiation-Assisted Synthesis of N-Cyclohexyl-1,2,4-Oxadiazole Derivatives with Antitumor Activity","volume":"48","author":"Oliveira","year":"2018","journal-title":"Synth. Commun."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/bs.aihch.2015.05.001","article-title":"Recent Advances in the Chemistry of 1,2,4-Oxadiazolesa","volume":"Volume 116","author":"Scriven","year":"2015","journal-title":"Advances in Heterocyclic Chemistry"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"113112","DOI":"10.1016\/j.ejmech.2020.113112","article-title":"2-Propargylamino-Naphthoquinone Derivatives as Multipotent Agents for the Treatment of Alzheimer\u2019s Disease","volume":"211","author":"Mezeiova","year":"2021","journal-title":"Eur. J. Med. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Lutsenko, K., Hagenow, S., Affini, A., Reiner, D., and Stark, H. (2019). Rasagiline Derivatives Combined with Histamine H3 Receptor Properties. Bioorgan. Med. Chem. Lett., 29.","DOI":"10.1016\/j.bmcl.2019.08.016"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3532","DOI":"10.1016\/j.bmc.2019.06.002","article-title":"The Synthesis and Evaluation of Quinolinequinones as Anti-Mycobacterial Agents","volume":"27","author":"Santoso","year":"2019","journal-title":"Bioorgan. Med. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.1515\/pac-2018-1102","article-title":"Current and Promising Novel Drug Candidates against Visceral Leishmaniasis","volume":"91","author":"Reguera","year":"2019","journal-title":"Pure Appl. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e000709","DOI":"10.1136\/bmjgh-2018-000709","article-title":"Why Miltefosine\u2014A Life-Saving Drug for Leishmaniasis\u2014Is Unavailable to People Who Need It the Most","volume":"3","author":"Sunyoto","year":"2018","journal-title":"BMJ Glob. Health"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"789","DOI":"10.4269\/ajtmh.18-0949","article-title":"Natural Resistance of Leishmania infantum to Miltefosine Contributes to the Low Efficacy in the Treatment of Visceral Leishmaniasis in Brazil","volume":"101","author":"Carnielli","year":"2019","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.addr.2012.09.019","article-title":"Experimental and Computational Approaches to Estimate Solubility and Permeability in Drug Discovery and Development Settings","volume":"64","author":"Lipinski","year":"2012","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_37","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_38","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1016\/j.ejmech.2018.04.003","article-title":"Anti-Leishmanial Click Modifiable Thiosemicarbazones: Design, Synthesis, Biological Evaluation and in Silico Studies","volume":"151","author":"Temraz","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4411","DOI":"10.1021\/acs.jmedchem.9b01476","article-title":"Application of Negative Design To Design a More Desirable Virtual Screening Library","volume":"63","author":"Yang","year":"2020","journal-title":"J. Med. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"de Souza, W. (2022). Leishmania and Their Vertebrate Host Cells. Lifecycles of Pathogenic Protists in Humans, Springer International Publishing.","DOI":"10.1007\/978-3-030-80682-8"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2121","DOI":"10.1084\/jem.191.12.2121","article-title":"Fibroblasts as Host Cells in Latent Leishmaniosis","volume":"191","author":"Bogdan","year":"2000","journal-title":"J. Exp. Med."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Valigurov\u00e1, A., and Kol\u00e1\u0159ov\u00e1, I. (2023). Unrevealing Mystery Latent Leishmaniasis: What Cells Can Host Leishmania?. Pathogens, 12.","DOI":"10.3390\/pathogens12020246"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3225","DOI":"10.1002\/chem.201603491","article-title":"Stereoelectronic Chameleons: The Donor\u2013Acceptor Dichotomy of Functional Groups","volume":"23","author":"Vatsadze","year":"2017","journal-title":"Chem.\u2014A Eur. J."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1111\/j.1462-5822.2007.01096.x","article-title":"The Leishmania\u2013Macrophage Interaction: A Metabolic Perspective","volume":"10","author":"Naderer","year":"2008","journal-title":"Cell. Microbiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1111\/j.1365-3024.2009.01134.x","article-title":"Antileishmanial and Immunomodulatory Activity of Xylopia Discreta","volume":"31","author":"Cuca","year":"2009","journal-title":"Parasite Immunol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"102218","DOI":"10.1016\/j.parint.2020.102218","article-title":"Leishmania amazonensis Response to Artemisinin and Derivatives","volume":"80","author":"Gille","year":"2021","journal-title":"Parasitol. Int."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"605","DOI":"10.3390\/stresses3030042","article-title":"Surprising Effects of Rocking Motion on Leishmania tarentolae Behavior in Culture and Implications for Cell Stress","volume":"3","author":"Ferrence","year":"2023","journal-title":"Stresses"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1111\/j.1550-7408.2010.00496.x","article-title":"Evidence for Rosettes as an Unrecognized Stage in the Life Cycle of Leishmania Parasites","volume":"57","author":"Iovannisci","year":"2010","journal-title":"J. Eukaryot. Microbiol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"925","DOI":"10.2174\/138161208784041033","article-title":"de Ultrastructural Alterations in Organelles of Parasitic Protozoa Induced by Different Classes of Metabolic Inhibitors","volume":"14","author":"Souza","year":"2008","journal-title":"Curr. Pharm. Des."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"e00079-19","DOI":"10.1128\/MMBR.00079-19","article-title":"Touching the Surface: Diverse Roles for the Flagellar Membrane in Kinetoplastid Parasites","volume":"84","author":"Kelly","year":"2020","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1111\/mmi.14635","article-title":"Nutrient Sensing in Leishmania: Flagellum and Cytosol","volume":"115","author":"Kelly","year":"2021","journal-title":"Mol. Microbiol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1590\/S0074-02762013000100014","article-title":"Regulatory Volume Decrease in Leishmania mexicana: Effect of Anti-Microtubule Drugs","volume":"108","author":"Dagger","year":"2013","journal-title":"Mem. Inst. Oswaldo Cruz"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/j.biochi.2021.06.015","article-title":"Analysis of the Mechanisms of Action of Isopentenyl Caffeate against Leishmania","volume":"189","author":"Oliveira","year":"2021","journal-title":"Biochimie"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Antinarelli, L.M.R., Midlej, V., da Silva, E.D.S., Coelho, E.A.F., da Silva, A.D., and Coimbra, E.S. (2023). Exploring the Repositioning of the Amodiaquine as Potential Drug against Visceral Leishmaniasis: The in Vitro Effect against Leishmania infantum Is Associated with Multiple Mechanisms, Involving Mitochondria Dysfunction, Oxidative Stress and Loss of Cell Cycle Control. Chem.\u2014Biol. Interact., 371.","DOI":"10.1016\/j.cbi.2022.110333"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Korotkov, S.M. (2023). Mitochondrial Oxidative Stress Is the General Reason for Apoptosis Induced by Different-Valence Heavy Metals in Cells and Mitochondria. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241914459"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Yamamoto, E.S., de Jesus, J.A., Bezerra-Souza, A., Brito, J.R., Lago, J.H.G., Laurenti, M.D., and Passero, L.F.D. (2020). Tolnaftate Inhibits Ergosterol Production and Impacts Cell Viability of Leishmania sp.. Bioorgan. Chem., 102.","DOI":"10.1016\/j.bioorg.2020.104056"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"e210157","DOI":"10.1590\/0074-02760210157","article-title":"Mitochondrial Dysfunction on Leishmania (Leishmania) amazonensis Induced by Ketoconazole: Insights into Drug Mode of Action","volume":"117","author":"Costa","year":"2022","journal-title":"Mem. Inst. Oswaldo Cruz"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"107139","DOI":"10.1016\/j.actatropica.2024.107139","article-title":"Clotrimazole Causes Membrane Depolarization and Induces Sub G0 Cell Cycle Arrest in Leishmania donovani","volume":"252","author":"Paul","year":"2024","journal-title":"Acta Trop."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"de Macedo-Silva, S.T., Visbal, G., Souza, G.F., dos Santos, M.R., C\u00e4mmerer, S.B., de Souza, W., and Rodrigues, J.C.F. (2022). Benzylamines as Highly Potent Inhibitors of the Sterol Biosynthesis Pathway in Leishmania amazonensis Leading to Oxidative Stress and Ultrastructural Alterations. Sci. Rep., 12.","DOI":"10.1038\/s41598-022-15449-3"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"127","DOI":"10.4161\/auto.7.2.13310","article-title":"Autophagy in Protists","volume":"7","author":"Duszenko","year":"2011","journal-title":"Autophagy"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2149211","DOI":"10.1080\/27694127.2022.2149211","article-title":"Autophagy in Protists and Their Hosts: When, How and Why?","volume":"2","author":"Romano","year":"2023","journal-title":"Autophagy Rep."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Pedra-Rezende, Y., Macedo, I.S., Midlej, V., Mariante, R.M., and Menna-Barreto, R.F.S. (2022). Different Drugs, Same End: Ultrastructural Hallmarks of Autophagy in Pathogenic Protozoa. Front. Microbiol., 13.","DOI":"10.3389\/fmicb.2022.856686"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Sandes, J.M., and de Figueiredo, R.C.B.Q. (2022). The Endoplasmic Reticulum of Trypanosomatids: An Unrevealed Road for Chemotherapy. Front. Cell. Infect. Microbiol., 12.","DOI":"10.3389\/fcimb.2022.1057774"},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Machado, P.d.A., Gomes, P.S., Midlej, V., Coimbra, E.S., and de Matos Guedes, H.L. (2021). PF-429242, a Subtilisin Inhibitor, Is Effective in Vitro Against Leishmania infantum. Front. Microbiol., 12.","DOI":"10.3389\/fmicb.2021.583834"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1038\/s41419-019-1370-2","article-title":"Cell Death Pathways in Pathogenic Trypanosomatids: Lessons of (over)Kill","volume":"10","year":"2019","journal-title":"Cell Death Dis."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Lamotte, S., Sp\u00e4th, G.F., Rachidi, N., and Prina, E. (2017). The Enemy within: Targeting Host\u2013Parasite Interaction for Antileishmanial Drug Discovery. PLoS Neglect. Trop. Dis., 11.","DOI":"10.1371\/journal.pntd.0005480"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s12639-010-0006-3","article-title":"Drug Targets in Leishmania","volume":"34","author":"Chawla","year":"2010","journal-title":"J. Parasit. Dis."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Beltran-Hortelano, I., Alcolea, V., Font, M., and P\u00e9rez-Silanes, S. (2022). Examination of Multiple Trypanosoma cruzi Targets in a New Drug Discovery Approach for Chagas Disease. Bioorgan. Med. Chem., 58.","DOI":"10.1016\/j.bmc.2021.116577"},{"key":"ref_69","first-page":"rs.3.rs-3185204","article-title":"CYP5122A1 Encodes an Essential Sterol C4-Methyl Oxidase in Leishmania donovani and Determines the Antileishmanial Activity of Antifungal Azoles","volume":"1","author":"Jin","year":"2023","journal-title":"Res. Sq."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2615","DOI":"10.2174\/1381612811319140011","article-title":"Target Sites for the Design of Anti-Trypanosomatid Drugs Based on the Structure of Dihydroorotate Dehydrogenase","volume":"19","year":"2013","journal-title":"Curr. Pharm. Des."},{"key":"ref_71","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_72","doi-asserted-by":"crossref","first-page":"3229","DOI":"10.1007\/s00436-022-07642-0","article-title":"Knockout of Tyrosine Aminotransferase Gene by Homologous Recombination Arrests Growth and Disrupts Redox Homeostasis in Leishmania Parasite","volume":"121","author":"Sasidharan","year":"2022","journal-title":"Parasitol. Res."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1007\/s00249-023-01677-6","article-title":"Structure and Dynamics of Pteridine Reductase 1: The Key Phenomena Relevant to Enzyme Function and Drug Design","volume":"52","author":"Poehner","year":"2023","journal-title":"Eur. Biophys. J."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Kourbeli, V., Chontzopoulou, E., Moschovou, K., Pavlos, D., Mavromoustakos, T., and Papanastasiou, I.P. (2021). An Overview on Target-Based Drug Design against Kinetoplastid Protozoan Infections: Human African Trypanosomiasis, Chagas Disease and Leishmaniases. Molecules, 26.","DOI":"10.3390\/molecules26154629"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1021\/acs.jcim.8b00036","article-title":"Determining the Relative Binding Affinity of Ricin Toxin A Inhibitors by Using Molecular Docking and Nonequilibrium Work","volume":"58","author":"Chaves","year":"2018","journal-title":"J. Chem. Inf. Model."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"2189","DOI":"10.1021\/acs.jcim.0c00057","article-title":"Improving Protein-Ligand Docking Results with High-Throughput Molecular Dynamics Simulations","volume":"60","author":"Guterres","year":"2020","journal-title":"J. Chem. Inf. Model."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Rocha, S.F.L.S., and Sant\u2019Anna, C.M.R. (2019). A Procedure Combining Molecular Docking and Semiempirical Method PM7 for Identification of Selective Shp2 Inhibitors. Biopolymers, 110.","DOI":"10.1002\/bip.23320"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"5520","DOI":"10.1021\/acs.chemrev.5b00630","article-title":"Ligand-Binding Affinity Estimates Supported by Quantum-Mechanical Methods","volume":"116","author":"Ryde","year":"2016","journal-title":"Chem. Rev."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1820","DOI":"10.1017\/S0031182018000562","article-title":"CYP51 as Drug Targets for Fungi and Protozoan Parasites: Past, Present and Future","volume":"145","author":"Lepesheva","year":"2018","journal-title":"Parasitology"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/B978-0-12-385863-4.00004-6","article-title":"Targeting Trypanosoma cruzi Sterol 14\u03b1-Demethylase (CYP51)","volume":"Volume 75","author":"Weiss","year":"2011","journal-title":"Advances in Parasitology"},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Mansoldo, F.R.P., Carta, F., Angeli, A., Cardoso, V.d.S., Supuran, C.T., and Vermelho, A.B. (2020). Chagas Disease: Perspectives on the Past and Present and Challenges in Drug Discovery. Molecules, 25.","DOI":"10.3390\/molecules25225483"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1093\/infdis\/jit042","article-title":"VNI Cures Acute and Chronic Experimental Chagas Disease","volume":"208","author":"Villalta","year":"2013","journal-title":"J. Infect. Dis."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1021\/acsinfecdis.8b00253","article-title":"Successful Aspects of the Coadministration of Sterol 14\u03b1-Demethylase Inhibitor VFV and Benznidazole in Experimental Mouse Models of Chagas Disease Caused by the Drug-Resistant Strain of Trypanosoma cruzi","volume":"5","author":"Batista","year":"2019","journal-title":"ACS Infect. Dis."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"5635","DOI":"10.1016\/j.ejmech.2010.09.016","article-title":"Convenient Synthesis and Biological Profile of 5-Amino-Substituted 1,2,4-Oxadiazole Derivatives","volume":"45","author":"Ispikoudi","year":"2010","journal-title":"Eur. J. Med. Chem."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/0022-1759(83)90303-4","article-title":"Rapid Colorimetric Assay for Cellular Growth and Survival: Application to Proliferation and Cytotoxicity Assays","volume":"65","author":"Mosmann","year":"1983","journal-title":"J. Immunol. Methods"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1590\/S0074-02762008000400008","article-title":"In Vitro and in Vivo Activity of Meglumine Antimoniate Produced at Farmanguinhos-Fiocruz, Brazil, against Leishmania (Leishmania) Amazonensis, L (L.) Chagasi and L (Viannia) Braziliensis","volume":"103","author":"Duarte","year":"2008","journal-title":"Mem. Inst. Oswaldo Cruz"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1590\/S1984-29612012000300002","article-title":"In Vitro Efficacy of Coriandrum Sativum, Lippia Sidoides and Copaifera Reticulata against Leishmania chagasi","volume":"21","author":"Rondon","year":"2012","journal-title":"Rev. Bras. Parasitol. Vet."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Holanda, V.N., da Silva, W.V., do Nascimento, P.H., Silva, S.R.B., Cabral Filho, P.E., Assis, S.P.d.O., da Silva, C.A., de Oliveira, R.N., de Figueiredo, R.C.B.Q., and Lima, V.L.d.M. (2020). Antileishmanial Activity of 4-Phenyl-1-[2-(Phthalimido-2-Yl)Ethyl]-1H-1,2,3-Triazole (PT4) Derivative on Leishmania amazonensis and Leishmania braziliensis: In Silico ADMET, in Vitro Activity, Docking and Molecular Dynamic Simulations. Bioorgan. Chem., 105.","DOI":"10.1016\/j.bioorg.2020.104437"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"26838","DOI":"10.1074\/jbc.M111.237099","article-title":"Substrate Preferences and Catalytic Parameters Determined by Structural Characteristics of Sterol 14\u03b1-Demethylase (CYP51) from Leishmania infantum","volume":"286","author":"Hargrove","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1107\/S2053230X14007845","article-title":"Structure of Tyrosine Aminotransferase from Leishmania infantum","volume":"70","author":"Moreno","year":"2014","journal-title":"Acta Crystall. Sect. F"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1007\/s00726-011-0997-9","article-title":"A Gold-Containing Drug against Parasitic Polyamine Metabolism: The X-Ray Structure of Trypanothione Reductase from Leishmania infantum in Complex with Auranofin Reveals a Dual Mechanism of Enzyme Inhibition","volume":"42","author":"Ilari","year":"2012","journal-title":"Amino Acids"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"W537","DOI":"10.1093\/nar\/gks375","article-title":"H++ 3.0: Automating pK Prediction and the Preparation of Biomolecular Structures for Atomistic Molecular Modeling and Simulations","volume":"40","author":"Anandakrishnan","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"044130","DOI":"10.1063\/5.0014475","article-title":"Scalable Molecular Dynamics on CPU and GPU Architectures with NAMD","volume":"153","author":"Phillips","year":"2020","journal-title":"J. Chem. Phys."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1006\/jmbi.1996.0897","article-title":"Development and Validation of a Genetic Algorithm for Flexible Docking","volume":"267","author":"Jones","year":"1997","journal-title":"J. Mol. Biol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1021\/acs.jctc.9b00591","article-title":"ff19SB: Amino-Acid-Specific Protein Backbone Parameters Trained against Quantum Mechanics Energy Surfaces in Solution","volume":"16","author":"Tian","year":"2020","journal-title":"J. Chem. Theory Comput."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1983","DOI":"10.1021\/acs.jctc.8b01039","article-title":"Assessment of GAFF2 and OPLS-AA General Force Fields in Combination with the Water Models TIP3P, SPCE, and OPC3 for the Solvation Free Energy of Druglike Organic Molecules","volume":"15","author":"Vassetti","year":"2019","journal-title":"J. Chem. Theory Comput."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"3084","DOI":"10.1021\/ct400341p","article-title":"PTRAJ and CPPTRAJ: Software for Processing and Analysis of Molecular Dynamics Trajectory Data","volume":"9","author":"Roe","year":"2013","journal-title":"J. Chem. Theory Comput."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1126\/science.abj8754","article-title":"Accurate prediction of protein structures and interactions using a three-track neural network","volume":"373","author":"Baek","year":"2021","journal-title":"Science"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/29\/19\/4654\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:07:41Z","timestamp":1760112461000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/29\/19\/4654"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,30]]},"references-count":98,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2024,10]]}},"alternative-id":["molecules29194654"],"URL":"https:\/\/doi.org\/10.3390\/molecules29194654","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,30]]}}}