{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T07:25:21Z","timestamp":1777620321278,"version":"3.51.4"},"reference-count":39,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2024,7,3]],"date-time":"2024-07-03T00:00:00Z","timestamp":1719964800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Agence Universitaire de la Francophonie (AUF)","award":["203134\/Z\/16\/Z"],"award-info":[{"award-number":["203134\/Z\/16\/Z"]}]},{"name":"Agence Universitaire de la Francophonie (AUF)","award":["218448\/Z\/19\/Z"],"award-info":[{"award-number":["218448\/Z\/19\/Z"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>A series of 61 thiazolidine-2,4-diones bearing a styryl group at position 5 was synthesized in 2\u20135 steps and their structure was proved by elemental and spectral analyses. The compounds obtained were evaluated in vitro against the promastigote stage of the kinetoplastid parasite Leishmania infantum and the human HepG2 cell line, to determine selectivity indices and to compare their activities with those of antileishmanial reference drugs. The study of structure\u2013activity relationships indicated the potential of some derivatives bearing a nitro group on the phenyl ring, especially when located at the meta position. Thus, among the tested series, compound 14c appeared as a hit compound with good antileishmanial activity (EC50 = 7 \u00b5M) and low cytotoxicity against both the hepatic HepG2 and macrophage THP-1 human cell lines (CC50 = 101 and 121 \u00b5M, respectively), leading to good selectivity indices (respectively, 14 and 17), in comparison with the reference antileishmanial drug compound miltefosine (EC50 = 3.3 \u00b5M, CC50 = 85 and 30 \u00b5M, SI = 26 and 9). Regarding its mechanism of action, among several possibilities, it was demonstrated that compound 14c is a prodrug bioactivated, predominantly by L. donovani nitroreductase 1, likely leading to the formation of cytotoxic metabolites that form covalent adducts in the parasite. Finally, compound 14c is lipophilic (measured CHI LogD7.7 = 2.85) but remains soluble in water (measured PBS solubility at pH7.4 = 16 \u00b5M), highlighting the antileishmanial potential of the nitrostyrylthiazolidine-2,4-dione scaffold.<\/jats:p>","DOI":"10.3390\/ph17070878","type":"journal-article","created":{"date-parts":[[2024,7,3]],"date-time":"2024-07-03T08:45:34Z","timestamp":1719996334000},"page":"878","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Synthesis of Nitrostyrylthiazolidine-2,4-dione Derivatives Displaying Antileishmanial Potential"],"prefix":"10.3390","volume":"17","author":[{"given":"Omar","family":"Khoumeri","sequence":"first","affiliation":[{"name":"Team Pharmaco-Chimie Radicalaire, Facult\u00e9 de Pharmacie, Aix Marseille University, CNRS, ICR UMR 7273, 27 Boulevard Jean Moulin, CS30064, CEDEX 05, 13385 Marseille, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S\u00e9bastien","family":"Hutter","sequence":"additional","affiliation":[{"name":"IHU M\u00e9diterran\u00e9e Infection, UMR RITMES, TEAM-VEPTE, Aix Marseille University, 19-21 Boulevard Jean Moulin, 13005 Marseille, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6713-6039","authenticated-orcid":false,"given":"Nicolas","family":"Primas","sequence":"additional","affiliation":[{"name":"Team Pharmaco-Chimie Radicalaire, Facult\u00e9 de Pharmacie, Aix Marseille University, CNRS, ICR UMR 7273, 27 Boulevard Jean Moulin, CS30064, CEDEX 05, 13385 Marseille, France"},{"name":"Service Central de la Qualit\u00e9 et de l\u2019Information Pharmaceutiques, H\u00f4pital de la Conception, AP-HM, 147 Boulevard Baille, 13005 Marseille, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caroline","family":"Castera-Ducros","sequence":"additional","affiliation":[{"name":"Team Pharmaco-Chimie Radicalaire, Facult\u00e9 de Pharmacie, Aix Marseille University, CNRS, ICR UMR 7273, 27 Boulevard Jean Moulin, CS30064, CEDEX 05, 13385 Marseille, France"},{"name":"Service Central de la Qualit\u00e9 et de l\u2019Information Pharmaceutiques, H\u00f4pital de la Conception, AP-HM, 147 Boulevard Baille, 13005 Marseille, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6695-1683","authenticated-orcid":false,"given":"Sandra","family":"Carvalho","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Anti-Infectives Research, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8810-5605","authenticated-orcid":false,"given":"Susan","family":"Wyllie","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Anti-Infectives Research, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6950-0519","authenticated-orcid":false,"given":"Mohamed Lotfi","family":"Efrit","sequence":"additional","affiliation":[{"name":"Laboratoire de Synth\u00e8se Organique et H\u00e9t\u00e9rocyclique S\u00e9lective-Evaluation D\u2019activit\u00e9 Biologique, LR17ES01, Facult\u00e9 des Sciences de Tunis, Universit\u00e9 de Tunis El Manar, Campus Universitaire, Tunis 2092, Tunisia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dimitri","family":"Fayolle","sequence":"additional","affiliation":[{"name":"Normandie Universit\u00e9, UNICAEN, CERMN, DruiD Platform, Boulevard Becquerel, 14000 Caen, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3984-5812","authenticated-orcid":false,"given":"Marc","family":"Since","sequence":"additional","affiliation":[{"name":"Normandie Universit\u00e9, UNICAEN, CERMN, DruiD Platform, Boulevard Becquerel, 14000 Caen, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9946-829X","authenticated-orcid":false,"given":"Patrice","family":"Vanelle","sequence":"additional","affiliation":[{"name":"Team Pharmaco-Chimie Radicalaire, Facult\u00e9 de Pharmacie, Aix Marseille University, CNRS, ICR UMR 7273, 27 Boulevard Jean Moulin, CS30064, CEDEX 05, 13385 Marseille, France"},{"name":"Service Central de la Qualit\u00e9 et de l\u2019Information Pharmaceutiques, H\u00f4pital de la Conception, AP-HM, 147 Boulevard Baille, 13005 Marseille, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0238-2447","authenticated-orcid":false,"given":"Pierre","family":"Verhaeghe","sequence":"additional","affiliation":[{"name":"CNRS, D\u00e9partement de Pharmacochimie Mol\u00e9culaire UMR 5063, University Grenoble Alpes, 38041 Grenoble, France"},{"name":"LCC-CNRS, UPR8241, Laboratoire de Chimie de Coordination, Universit\u00e9 de Toulouse, CNRS, UPS, 31400 Toulouse, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nadine","family":"Azas","sequence":"additional","affiliation":[{"name":"IHU M\u00e9diterran\u00e9e Infection, UMR RITMES, TEAM-VEPTE, Aix Marseille University, 19-21 Boulevard Jean Moulin, 13005 Marseille, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0749-2901","authenticated-orcid":false,"given":"Hussein","family":"El-Kashef","sequence":"additional","affiliation":[{"name":"Chemistry Department, Faculty of Science, Assiut University, Assiut 71516, Egypt"},{"name":"Faculty of Pharmacy, Sphinx University, Regional Road, New Assiut 71515, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,3]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2023, February 01). Leishmaniasis. Available online: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/leishmaniasis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1454","DOI":"10.2174\/1568026618666181002110116","article-title":"Design, Synthesis and Antileishmanial Activity of Naphthotriazolyl-4-Oxoquinolines","volume":"18","author":"Oliveira","year":"2018","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"5734","DOI":"10.1021\/acs.jmedchem.9b02016","article-title":"O-Alkyl Hydroxamates Display Potent and Selective Antileishmanial Activity","volume":"63","year":"2020","journal-title":"J. Med. Chem."},{"key":"ref_4","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_5","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1007\/s11686-021-00457-6","article-title":"Synthesis and Biological Evaluation of Tetrahydropyrimidine and Dihydropyridine Derivatives against Leishmania major","volume":"67","author":"Jeddi","year":"2022","journal-title":"Acta Parasitol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1039\/D0MD00083C","article-title":"Antileishmanial Assessment of Isoxazole Derivatives against L. donovani","volume":"11","author":"Mukhopadhyay","year":"2020","journal-title":"RSC Med. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1900241","DOI":"10.1002\/ardp.201900241","article-title":"Design, Synthesis, Antileishmanial, and Antifungal Biological Evaluation of Novel 3,5-Disubstituted Isoxazole Compounds Based on 5-Nitrofuran Scaffolds","volume":"353","author":"Trefzger","year":"2020","journal-title":"Arch. Pharm."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"131604","DOI":"10.1016\/j.molstruc.2021.131604","article-title":"Antileishmanial Activity of 3,4,5-Trisubstituted Isoxazoles by Interaction with Leishmania amazonensis Plasma Membrane","volume":"1249","author":"Alonso","year":"2022","journal-title":"J. Mol. Struct."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"9615","DOI":"10.1021\/acs.jmedchem.5b01456","article-title":"Novel Amino-Pyrazole Ureas with Potent In Vitro and In Vivo Antileishmanial Activity","volume":"58","author":"Mowbray","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/j.ejmech.2016.04.077","article-title":"The Therapeutic Voyage of Pyrazole and Its Analogs: A Review","volume":"120","author":"Khan","year":"2016","journal-title":"Eur. J. Med. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"5891","DOI":"10.1016\/j.bmc.2017.09.035","article-title":"Recently Reported Biological Activities of Pyrazole Compounds","volume":"25","author":"Faria","year":"2017","journal-title":"Bioorg. Med. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/s40409-018-0163-x","article-title":"4-Phenyl-1,3-Thiazole-2-Amines as Scaffolds for New Antileishmanial Agents","volume":"24","author":"Rodrigues","year":"2018","journal-title":"J. Venom Anim. Toxins Incl. Trop. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1139\/cjp-2017-0710","article-title":"1,2,4-Triazole Derivatives with Morpholine; DFT Study and Antileishmanial Activity","volume":"96","author":"Direkel","year":"2018","journal-title":"Can. J. Phys."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1111\/cbdd.13757","article-title":"Anticancer and Antileishmanial in Vitro Activity of Gold(I) Complexes with 1,3,4-Oxadiazole-2(3H)-Thione Ligands Derived from \u03b4-D-Gluconolactone","volume":"97","author":"Espinosa","year":"2021","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3213","DOI":"10.1080\/07391102.2020.1845979","article-title":"Thiohydantoins as Anti-Leishmanial Agents: N Vitro Biological Evaluation and Multi-Target Investigation by Molecular Docking Studies","volume":"40","author":"Camargo","year":"2022","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1016\/j.ejmech.2014.12.056","article-title":"Looking for New Antileishmanial Derivatives in 8-Nitroquinolin-2(1H)-One Series","volume":"92","author":"Kieffer","year":"2015","journal-title":"Eur. J. Med. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.ejmech.2018.06.001","article-title":"Novel 8-Nitroquinolin-2(1H)-Ones as NTR-Bioactivated Antikinetoplastid Molecules: Synthesis, Electrochemical and SAR Study","volume":"155","author":"Pedron","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"12152","DOI":"10.1021\/acs.jmedchem.1c00813","article-title":"Amino-Substituted 3-Aryl- and 3-Heteroarylquinolines as Potential Antileishmanial Agents","volume":"64","author":"Hammill","year":"2021","journal-title":"J. Med. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"5141","DOI":"10.1021\/jm5000408","article-title":"Antileishmanial Activity of a Series of N2,N4-Disubstituted Quinazoline-2,4-Diamines","volume":"57","author":"Zhu","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1039\/D1MD00336D","article-title":"Identification of 2-Arylquinazolines with Alkyl-Polyamine Motifs as Potent Antileishmanial Agents: Synthesis and Biological Evaluation Studies","volume":"13","author":"Kumari","year":"2022","journal-title":"RSC Med. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"5427","DOI":"10.1021\/jm0401006","article-title":"Antileishmanial Pyrazolopyridine Derivatives: Synthesis and Structure-Activity Relationship Analysis","volume":"47","author":"Echevarria","year":"2004","journal-title":"J. Med. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1021\/acs.jmedchem.6b01447","article-title":"Antileishmanial Activity of Pyrazolopyridine Derivatives and Their Potential as an Adjunct Therapy with Miltefosine","volume":"60","author":"Anand","year":"2017","journal-title":"J. Med. Chem."},{"key":"ref_23","first-page":"2657","article-title":"Potential Antileishmanial Activity of 4-N-Acylhydrazone Pyrazolo[3,4-d]Pyridazin-7-Ones: Synthesis, In Vitro Biological Evaluations and Computational Studies","volume":"29","author":"Jacomini","year":"2018","journal-title":"J. Braz. Chem. Soc."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1021\/acsmedchemlett.8b00347","article-title":"Nongenotoxic 3-Nitroimidazo[1,2-a]Pyridines Are NTR1 Substrates That Display Potent in Vitro Antileishmanial Activity","volume":"10","author":"Fersing","year":"2019","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"38328","DOI":"10.1039\/D0RA07881F","article-title":"Synthesis, Study of Antileishmanial and Antitrypanosomal Activity of Imidazo Pyridine Fused Triazole Analogues","volume":"10","author":"Nandikolla","year":"2020","journal-title":"RSC Adv."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Paoli-Lombardo, R., Primas, N., Bourgeade-Delmas, S., Hutter, S., Sournia-Saquet, A., Boudot, C., Brenot, E., Castera-Ducros, C., Corvaisier, S., and Since, M. (2022). Improving Aqueous Solubility and In Vitro Pharmacokinetic Properties of the 3-Nitroimidazo[1,2-a]Pyridine Antileishmanial Pharmacophore. Pharmaceuticals, 15.","DOI":"10.3390\/ph15080998"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1016\/j.bioorg.2018.02.009","article-title":"Thiazolidinediones as Antidiabetic Agents: A Critical Review","volume":"77","author":"Nanjan","year":"2018","journal-title":"Bioorg. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Kumar, H., Aggarwal, N., Marwaha, M.G., Deep, A., Chopra, H., Matin, M.M., Roy, A., Emran, T.B., Mohanta, Y.K., and Ahmed, R. (2022). Thiazolidin-2,4-Dione Scaffold: An Insight into Recent Advances as Antimicrobial, Antioxidant, and Hypoglycemic Agents. Molecules, 27.","DOI":"10.3390\/molecules27196763"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"El-Kashef, H., Badr, G., Abo El-Maali, N., Sayed, D., Melnyk, P., Lebegue, N., and Abd El-Khalek, R. (2020). Synthesis of a Novel Series of (Z)-3,5-Disubstituted Thiazolidine-2,4-Diones as Promising Anti-Breast Cancer Agents. Bioorg. Chem., 96.","DOI":"10.1016\/j.bioorg.2020.103569"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1749","DOI":"10.1158\/1535-7163.MCT-13-0075","article-title":"S49076 Is a Novel Kinase Inhibitor of MET, AXL, and FGFR with Strong Preclinical Activity Alone and in Association with Bevacizumab","volume":"12","author":"Burbridge","year":"2013","journal-title":"Mol. Cancer Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1016\/j.ejmech.2016.07.060","article-title":"Structure-Guided Discovery of Thiazolidine-2,4-Dione Derivatives as a Novel Class of Leishmania Major Pteridine Reductase 1 Inhibitors","volume":"123","author":"Leite","year":"2016","journal-title":"Eur. J. Med. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"x161959","DOI":"10.1107\/S2414314616019593","article-title":"(5Z)-3-(2-Oxopropyl)-5-(3,4,5-Trimethoxybenzylidene)-1,3-Thiazolidine-2,4-Dione","volume":"1","author":"Mague","year":"2016","journal-title":"IUCrData"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2809","DOI":"10.1016\/j.bmc.2005.02.026","article-title":"Structure-Activity Relationships and Molecular Modelling of 5-Arylidene-2,4-Thiazolidinediones Active as Aldose Reductase Inhibitors","volume":"13","author":"Maccari","year":"2005","journal-title":"Bioorg. Med. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/j.pt.2014.04.003","article-title":"Nitro Drugs for the Treatment of Trypanosomatid Diseases: Past, Present, and Future Prospects","volume":"30","author":"Patterson","year":"2014","journal-title":"Trends Parasitol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.jpba.2016.04.009","article-title":"Lipophilicity and Biomimetic Properties Measured by HPLC to Support Drug Discovery","volume":"130","year":"2016","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Michel, G., Ferrua, B., Lang, T., Maddugoda, M.P., Munro, P., Pomares, C., Lemichez, E., and Marty, P. (2011). Luciferase-Expressing Leishmania Infantum Allows the Monitoring of Amastigote Population Size, In Vivo, Ex Vivo and In Vitro. PLoS Negl. Trop. Dis., 5.","DOI":"10.1371\/journal.pntd.0001323"},{"key":"ref_37","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_38","doi-asserted-by":"crossref","first-page":"4699","DOI":"10.1128\/AAC.00722-13","article-title":"The R Enantiomer of the Antitubercular Drug PA-824 as a Potential Oral Treatment for Visceral Leishmaniasis","volume":"57","author":"Patterson","year":"2013","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Wyllie, S., Roberts, A.J., Norval, S., Patterson, S., Foth, B.J., Berriman, M., Read, K.D., and Fairlamb, A.H. (2016). Activation of Bicyclic Nitro-Drugs by a Novel Nitroreductase (NTR2) in Leishmania. PLoS Pathog., 12.","DOI":"10.1371\/journal.ppat.1005971"}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/17\/7\/878\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:09:39Z","timestamp":1760108979000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/17\/7\/878"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,3]]},"references-count":39,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2024,7]]}},"alternative-id":["ph17070878"],"URL":"https:\/\/doi.org\/10.3390\/ph17070878","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,3]]}}}