{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,25]],"date-time":"2026-01-25T15:21:15Z","timestamp":1769354475585,"version":"3.49.0"},"reference-count":40,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2020,3,18]],"date-time":"2020-03-18T00:00:00Z","timestamp":1584489600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"CODI-UdeA","award":["CIQF-217"],"award-info":[{"award-number":["CIQF-217"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Snakebite is a neglected disease with a high impact in tropical and subtropical countries. Therapy based on antivenom has limited efficacy in local tissue damage caused by venoms. Phospholipases A2 (PLA2) are enzymes that abundantly occur in snake venoms and induce several systemic and local effects. Furthermore, sulfur compounds such as thioesters have an inhibitory capacity against a snake venom PLA2. Hence, the objective of this work was to obtain a carbodithioate from a thioester with known activity against PLA2 and test its ability to inhibit the same enzyme. Benzyl 4-nitrobenzenecarbodithioate (I) was synthesized, purified, and characterized using as precursor 4-nitrothiobenzoic acid S-benzyl ester (II). Compound I showed inhibition of the enzymatic activity a PLA2 isolated from the venom of the Colombian rattlesnake Crotalus durissus cumanensis with an IC50 of 55.58 \u03bcM. This result is comparable with the reported inhibition obtained for II. Computational calculations were performed to support the study, and molecular docking results suggested that compounds I and II interact with the active site residues of the enzyme, impeding the normal catalysis cycle and attachment of the substrate to the active site of the PLA2.<\/jats:p>","DOI":"10.3390\/molecules25061373","type":"journal-article","created":{"date-parts":[[2020,3,20]],"date-time":"2020-03-20T07:29:07Z","timestamp":1584689347000},"page":"1373","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Sulfur Compounds as Inhibitors of Enzymatic Activity of a Snake Venom Phospholipase A2: Benzyl 4-nitrobenzenecarbodithioate as a Case of Study"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1893-2191","authenticated-orcid":false,"given":"Isabel","family":"Henao Casta\u00f1eda","sequence":"first","affiliation":[{"name":"Grupo de Investigaci\u00f3n en Productos Naturales Marinos, Departamento de Farmacia, Facultad de Ciencias Farmac\u00e9uticas y Alimentarias, Universidad de Antioquia UdeA, Calle 70 No. 52\u201321, 050010 Medell\u00edn, Colombia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9612-2827","authenticated-orcid":false,"given":"Jaime Andr\u00e9s","family":"Perea\u00f1ez","sequence":"additional","affiliation":[{"name":"Programa de Ofidismo\/Escorpionismo, Departamento de Farmacia, Facultad de Ciencias Farmac\u00e9uticas y Alimentarias, Universidad de Antioquia UdeA, Calle 70 No. 52\u201321, 050010 Medell\u00edn, Colombia."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3096-2134","authenticated-orcid":false,"given":"Lina Mar\u00eda","family":"Preciado","sequence":"additional","affiliation":[{"name":"Programa de Ofidismo\/Escorpionismo, Departamento de Farmacia, Facultad de Ciencias Farmac\u00e9uticas y Alimentarias, Universidad de Antioquia UdeA, Calle 70 No. 52\u201321, 050010 Medell\u00edn, Colombia."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7812-0043","authenticated-orcid":false,"given":"Jorge","family":"Jios","sequence":"additional","affiliation":[{"name":"Laboratorio UPL (Unidad PLAPIMU-LASEISIC), Campus Tecnol\u00f3gico Gonnet (CIC-BA), Cno. Centenario e\/505 y 508, 1897 Gonnet, Argentina"},{"name":"Departamento de Qu\u00edmica, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, 47 esq. 115, 1900 La Plata, Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,3,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1186\/s40409-017-0127-6","article-title":"Snakebite envenomation turns again into a neglected tropical disease","volume":"23","author":"Chippaux","year":"2017","journal-title":"J. Venom. Anim. Toxins Incl. Trop. Dis."},{"key":"ref_2","unstructured":"(2019, December 18). Available online: https:\/\/www.who.int\/snakebites\/epidemiology\/en."},{"key":"ref_3","first-page":"1","article-title":"Snakebite envenoming","volume":"3","author":"Calvete","year":"2017","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_4","unstructured":"(2019, December 18). Instituto Nacional de Salud, Available online: https:\/\/www.ins.gov.co\/buscador-eventos\/Informesdeevento\/ACCIDENTE%20OF%C3%8DDICO_2018.pdf."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"49","DOI":"10.16925\/cu.v1i1.308","article-title":"Toxinas provenientes de venenos de serpiente: Blancos terap\u00e9uticos, herramientas en investigaci\u00f3n biom\u00e9dica y agentes con potencial terap\u00e9utico","volume":"1","year":"2014","journal-title":"Curare"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S1388-1981(00)00105-0","article-title":"The expanding superfamily of phospholipase A2 enzymes: Classification and characterization","volume":"1488","author":"Six","year":"2000","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1016\/j.toxicon.2003.11.002","article-title":"Excitement ahead: Structure, function and mechanism of snake venom phospholipase A2 enzymes","volume":"42","author":"Kini","year":"2003","journal-title":"Toxicon"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2613","DOI":"10.1021\/cr990139w","article-title":"Interfacial Enzymology: The Secreted Phospholipase A2-Paradigm","volume":"101","author":"Berg","year":"2001","journal-title":"Chem. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"15514","DOI":"10.1038\/s41598-017-15614-z","article-title":"PLA2-like proteins myotoxic mechanism: A dynamic model description","volume":"7","author":"Borges","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.toxicon.2018.05.008","article-title":"The history of antivenoms development: Beyond Calmette and Vital Brazil","volume":"150","author":"Marcelino","year":"2018","journal-title":"Toxicon"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.toxicon.2018.04.016","article-title":"Unresolved issues in the understanding of the pathogenesis of local tissue damage induced by snake venoms","volume":"148","author":"Rucavado","year":"2018","journal-title":"Toxicon"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.molstruc.2012.06.031","article-title":"Substituted thiobenzoic acid S-benzyl esters as potential inhibitors of a snake venom phospholipase A2: Synthesis, spectroscopic and computational studies","volume":"1028","author":"Jios","year":"2012","journal-title":"J. Mol. Struct."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1007\/s10822-007-9129-8","article-title":"Mechanism of inhibition of human secretory phospholipase A2 by flavonoids: Rationale for lead design","volume":"21","author":"Fischer","year":"2007","journal-title":"J. Comput. Mol. Des."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1548","DOI":"10.1016\/j.toxicon.2008.03.021","article-title":"Isolation of a snake venom phospholipase A2 (PLA2) inhibitor (AIPLAI) from leaves of Azadirachta indica (Neem): Mechanism of PLA2 inhibition by AIPLAI in vitro condition","volume":"51","author":"Mukherjee","year":"2008","journal-title":"Toxicon"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1007\/s10930-011-9327-z","article-title":"Inhibitory Effects of Bile Acids on Enzymatic and Pharmacological Activities of a Snake Venom Phospholipase A2 from Group IIA","volume":"30","year":"2011","journal-title":"Protein J."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Lewin, M.R., Samuel, S., Merkel, J., and E Bickler, P. (2016). Varespladib (LY315920) Appears to Be a Potent, Broad-Spectrum, Inhibitor of Snake Venom Phospholipase A2 and a Possible Pre-Referral Treatment for Envenomation. Toxins, 8.","DOI":"10.3390\/toxins8090248"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.ijbiomac.2016.04.042","article-title":"Inhibitory effect of pinostrobin from Renealmia alpinia, on the enzymatic and biological activities of a PLA2","volume":"89","author":"Benjumea","year":"2016","journal-title":"Int. J. Boil. Macromol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.cbi.2014.06.015","article-title":"The biflavonoid morelloflavone inhibits the enzymatic and biological activities of a snake venom phospholipase A2","volume":"220","author":"Osorio","year":"2014","journal-title":"Chem. Interact."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Casta\u00f1eda, I.C.H., Perea\u00f1ez, J.A., and Preciado, L.M. (2019). Synthetic Inhibitors of Snake Venom Enzymes: Thioesters Derived from 2-Sulfenyl Ethylacetate. Pharmaceuticals, 12.","DOI":"10.3390\/ph12020080"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.molstruc.2006.12.007","article-title":"Conformational and vibrational analysis of S-(2-methoxyphenyl)-4-substituted-benzenecarbothioates, using X-ray, infrared and Raman spectroscopy and theoretical calculations","volume":"842","author":"Jios","year":"2007","journal-title":"J. Mol. Struct."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1016\/j.poly.2009.11.006","article-title":"Synthesis of two new thioesters bearing ferrocene: Vibrational characterization and ab initio calculations. X-ray crystal structure of S-(2-methoxyphenyl)ferrocenecarbothioate","volume":"29","author":"Castaneda","year":"2010","journal-title":"Polyhedron"},{"key":"ref_22","unstructured":"Henao Casta\u00f1eda, C., Cadavid Vargas, J.F., Jios, J.L., Della V\u00e9dova, C.O., Echeverr\u00eda, G.A., and Piro, O.E. (2013, March 06). CCDC 928055: Experimental Crystal Structure Determination. Available online: https:\/\/www.ccdc.cam.ac.uk\/structures\/search?id=doi:10.5517\/ccdc.csd.cc104q84&sid=DataCite."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2567","DOI":"10.1016\/S0040-4020(01)96363-X","article-title":"Tetrahedron report number 186: Organothiophosphorus reagents in organic synthesis","volume":"41","author":"Cherkasov","year":"1985","journal-title":"Tetrahedron"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"5061","DOI":"10.1016\/S0040-4020(01)96753-5","article-title":"Thionation reactions of lawesson\u2019s reagents","volume":"41","author":"Cava","year":"1985","journal-title":"Tetrahedron"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2663","DOI":"10.1016\/S0040-4020(01)96883-8","article-title":"Studies on organophosphorus compounds XLVIII Synthesis of Dithioesters from P,S-Containing Reagents and Carboxylic Acids and Their Derivatives","volume":"40","author":"Yousif","year":"1984","journal-title":"Tetrahedron"},{"key":"ref_26","unstructured":"Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M.A., and Cheeseman, J.R. (2010). Gaussian 09, Revision, B.01, Gaussian, Inc."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3526","DOI":"10.1016\/j.bmcl.2018.09.038","article-title":"Structure-activity relationships of pyrazole-4-carbodithioates as antibacterials against methicillin\u2013resistant Staphylococcus aureus","volume":"28","author":"Majed","year":"2018","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"103060","DOI":"10.1016\/j.bioorg.2019.103060","article-title":"New potent antifungal triazole alcohols containing N-benzylpiperazine carbodithioate moiety: Synthesis, in vitro evaluation and in silico study","volume":"90","author":"Mahmoudi","year":"2019","journal-title":"Bioorganic Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4666","DOI":"10.1016\/j.bmcl.2016.08.060","article-title":"Synthesis and antitumor activity evaluation of quinazoline derivatives bearing piperazine-1-carbodithioate moiety at C4-position","volume":"26","author":"Zhang","year":"2016","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-019-53755-5","article-title":"Structural basis for phospholipase A2-like toxin inhibition by the synthetic compound Varespladib (LY315920)","volume":"9","author":"Salvador","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/0022-2860(77)85026-6","article-title":"Dynamic nuclear magnetic resonance spectroscopy","volume":"36","author":"Jackman","year":"1977","journal-title":"J. Mol. Struct."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2594","DOI":"10.1063\/1.1733060","article-title":"Proton NMR Spectra of Disubstituted Benzenes","volume":"37","author":"Martin","year":"1962","journal-title":"J. Chem. Phys."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"5861","DOI":"10.1016\/S0040-4020(01)90441-7","article-title":"NMR spectroscopy of organolithium compounds, Part XVI","volume":"50","author":"Bergander","year":"1994","journal-title":"Tetrahedron"},{"key":"ref_34","unstructured":"Dennington, R., Keith, T., and Millam, J. (2009). Gauss View, Version 5, Semichem Inc."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"Software News and Update AutoDock Vina: Improving the Speed and Accuracy of Docking with a New Scoring Function, Efficient Optimization, and Multithreading","volume":"31","author":"Trott","year":"2009","journal-title":"J. Comput. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.biochi.2016.12.015","article-title":"Biochimie: Crystal structure of a phospholipase A2 from Bothrops asper venom: Insights into a new putative \u201cmyotoxic cluster\u201d","volume":"133","author":"Salvador","year":"2017","journal-title":"Biochimie"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1002\/jcc.20084","article-title":"UCSF Chimera\u2013a visualization system for exploratory research and analysis","volume":"25","author":"Pettersen","year":"2004","journal-title":"J. Comput. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"(2006). Molinspiration cheminformatics. Choice Rev. Online, 43, 43.","DOI":"10.5860\/CHOICE.43-6538"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1016\/j.toxicon.2009.01.021","article-title":"Biochemical and biological characterization of a PLA2 from crotoxin complex of Crotalus durissus cumanensis","volume":"53","author":"Marangoni","year":"2009","journal-title":"Toxicon"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1016\/0041-0101(96)00057-8","article-title":"An aqueous endpoint assay of snake venom phospholipase A2","volume":"34","author":"Holzer","year":"1996","journal-title":"Toxicon"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/25\/6\/1373\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:07:37Z","timestamp":1760173657000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/25\/6\/1373"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,18]]},"references-count":40,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2020,3]]}},"alternative-id":["molecules25061373"],"URL":"https:\/\/doi.org\/10.3390\/molecules25061373","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,3,18]]}}}