{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T20:33:28Z","timestamp":1786480408694,"version":"build-2736575974"},"reference-count":43,"publisher":"American Chemical Society (ACS)","issue":"31","license":[{"start":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T00:00:00Z","timestamp":1785369600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100031478","name":"NextGenerationEU","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/100031478","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100032005","name":"Latvijas Organiskas sintezes instituts","doi-asserted-by":"publisher","award":["34\/OSI\/ZG"],"award-info":[{"award-number":["34\/OSI\/ZG"]}],"id":[{"id":"10.13039\/100032005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100032005","name":"Latvijas Organiskas sintezes instituts","doi-asserted-by":"publisher","award":["67\/OSI\/PG"],"award-info":[{"award-number":["67\/OSI\/PG"]}],"id":[{"id":"10.13039\/100032005","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The growing resistance to existing antimalarial drugs, along with the expanding distribution of mosquito vectors transmitting Plasmodium species, underscores the urgent need for new therapeutic agents. Plasmepsins (PMs), a family of aspartic proteases in Plasmodium, among which plasmepsin V (PMV) is the most structurally distinct enzyme compared to other Plasmodium and human aspartic proteases, allowing for the achievement of selectivity against nontarget proteases. The current literature demonstrates that depletion of PMV leads to the immediate cessation of parasite growth after its invasion into red blood cells, establishing PMV as a compelling target for drug discovery. Here, we performed grating-coupled interferometry (GCI) and fluorescence resonance energy transfer (FRET) enzymatic assay screening of a fragment library to identify novel nonpeptidomimetic PMV inhibitors. A 1,3,4-thiadiazole-based compound 11b (LE = 0.45) was identified as a promising hit and subjected to a preliminary structure\u2013activity relationship (SAR) exploration. A total of more than 30 hit analogues were synthesized or obtained commercially and evaluated. A structure\u2013activity relationship exploration led to compounds 11ad and 11ae with IC50 (PvPMV) values of 22.0 and 20.7 \u03bcM, respectively. The resulting SAR proved largely flat, with modifications failing to break the sub-10 \u03bcM potency threshold. This plateau suggests that the current 1,3,4-thiadiazole core may be approaching its potency ceiling. Although these compounds display suboptimal inhibitory potency, they map out the structural boundaries of this novel nonpeptidomimetic chemotype against PMV.<\/jats:p>","DOI":"10.1021\/acsomega.6c02719","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T13:23:24Z","timestamp":1785849804000},"page":"46143-46153","source":"Crossref","is-referenced-by-count":0,"title":["Identification\nof a Novel 1,3,4-Thiadiazole-Based\nScaffold as a Plasmepsin V Inhibitor"],"prefix":"10.1021","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6931-2294","authenticated-orcid":true,"given":"Diana","family":"Zelencova-Gopejenko","sequence":"first","affiliation":[{"name":"Latvian Institute of Organic Synthesis , Aizkraukles Street 21 , ,","place":["Riga, Latvia, LV-1006"]},{"name":"Molport Company , Lacplesa 41 , ,","place":["Riga, Latvia, LV-1011"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jekaterina","family":"Bolsakova","sequence":"additional","affiliation":[{"name":"Latvian Institute of Organic Synthesis , Aizkraukles Street 21 , ,","place":["Riga, Latvia, LV-1006"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Rudusa","sequence":"additional","affiliation":[{"name":"Latvian Institute of Organic Synthesis , Aizkraukles Street 21 , ,","place":["Riga, Latvia, LV-1006"]},{"name":"Riga Technical University , , Paula Valdena Street 3 , ,","place":["Riga, Latvia, LV-1048"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristine","family":"Kitoka","sequence":"additional","affiliation":[{"name":"Latvian Institute of Organic Synthesis , Aizkraukles Street 21 , ,","place":["Riga, Latvia, LV-1006"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1206-3741","authenticated-orcid":true,"given":"Atis","family":"Jekabsons","sequence":"additional","affiliation":[{"name":"Latvian Institute of Organic Synthesis , Aizkraukles Street 21 , ,","place":["Riga, Latvia, LV-1006"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marija","family":"Skvorcova","sequence":"additional","affiliation":[{"name":"Latvian Institute of Organic Synthesis , Aizkraukles Street 21 , ,","place":["Riga, Latvia, LV-1006"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8937-8792","authenticated-orcid":true,"given":"Aigars","family":"Jirgensons","sequence":"additional","affiliation":[{"name":"Latvian Institute of Organic Synthesis , Aizkraukles Street 21 , ,","place":["Riga, Latvia, LV-1006"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0221-8658","authenticated-orcid":true,"given":"Raitis","family":"Bobrovs","sequence":"additional","affiliation":[{"name":"Latvian Institute of Organic Synthesis , Aizkraukles Street 21 , ,","place":["Riga, Latvia, LV-1006"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,30]]},"reference":[{"key":"2026081116172928500_cit1","doi-asserted-by":"crossref","DOI":"10.30875\/9789287074560","volume-title":"World Malaria Report\n2025","author":"World Health Organization.","year":"2025"},{"issue":"4","key":"2026081116172928500_cit2","doi-asserted-by":"publisher","first-page":"564","DOI":"10.1128\/CMR.15.4.564-594.2002","article-title":"Evolutionary and\nHistorical Aspects of the Burden of\nMalaria","volume":"15","author":"Carter","year":"2002","journal-title":"Clin. Microbiol. Rev."},{"issue":"1","key":"2026081116172928500_cit3","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1016\/S1473-3099(16)30326-7","article-title":"The Geography of\nImported Malaria to Non-Endemic Countries: A Meta-analysis of Nationally\nReported Statistics","volume":"17","author":"Tatem","year":"2017","journal-title":"Lancet Infect. Dis."},{"issue":"2","key":"2026081116172928500_cit4","doi-asserted-by":"publisher","first-page":"161","DOI":"10.2174\/092986708783330575","article-title":"The Fight Against Drug-Resistant\nMalaria: Novel Plasmodial Targets and Antimalarial Drugs","volume":"15","author":"Avery","year":"2008","journal-title":"Curr. Med. Chem."},{"issue":"10","key":"2026081116172928500_cit5","doi-asserted-by":"publisher","first-page":"807","DOI":"10.1038\/s41573-023-00772-9","article-title":"Antimalarial Drug\nDiscovery: Progress and Approaches","volume":"22","author":"Siqueira-Neto","year":"2023","journal-title":"Nat. Rev.\nDrug Discovery"},{"key":"2026081116172928500_cit6","doi-asserted-by":"publisher","DOI":"10.1186\/s12936-023-04651-x","article-title":"Nationwide Spatiotemporal Drug Resistance\nGenetic Profiling from over Three Decades in Indian Plasmodium falciparum\nand Plasmodium vivax Isolates","volume":"22","author":"Kojom Foko","year":"2023","journal-title":"Malar. J."},{"issue":"5","key":"2026081116172928500_cit7","doi-asserted-by":"publisher","first-page":"626","DOI":"10.1002\/med.20082","article-title":"Plasmepsins as Potential Targets\nfor New Antimalarial Therapy","volume":"26","author":"Ersmark","year":"2006","journal-title":"Med. Res. Rev."},{"issue":"11","key":"2026081116172928500_cit8","doi-asserted-by":"publisher","first-page":"532","DOI":"10.1016\/S1471-4922(01)02037-2","article-title":"Aspartic Proteases\nof Plasmodium falciparum and Other\nParasitic Protozoa as Drug Targets","volume":"17","author":"Coombs","year":"2001","journal-title":"Trends Parasitol."},{"issue":"7","key":"2026081116172928500_cit9","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.1001897","article-title":"Inhibition\nof Plasmepsin V Activity Demonstrates Its Essential Role in Protein\nExport, PfEMP1 Display, and Survival of Malaria Parasites","volume":"12","author":"Sleebs","year":"2014","journal-title":"PLoS Biol."},{"issue":"6362","key":"2026081116172928500_cit10","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1126\/science.aaq0002","article-title":"Plasmepsins\non the Antimalarial Hit List","volume":"358","author":"Boddey","year":"2017","journal-title":"Science"},{"issue":"18","key":"2026081116172928500_cit11","doi-asserted-by":"publisher","first-page":"7644","DOI":"10.1021\/jm500797g","article-title":"Transition State Mimetics of the\nPlasmodium Export Element Are Potent Inhibitors of Plasmepsin V from\nPlasmodium falciparum and P. vivax","volume":"57","author":"Sleebs","year":"2014","journal-title":"J. Med.\nChem."},{"issue":"4","key":"2026081116172928500_cit12","doi-asserted-by":"publisher","first-page":"738","DOI":"10.1021\/acsinfecdis.9b00460","article-title":"Assessment of Biological\nRole and Insight into Druggability of the Plasmodium falciparum Protease\nPlasmepsin V","volume":"6","author":"Polino","year":"2020","journal-title":"ACS Infect. Dis."},{"issue":"9","key":"2026081116172928500_cit13","doi-asserted-by":"publisher","first-page":"1993","DOI":"10.1016\/j.bmc.2016.03.027","article-title":"Exploration\nof the P3 Region of PEXEL Peptidomimetics Leads to a Potent\nInhibitor of the Plasmodium Protease, Plasmepsin V","volume":"24","author":"Gazdik","year":"2016","journal-title":"Bioorg. Med. Chem."},{"issue":"5","key":"2026081116172928500_cit14","doi-asserted-by":"publisher","first-page":"445","DOI":"10.2174\/156802612799362959","article-title":"Recent Advances in Plasmepsin Medicinal\nChemistry and Implications for Future Antimalarial Drug Discovery\nEfforts","volume":"12","author":"J Meyers","year":"2012","journal-title":"Curr. Top. Med. Chem."},{"issue":"1","key":"2026081116172928500_cit15","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1021\/ml400412x","article-title":"Evaluation of Aminohydantoins\nas a Novel Class\nof Antimalarial Agents","volume":"5","author":"Meyers","year":"2014","journal-title":"ACS Med. Chem. Lett."},{"key":"2026081116172928500_cit16","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1016\/j.biochi.2018.07.002","article-title":"In Vitro and\nIn Silico Studies of Naphthoquinones and Peptidomimetics toward Plasmodium\nfalciparum Plasmepsin V","volume":"152","author":"Sittikul","year":"2018","journal-title":"Biochimie"},{"issue":"21","key":"2026081116172928500_cit17","doi-asserted-by":"publisher","first-page":"6890","DOI":"10.1021\/acs.jcim.3c00826","article-title":"Exploring the Binding\nPathway of Novel Nonpeptidomimetic Plasmepsin V Inhibitors","volume":"63","author":"Bobrovs","year":"2023","journal-title":"J. Chem. Inf. Model."},{"issue":"11","key":"2026081116172928500_cit18","doi-asserted-by":"publisher","first-page":"2843","DOI":"10.1111\/febs.70038","article-title":"Structure\u2013Activity\nAnalysis of Imino-Pyrimidinone-Fused Pyrrolidines Aids the Development\nof Dual Plasmepsin V and Plasmepsin X Inhibitors","volume":"292","author":"Hodder","year":"2025","journal-title":"FEBS J."},{"key":"2026081116172928500_cit19","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1016\/j.biochi.2025.12.006","article-title":"Inhibiting Catalytic Activity of\nPlasmodium falciparum Aspartate Protease Plasmepsin V: A Biochemical\nApproach to Malaria Intervention","volume":"242","author":"Prajapati","year":"2026","journal-title":"Biochimie"},{"issue":"8","key":"2026081116172928500_cit20","doi-asserted-by":"publisher","first-page":"590","DOI":"10.1038\/nsmb.3061","article-title":"Structural\nBasis for Plasmepsin V Inhibition That Blocks Export of Malaria Proteins\nto Human Erythrocytes","volume":"22","author":"Hodder","year":"2015","journal-title":"Nat. Struct. Mol. Biol."},{"key":"2026081116172928500_cit21","doi-asserted-by":"publisher","first-page":"632","DOI":"10.1038\/nature08726","article-title":"Plasmepsin V Licenses Plasmodium Proteins\nfor Export into the Host Erythrocyte","volume":"463","author":"Russo","year":"2010","journal-title":"Nature"},{"issue":"7281","key":"2026081116172928500_cit22","doi-asserted-by":"publisher","first-page":"627","DOI":"10.1038\/nature08728","article-title":"An Aspartyl\nProtease\nDirects Malaria Effector Proteins to the Host Cell","volume":"463","author":"Boddey","year":"2010","journal-title":"Nature"},{"issue":"11","key":"2026081116172928500_cit23","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0142509","article-title":"Picomolar\nInhibition\nof Plasmepsin V, an Essential Malaria Protease, Achieved Exploiting\nthe Prime Region","volume":"10","author":"Gambini","year":"2015","journal-title":"PLoS One"},{"issue":"1\u20133","key":"2026081116172928500_cit24","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1016\/j.theochem.2005.04.019","article-title":"Investigation\non the Aromaticity of 1,3,4-Thiadiazole-2-Thione and Its Oxygen Analogs\nIncluding Their Tautomeric Forms","volume":"726","author":"Erdem","year":"2005","journal-title":"J. Mol. Struct.:\nTHEOCHEM"},{"issue":"12","key":"2026081116172928500_cit25","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0207621","article-title":"Essentiality of Plasmodium falciparum\nPlasmepsin V","volume":"13","author":"Boonyalai","year":"2018","journal-title":"PLoS One"},{"issue":"29","key":"2026081116172928500_cit26","doi-asserted-by":"publisher","first-page":"16069","DOI":"10.1021\/jacs.3c04444","article-title":"Thiomethyltetrazines\nAre Reversible Covalent Cysteine Warheads Whose Dynamic Behavior Can\nBe \u201cSwitched Off\u201d via Bioorthogonal Chemistry Inside\nLive Cells","volume":"145","author":"Tallon","year":"2023","journal-title":"J. Am. Chem. Soc."},{"issue":"25","key":"2026081116172928500_cit27","doi-asserted-by":"publisher","first-page":"23837","DOI":"10.1074\/jbc.M501519200","article-title":"X-Ray Structure of\nPlasmepsin II Complexed with a Potent Achiral Inhibitor","volume":"280","author":"Prade","year":"2005","journal-title":"J. Biol. Chem."},{"key":"2026081116172928500_cit28","doi-asserted-by":"publisher","first-page":"1341","DOI":"10.1002\/cmdc.200600223","article-title":"Achiral, Cheap,\nand Potent Inhibitors of Plasmepsins I, II, and IV","volume":"1","author":"Boss","year":"2006","journal-title":"ChemMedChem"},{"issue":"20","key":"2026081116172928500_cit29","doi-asserted-by":"publisher","first-page":"8931","DOI":"10.1021\/acs.jmedchem.9b00184","article-title":"Exploiting Structural Dynamics To\nDesign Open-Flap Inhibitors of Malarial Aspartic Proteases","volume":"62","author":"Bobrovs","year":"2019","journal-title":"J. Med. Chem."},{"issue":"13","key":"2026081116172928500_cit30","doi-asserted-by":"publisher","first-page":"3263","DOI":"10.1021\/acs.jcim.2c00422","article-title":"Exploring Aspartic\nProtease Inhibitor Binding to Design Selective Antimalarials","volume":"62","author":"Bobrovs","year":"2022","journal-title":"J. Chem. Inf. Model."},{"issue":"3","key":"2026081116172928500_cit31","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1080\/10426500500269851","article-title":"Synthesis\nand Antibacterial Activity of Substituted Thiosemicarbazides and of\n1,3,4-Thiadiazole or 1,2,4-Triazole Derivatives","volume":"181","author":"Spalin\u0301ska","year":"2006","journal-title":"Phosphorus, Sulfur Silicon Relat. Elem."},{"issue":"12","key":"2026081116172928500_cit32","doi-asserted-by":"publisher","first-page":"923","DOI":"10.1055\/s-1989-27431","article-title":"Synthesis of 1,2,4-Triazole and 1,3,4-Thiadiazole\nDerivatives from Methyl 2-Methyldithiocarbazate and Heterocumulenes","volume":"1989","author":"Molina","year":"1989","journal-title":"Synthesis"},{"issue":"3","key":"2026081116172928500_cit33","doi-asserted-by":"publisher","first-page":"1305","DOI":"10.1007\/s00044-012-0107-x","article-title":"Synthesis of Some 1,3,4-Thiadiazole\nDerivatives as Inhibitors of Entamoeba histolytica","volume":"22","author":"Siddiqui","year":"2013","journal-title":"Med. Chem. Res."},{"key":"2026081116172928500_cit34","doi-asserted-by":"publisher","DOI":"10.1016\/j.inoche.2025.114432","article-title":"Phenyl Thiosemicarbazide\nCyclization Leads to the Versatile 1,3,4-Thiadiazole Scaffold: Structural\nAnalysis of Its Copper(I) Complex","volume":"177","author":"Zavaroni","year":"2025","journal-title":"Inorg. Chem.\nCommun."},{"issue":"9","key":"2026081116172928500_cit35","doi-asserted-by":"publisher","first-page":"13631","DOI":"10.3390\/molecules190913631","article-title":"A One-Pot Approach to Pyridyl Isothiocyanates from\nAmines","volume":"19","author":"Zhang","year":"2014","journal-title":"Molecules"},{"issue":"8","key":"2026081116172928500_cit36","doi-asserted-by":"publisher","first-page":"995","DOI":"10.1177\/24725552211013827","article-title":"waveRAPID\u2500A\nRobust Assay for High-Throughput Kinetic Screens with the Creoptix\nWAVEsystem","volume":"26","author":"Kartal","year":"2021","journal-title":"SLAS Discovery"},{"issue":"5","key":"2026081116172928500_cit37","doi-asserted-by":"publisher","first-page":"1392","DOI":"10.1074\/mcp.O113.037200","article-title":"MS-Viewer: A Web-based\nSpectral Viewer for Proteomics\nResults","volume":"13","author":"Baker","year":"2014","journal-title":"Mol. Cell. Proteomics"},{"issue":"3","key":"2026081116172928500_cit38","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1007\/s10822-013-9644-8","article-title":"Protein and ligand preparation: parameters, protocols,\nand influence on virtual screening enrichments","volume":"27","author":"Madhavi Sastry","year":"2013","journal-title":"J. Comput.-Aided Mol. Des."},{"issue":"12","key":"2026081116172928500_cit39","doi-asserted-by":"publisher","first-page":"2439","DOI":"10.1110\/ps.25801","article-title":"Analysis of Crystal Structures of\nAspartic Proteinases:\nOn the Role of Amino Acid Residues Adjacent to the Catalytic Site\nof Pepsin-Like Enzymes","volume":"10","author":"Andreeva","year":"2001","journal-title":"Protein Sci."},{"key":"2026081116172928500_cit40","unstructured":"Prime.\n          .  Schro\u0308dinger\nRelease 2024-4, Schro\u0308dinger LLC."},{"issue":"7","key":"2026081116172928500_cit41","doi-asserted-by":"publisher","first-page":"1739","DOI":"10.1021\/jm0306430","article-title":"Glide:\nA New Approach for Rapid, Accurate Docking and Scoring. 1. Method\nand Assessment of Docking Accuracy","volume":"47","author":"Friesner","year":"2004","journal-title":"J. Med.\nChem."},{"key":"2026081116172928500_cit42","unstructured":"LigPrep.\n          .  Schro\u0308dinger\nRelease 2024-4, Schro\u0308dinger LLC."},{"key":"2026081116172928500_cit43","unstructured":"The PyMOL Molecular\nGraphics System Version 3.0 Schro\u0308dinger, LLC."}],"container-title":["ACS Omega"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsomega.6c02719","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/acsodf\/article-pdf\/11\/31\/46143\/66343562\/acsomega.6c02719.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/acsodf\/article-pdf\/11\/31\/46143\/66343562\/acsomega.6c02719.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T20:17:33Z","timestamp":1786479453000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/acsodf\/article\/11\/31\/46143\/5237439\/Identification-of-a-Novel-1-3-4-Thiadiazole-Based"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,30]]},"references-count":43,"journal-issue":{"issue":"31","published-online":{"date-parts":[[2026,7,30]]},"published-print":{"date-parts":[[2026,8,11]]}},"URL":"https:\/\/doi.org\/10.1021\/acsomega.6c02719","relation":{},"ISSN":["2470-1343"],"issn-type":[{"value":"2470-1343","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,30]]}}}