{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T20:03:05Z","timestamp":1775851385162,"version":"3.50.1"},"reference-count":42,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2023,9,23]],"date-time":"2023-09-23T00:00:00Z","timestamp":1695427200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The 4-substituted 3-amino-1,2,5-oxadiazole 1 from the Malaria Box Project of the Medicines for Malaria Venture foundation shows very promising selectivity and in vitro activity against Plasmodium\u00a0falciparum. Within the first series of new compounds, various 3-acylamino analogs were prepared. This paper now focuses on the investigation of the importance of the aromatic substituent in ring position 4. A number of new structure\u2013activity relationships were elaborated, showing that antiplasmodial activity and selectivity strongly depend on the substitution pattern of the 4-phenyl moiety. In addition, physicochemical parameters relevant for drug development were calculated (logP and ligand efficiency) or determined experimentally (CYP3A4-inhibition and aqueous solubility). N-[4-(3-ethoxy-4-methoxyphenyl)-1,2,5-oxadiazol-3-yl]-3-methylbenzamide 51 showed high in vitro activity against the chloroquine-sensitive strain NF54 of P. falciparum (PfNF54 IC50 = 0.034 \u00b5M), resulting in a very promising selectivity index of 1526.<\/jats:p>","DOI":"10.3390\/ijms241914480","type":"journal-article","created":{"date-parts":[[2023,9,24]],"date-time":"2023-09-24T10:36:26Z","timestamp":1695551786000},"page":"14480","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Structure\u2013Activity Relationships and Antiplasmodial Potencies of Novel 3,4-Disubstituted 1,2,5-Oxadiazoles"],"prefix":"10.3390","volume":"24","author":[{"given":"Patrick","family":"Hochegger","sequence":"first","affiliation":[{"name":"Institute of Pharmaceutical Sciences, Pharmaceutical Chemistry, University of Graz, Schubertstra\u00dfe 1, A-8010 Graz, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5267-7852","authenticated-orcid":false,"given":"Theresa","family":"Hermann","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Sciences, Pharmaceutical Chemistry, University of Graz, Schubertstra\u00dfe 1, A-8010 Graz, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johanna","family":"Dolensky","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Sciences, Pharmaceutical Chemistry, University of Graz, Schubertstra\u00dfe 1, A-8010 Graz, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5673-0470","authenticated-orcid":false,"given":"Werner","family":"Seebacher","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Sciences, Pharmaceutical Chemistry, University of Graz, Schubertstra\u00dfe 1, A-8010 Graz, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert","family":"Saf","sequence":"additional","affiliation":[{"name":"Institute for Chemistry and Technology of Materials (ICTM), Graz University of Technology, Stremayrgasse 9, A-8010 Graz, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8327-0732","authenticated-orcid":false,"given":"Eva-Maria","family":"Pferschy-Wenzig","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Sciences, Pharmacognosy, University of Graz, Beethovenstra\u00dfe 8, A-8010 Graz, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1785-7302","authenticated-orcid":false,"given":"Marcel","family":"Kaiser","sequence":"additional","affiliation":[{"name":"Swiss Tropical and Public Health Institute, Kreuzstra\u00dfe 2, CH-4123 Allschwil, Switzerland"},{"name":"Faculty of Philosophy and Natural Sciences, University of Basel, Swiss TPH, Petersplatz 1, CH-4003 Basel, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3122-1941","authenticated-orcid":false,"given":"Pascal","family":"M\u00e4ser","sequence":"additional","affiliation":[{"name":"Swiss Tropical and Public Health Institute, Kreuzstra\u00dfe 2, CH-4123 Allschwil, Switzerland"},{"name":"Faculty of Philosophy and Natural Sciences, University of Basel, Swiss TPH, Petersplatz 1, CH-4003 Basel, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7174-6673","authenticated-orcid":false,"given":"Robert","family":"Weis","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Sciences, Pharmaceutical Chemistry, University of Graz, Schubertstra\u00dfe 1, A-8010 Graz, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,23]]},"reference":[{"key":"ref_1","unstructured":"WHO (2022). World Malaria Report, World Health Organization."},{"key":"ref_2","unstructured":"WHO (2023). Guidelines for Malaria, World Health Organization."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2678","DOI":"10.1038\/s41467-022-30133-w","article-title":"Malaria in 2022: Increasing challenges, cautious optimism","volume":"13","author":"Jagannathan","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/s40794-016-0027-8","article-title":"The threat of antimalarial drug resistance","volume":"2","author":"Hanboonkunupakarn","year":"2016","journal-title":"Trop. Dis. Travel Med. Vaccines"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"104275","DOI":"10.1016\/j.phrs.2019.104275","article-title":"Development of artemisinin resistance in malaria therapy","volume":"146","author":"Efferth","year":"2019","journal-title":"Pharmacol. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1056\/NEJMoa2101746","article-title":"Evidence of Artemisinin-Resistant Malaria in Africa","volume":"385","author":"Balikagala","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.pt.2016.11.006","article-title":"Changes in Malaria Epidemiology in Africa and New Challenges for Elimination","volume":"33","author":"Nkumama","year":"2016","journal-title":"Trends Parasitol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"eaau1458","DOI":"10.1126\/scitranslmed.aau1458","article-title":"Challenges and strategies for developing efficacious and long-lasting malaria vaccines","volume":"11","author":"Beeson","year":"2019","journal-title":"Sci. Transl. Med."},{"key":"ref_9","first-page":"15","article-title":"Triple Artemisinin-Based Combination Therapies for Malaria\u2014A New Paradigm?","volume":"37","author":"Amaratunga","year":"2020","journal-title":"Trends Parasitol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1186\/s12936-021-03649-7","article-title":"Deploying triple artemisinin-based combination therapy (TACT) for malaria treatment in Africa: Ethical and practical considerations","volume":"20","author":"Tindana","year":"2021","journal-title":"Malar. J."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1016\/S1473-3099(21)00692-7","article-title":"Triple therapy with artemether-lumefantrine plus amodiaquine versus artemether-lumefantrine alone for artemisininresistant, uncomplicated falciparum malaria: An open-label, randomized, multicentre trial","volume":"22","author":"Peto","year":"2022","journal-title":"Lancet Infect. Dis."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Van Voorhis, W.C., Adams, J.H., Adelfio, R., Ahyong, V., Akabas, M.H., Alano, P., Alday, A., Resto, Y.A., Alsibaee, A., and Alzualde, A. (2016). Open Source Drug Discovery with the Malaria Box Compound Collection for Neglected Diseases and Beyond. PLoS Pathog., 12.","DOI":"10.1371\/journal.ppat.1005763"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.chembiol.2012.01.004","article-title":"Global Phenotypic Screening for Antimalarials","volume":"19","author":"Guiguemde","year":"2012","journal-title":"Chem. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Hermann, T., Hochegger, P., Dolensky, J., Seebacher, W., Saf, R., Kaiser, M., M\u00e4ser, P., and Weis, R. (2021). New Acyl Derivatives of 3-Aminofuarazans and Their Antiplasmodial Activity. Pharmaceuticals, 14.","DOI":"10.3390\/ph14050412"},{"key":"ref_15","first-page":"235","article-title":"Synthesis of new dithiolethione and methanethiosulfonate systems endowed with pharmaceutical interest","volume":"ii","author":"Gabriele","year":"2017","journal-title":"Arkivoc"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3157","DOI":"10.1002\/adsc.201800407","article-title":"Tandem Condensation\/Rearrangement Reaction of 2-Aminohetarene N-Oxides for the Synthesis of Hetaryl Carbamates","volume":"360","author":"Bystrov","year":"2018","journal-title":"Adv. Synth. Catal."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2220","DOI":"10.1016\/j.bmc.2014.02.013","article-title":"Synthesis and methemoglobinemia-inducing properties of benzocaine isosters designed as human rhodenticides","volume":"22","author":"Conole","year":"2014","journal-title":"Bioorg. Med. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1002\/jhet.1697","article-title":"Synthesis of Novel Fluorescent 2-{4-[1-Pyridine-2yl)-1 H-pyrazol-3-yl]phenyl}-2 H -naphtho[1,2-d][1,2,3]triazolyl Derivatives and Evaluation of Their Thermal and Photophysical Properties","volume":"50","author":"Padalkar","year":"2013","journal-title":"J. Heterocycl. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.1248\/cpb.50.1349","article-title":"Studies on non-thiazolidinedione antidiabetic agents. 1. Discovery of novel oxyiminoacetic acid derivatives","volume":"50","author":"Imoto","year":"2002","journal-title":"Chem. Pharm. Bull."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1002\/hlca.200390036","article-title":"An Improved and Versatile Method for the Rapid Synthesis of Aryldihydrobenzofuran Systems by a Boron Tribromide-Mediated Cyclization Reaction","volume":"86","author":"Detterbeck","year":"2003","journal-title":"Helv. Chim. Acta"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.1016\/j.tet.2017.11.011","article-title":"Norbornene probes for the study of cysteine oxidation","volume":"74","author":"Alcock","year":"2018","journal-title":"Tetrahedron"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3973","DOI":"10.1021\/jm901870q","article-title":"Discovery of GSK1070916, a potent and selective inhibitor of Aurora B\/C kinase","volume":"53","author":"Adams","year":"2010","journal-title":"J. Med. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1038\/nrd4163","article-title":"The role of ligand efficiency metrics un drug discovery","volume":"13","author":"Hopkins","year":"2014","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1016\/j.jpba.2006.05.004","article-title":"Integration of rapid automated solubility classification into early validation of hits obtained by high throughput screening","volume":"42","author":"Fligge","year":"2006","journal-title":"Biomed. Anal."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1781","DOI":"10.1021\/ac9912247","article-title":"a High-Throughput Screening Method for the Determination of Aqueous Drug Solubility Using Laser Nephelometry in Microtiter Plates","volume":"72","author":"Beva","year":"2000","journal-title":"Anal. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"6460","DOI":"10.1016\/j.tetlet.2015.09.154","article-title":"Highly chemoselective hydrogenation of active benzaldehydes to benzyl alcohols catalyzed by bimetallic nanoparticles","volume":"56","author":"Liu","year":"2015","journal-title":"Tetrahedron Lett."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"6046","DOI":"10.1021\/acs.orglett.8b02422","article-title":"Development and Utilization of a Palladium-Catalyzed Dehydration of Primary Amides to Form Nitriles","volume":"20","author":"Stanles","year":"2018","journal-title":"Org. Lett."},{"key":"ref_28","first-page":"59","article-title":"Translational impact of novel widely pharmacological characterized mofezolac-derived COX-1 inhibitors combined with bortezomib on human multiple myeloma cell lines viability","volume":"164","author":"Pati","year":"2019","journal-title":"EJMC"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1021\/acs.orglett.8b03829","article-title":"In Situ Generation of Nitrile Oxides from NaCl\u2013Oxone Oxidation of Various Aldoximes and Their 1,3-Dipolar Cycloaddition","volume":"21","author":"Zhao","year":"2012","journal-title":"Org. Lett."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3728","DOI":"10.1021\/acs.orglett.0c01235","article-title":"Visible-Light-Induced Difunctionalization of Styrenes: Synthesis of N-Hydroxybenzimidoyl Cyanides","volume":"22","author":"Alam","year":"2020","journal-title":"Org. Lett."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"6629","DOI":"10.1016\/j.bmcl.2013.10.046","article-title":"Synthesis and methemoglobinemia-inducing properties of analogues of para-aminopropiophenone designed as humane rodenticides","volume":"23","author":"Rennison","year":"2013","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1007\/s11172-005-0359-4","article-title":"One-pot synthesis of 3-amino-4-aryl- and 3-amino-4-hetarylfurazans","volume":"54","author":"Sheremetev","year":"2005","journal-title":"Russ. Chem. Bull."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1007\/s11172-011-0084-0","article-title":"Generation of oxodiazonium ions 1. Synthesis of [1,2,5]oxadiazolo[3,4-c]cinnoline 5-oxides","volume":"60","author":"Klenov","year":"2011","journal-title":"Russ. Chem. Bull."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1111\/cbdd.13003","article-title":"A field-based disparity analysis of new 1,2,5-oxadiazole derivatives endowed with antiproliferative activity","volume":"90","author":"Porta","year":"2017","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1128\/AAC.16.6.710","article-title":"Quantitative assessement of antimalaria activity in vitro by a semiautomated microdilution technique","volume":"16","author":"Desjardins","year":"1979","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/B978-0-12-442704-4.50021-9","article-title":"Plasmodium falciparum malaria parasite cultures and their use in immunology","volume":"Volume 4","author":"Matile","year":"1990","journal-title":"Immunological Methods"},{"key":"ref_37","first-page":"50","article-title":"Chloroquine sensitivity of isolates of Plasmodium falciparum adapted into in vitro culture","volume":"33","author":"Ponndurai","year":"1981","journal-title":"Trop. Geogr. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/0001-706X(93)90083-N","article-title":"A comparison of three methods of estimating EC50 in studies of drug resistance of malaria parasites","volume":"55","author":"Huber","year":"1993","journal-title":"Acta Trop."},{"key":"ref_39","first-page":"473","article-title":"A new fluorometric assay for cytotoxicity measurements in-vitro","volume":"3","author":"Page","year":"1993","journal-title":"Int. J. Oncol."},{"key":"ref_40","first-page":"221","article-title":"A new rapid and simple non-radioactive assay to monito and determine the proliferation of lymphocytes: An alternative to [3H]thymidine incorporation assay","volume":"170","author":"Ahmed","year":"1994","journal-title":"J. Immunol. Methods"},{"key":"ref_41","unstructured":"(2023, July 20). P450-GloTM CYP3A4 Assay and Screening System. Available online: http:\/\/at.promegacom\/products\/cell-health-assays\/adme-assays\/p450-glo-cyp3a4-assay-and-screening-system\/?catNum=V9001."},{"key":"ref_42","unstructured":"Laser Nephelometry (2023, July 20). Bienta. Available online: https:\/\/bienta.net\/laser-nephelometry-method."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/19\/14480\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:56:40Z","timestamp":1760129800000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/19\/14480"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,23]]},"references-count":42,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2023,10]]}},"alternative-id":["ijms241914480"],"URL":"https:\/\/doi.org\/10.3390\/ijms241914480","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,23]]}}}