{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T22:41:46Z","timestamp":1785796906438,"version":"3.56.0"},"reference-count":32,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2023,5,9]],"date-time":"2023-05-09T00:00:00Z","timestamp":1683590400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Belgrade\u2014Faculty of Pharmacy","award":["451-03-47\/2023-01\/200161"],"award-info":[{"award-number":["451-03-47\/2023-01\/200161"]}]},{"name":"University of Belgrade\u2014Faculty of Pharmacy","award":["7739840"],"award-info":[{"award-number":["7739840"]}]},{"name":"Science Fund of the Republic of Serbia","award":["451-03-47\/2023-01\/200161"],"award-info":[{"award-number":["451-03-47\/2023-01\/200161"]}]},{"name":"Science Fund of the Republic of Serbia","award":["7739840"],"award-info":[{"award-number":["7739840"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Cancer is the disease with the highest mortality. Drug studies contribute to promising treatments; however there is an urgent need for selective drug candidates. Pancreatic cancer is difficult to treat and the cancer progresses rapidly. Unfortunately, current treatments are ineffective. In this study, ten new diarylthiophene-2-carbohydrazide derivatives were synthesized and evaluated for their pharmacological activity. The 2D and 3D anticancer activity studies suggested the compounds 7a, 7d, and 7f were promising. Among these, 7f (4.86 \u00b5M) showed the best 2D inhibitory activity against PaCa-2 cells. Compounds 7a, 7d and 7f were also tested for their cytotoxic effects on healthy cell line but only compound 7d showed selectivity. Compounds 7a, 7d, and 7f showed the best 3D cell line inhibitory effect according to spheroid diameters. The compounds were screened for their COX-2 and 5-LOX inhibitory activity. For COX-2, the best IC50 value was observed for 7c (10.13 \u00b5M) and all compounds showed significantly lower inhibition compared to standard. In the 5-LOX inhibition study, compounds 7a (3.78 \u00b5M), 7c (2.60 \u00b5M), 7e (3.3 \u00b5M), and 7f (2.94 \u00b5M) demonstrated influential activity compared to standard. Regarding molecular docking studies, binding mode of compounds 7c, 7e, and 7f to the 5-LOX enzyme were non-redox or redox types, but not the iron-binding type. As dual inhibitors of 5-LOX and pancreatic cancer cell line, 7a and 7f were identified as the most promising compounds.<\/jats:p>","DOI":"10.3390\/pharmaceutics15051441","type":"journal-article","created":{"date-parts":[[2023,5,10]],"date-time":"2023-05-10T01:40:02Z","timestamp":1683682802000},"page":"1441","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Discovery of Novel Thiophene\/Hydrazones: In Vitro and In Silico Studies against Pancreatic Cancer"],"prefix":"10.3390","volume":"15","author":[{"given":"Goknil Pelin","family":"Coskun","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Acibadem Mehmet Ali Aydinlar University, 34752 Istanbul, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yagmur","family":"Ozhan","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Yeditepe University, 34755 Istanbul, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5086-9017","authenticated-orcid":false,"given":"Vladimir","family":"Dobri\u010di\u0107","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, 11221 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jelena","family":"Bo\u0161kovi\u0107","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, 11221 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rengin","family":"Reis","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Acibadem Mehmet Ali Aydinlar University, 34752 Istanbul, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hande","family":"Sipahi","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Yeditepe University, 34755 Istanbul, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5976-676X","authenticated-orcid":false,"given":"Zafer","family":"Sahin","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Hamidiye Faculty of Pharmacy, University of Health Sciences, 34668 Istanbul, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seref","family":"Demirayak","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kocaeli Health and Technology University, 41090 Kocaeli, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1533033820962117","DOI":"10.1177\/1533033820962117","article-title":"Pancreatic Cancer: A Review of Risk Factors, Diagnosis, and Treatment","volume":"19","author":"Zhao","year":"2020","journal-title":"Technol. Cancer Res. Treat."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.ejphar.2004.07.062","article-title":"Antiangiogenic versus cytotoxic therapeutic approaches to human pancreas cancer: An experimental study with a vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor and gemcitabine","volume":"498","author":"Bocci","year":"2004","journal-title":"Eur. J. Pharmacol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"5619","DOI":"10.7314\/APJCP.2015.16.14.5619","article-title":"Pancreatic Cancer: Pathogenesis and Diagnosis","volume":"16","author":"Goral","year":"2015","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_4","first-page":"448","article-title":"Relationships of pain in pancreatic cancer patients with pathological stage and expressions of NF-\u03baB and COX-2","volume":"25","author":"Wang","year":"2020","journal-title":"J. BUON Off. J. Balk. Union Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1016\/j.biopha.2011.06.009","article-title":"Enhancing antitumor effects in pancreatic cancer cells by combined use of COX-2 and 5-LOX inhibitors","volume":"65","author":"Ding","year":"2011","journal-title":"Biomed. Pharmacother."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2127","DOI":"10.1158\/1535-7163.MCT-12-0342","article-title":"Cell intrinsic role of COX-2 in pancreatic cancer development","volume":"11","author":"Hill","year":"2012","journal-title":"Mol. Cancer Ther."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1093\/carcin\/21.2.139","article-title":"Cyclooxygenase-2 expression in human pancreatic adenocarcinomas","volume":"21","author":"Barnard","year":"2000","journal-title":"Carcinogenesis"},{"key":"ref_8","first-page":"15","article-title":"Synthesis, characterization, COX1\/2 inhibition and molecular modeling studies on novel 2-thio-diarylimidazoles","volume":"45","author":"Kalkan","year":"2021","journal-title":"Turk. J. Chem."},{"key":"ref_9","first-page":"83","article-title":"Synthesis of novel 3, 5, 6-trisubstituted triazine derivatives and their biological activity evaluation as potential antitumor and anti-inflammatory agents","volume":"54","author":"Temel","year":"2016","journal-title":"Acta Pharm. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1515\/znc-2021-0217","article-title":"Novel benzofurane-pyrazole derivatives with anti-inflammatory, cyclooxygenase inhibitory and cytotoxicity evaluation","volume":"77","author":"Sahin","year":"2022","journal-title":"Z. F\u00fcr Nat. C."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"33290","DOI":"10.18632\/oncotarget.5396","article-title":"Simultaneous targeting of 5-LOX-COX and EGFR blocks progression of pancreatic ductal adenocarcinoma","volume":"6","author":"Rao","year":"2015","journal-title":"Oncotarget"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/j.bioorg.2017.08.014","article-title":"Pyrazole-hydrazone derivatives as anti-inflammatory agents: Design, synthesis, biological evaluation, COX-1,2\/5-LOX inhibition and docking study","volume":"74","author":"Abdelgawad","year":"2017","journal-title":"Bioorganic Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"104300","DOI":"10.1016\/j.arabjc.2022.104300","article-title":"Identification of novel diclofenac acid and naproxen bearing hydrazones as 15-LOX inhibitors: Design, synthesis, in vitro evaluation, cytotoxicity, and in silico studies","volume":"15","author":"Sardar","year":"2022","journal-title":"Arab. J. Chem."},{"key":"ref_14","unstructured":"Masashi, H., Yoichi, K., Nobuo, M., and Shigeyuki, N. (2009). Pharmaceutical Compositions Containing Novel Amidopropionic Acids as Sphingosine-1-Phosphate (S1P) Receptor Agonists. (No. JP2009040702), Patent, Available online: https:\/\/scifinder-n.cas.org\/searchDetail\/reference\/6384934f5aefd615b687e831\/referenceDetails."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1543","DOI":"10.2147\/CMAR.S163747","article-title":"Comparison of NSAIDs activity in COX-2 expressing and non-expressing 2D and 3D pancreatic cancer cell cultures","volume":"10","year":"2018","journal-title":"Cancer Manag. Res."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Guzelmeric, E., Reis, R., Sen, N.B., Celik, C., Ozhan, Y., Petrikaite, V., Sipahi, H., Ayd\u0131n, A., and Yesilada, E. (2023, April 30). Insights into the Anti-Inflammatory, Analgesic, and Anti-Cancer Potentials of the Standardized Extracts from Three cistus L. Species. Available online: https:\/\/ssrn.com\/abstract=4122153.","DOI":"10.2139\/ssrn.4122153"},{"key":"ref_17","unstructured":"(2023, April 30). COX2 Inhibitor Screening Kit. Available online: https:\/\/www.abcam.com\/products\/assay-kits\/cox2-inhibitor-screening-kit-fluorometric-ab283401.html."},{"key":"ref_18","unstructured":"(2023, April 30). COX1 Inhibitor Assay Kit. Available online: https:\/\/www.abcam.com\/cyclooxygenase-1-cox1-inhibitor-assay-kit-fluorometric-ab204698.html."},{"key":"ref_19","unstructured":"(2023, April 30). ALOX5 Assay Kit. Available online: https:\/\/www.mybiosource.com\/human-assay-kits\/5-lipoxygenase\/846911."},{"key":"ref_20","unstructured":"(2023, April 30). Protein Data Bank. Available online: http:\/\/www.rcsb.org\/."},{"key":"ref_21","unstructured":"(2023, April 30). MAKE Receptor 3.2.0.2: OpenEye Scientific Software, Santa Fe, NM. Available online: https:\/\/www.eyesopen.com\/."},{"key":"ref_22","unstructured":"(2023, April 30). FRED 3.2.0.2: OpenEye Scientific Software, Santa Fe, NM. Available online: https:\/\/www.eyesopen.com\/."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1021\/ci100436p","article-title":"FRED pose prediction and virtual screening accuracy","volume":"51","author":"McGann","year":"2011","journal-title":"J. Chem. Inf. Model"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1007\/s10822-012-9584-8","article-title":"FRED and HYBRID docking performance on standardized datasets","volume":"26","author":"McGann","year":"2012","journal-title":"J. Comput. Aided Mol. Des."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1470","DOI":"10.1110\/ps.690101","article-title":"A normalized root-mean-spuare distance for comparing protein three-dimensional structures","volume":"10","author":"Carugo","year":"2001","journal-title":"Protein Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"384","DOI":"10.17776\/csj.1105811","article-title":"Synthesis, Structure Elucidation and Biological Activity of New Hybrid Hydrazone-Amide Compounds","volume":"43","author":"Aklamuz","year":"2022","journal-title":"Cumhur. Sci. J."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"\u0160ermuk\u0161nyt\u0117, A., Kantminien\u0117, K., Jonu\u0161kien\u0117, I., Tumosien\u0117, I., and Petrikait\u0117, V. (2022). The Effect of 1, 2, 4-Triazole-3-thiol Derivatives Bearing Hydrazone Moiety on Cancer Cell Migration and Growth of Melanoma, Breast, and Pancreatic Cancer Spheroids. Pharmaceuticals, 15.","DOI":"10.3390\/ph15081026"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Mohsin, N.U.A., Aslam, S., Ahmad, M., Irfan, M., Al-Hussain, S.A., and Zaki, M.E. (2022). Cyclooxygenase-2 (COX-2) as a Target of Anticancer Agents: A Review of Novel Synthesized Scaffolds Having Anticancer and COX-2 Inhibitory Potentialities. Pharmaceuticals, 15.","DOI":"10.3390\/ph15121471"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1111\/j.1476-5381.2010.00915.x","article-title":"5-Lipoxygenase inhibitors induce potent anti-proliferative and cytotoxic effects in human tumour cells independently of suppression of 5-lipoxygenase activity","volume":"161","author":"Fischer","year":"2010","journal-title":"Br. J. Pharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"5683","DOI":"10.1002\/jcp.27411","article-title":"Cyclooxygenase-2 in cancer: A review","volume":"234","author":"Goradel","year":"2019","journal-title":"J. Cell. Physiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"782584","DOI":"10.3389\/fphar.2021.782584","article-title":"Inhibitors of human 5-lipoxygenase potently interfere with prostaglandin transport","volume":"12","author":"Kahnt","year":"2022","journal-title":"Front. Pharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1038\/s41589-020-0544-7","article-title":"Structural and mechanistic insights into 5-lipoxygenase inhibition by natural products","volume":"16","author":"Gilbert","year":"2020","journal-title":"Nat. Chem. Biol."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/15\/5\/1441\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:32:00Z","timestamp":1760124720000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/15\/5\/1441"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,9]]},"references-count":32,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2023,5]]}},"alternative-id":["pharmaceutics15051441"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics15051441","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,9]]}}}