{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T20:39:27Z","timestamp":1788381567892,"version":"build-2803163510"},"reference-count":51,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2022,7,8]],"date-time":"2022-07-08T00:00:00Z","timestamp":1657238400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Nicolaus Copernicus University","award":["IDUB 2020-1 NZ"],"award-info":[{"award-number":["IDUB 2020-1 NZ"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>A series of 3,3-diethylazetidine-2,4-dione based thiazoles 3a\u20133j were designed and synthesized as new human neutrophil elastase (HNE) inhibitors in nanomolar range. The representative compounds 3c, 3e, and 3h exhibit high HNE inhibitory activity with IC50 values of 35.02\u201344.59 nM, with mixed mechanism of action. Additionally, the most active compounds 3c and 3e demonstrate high stability under physiological conditions. The molecular docking study showed good correlation of the binding energies with the IC50 values, suggesting that the inhibition properties are largely dependent on the stage of ligand alignment in the binding cavity. The inhibition properties are correlated with the energy level of substrates of the reaction of ligand with Ser195. Moreover, most compounds showed high and broad-spectrum antiproliferative activity against human leukemia (MV4-11), human lung carcinoma (A549), human breast adenocarcinoma (MDA-MB-231), and urinary bladder carcinoma (UMUC-3), with IC50 values of 4.59\u20139.86 \u03bcM. Additionally, compounds 3c and 3e can induce cell cycle arrest at the G2\/M phase and apoptosis via caspase-3 activation, leading to inhibition of A549 cell proliferation. These findings suggest that these new types of drugs could be used to treat cancer and other diseases in which immunoreactive HNE is produced.<\/jats:p>","DOI":"10.3390\/ijms23147566","type":"journal-article","created":{"date-parts":[[2022,7,8]],"date-time":"2022-07-08T11:37:08Z","timestamp":1657280228000},"page":"7566","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Discovery of New 3,3-Diethylazetidine-2,4-dione Based Thiazoles as Nanomolar Human Neutrophil Elastase Inhibitors with Broad-Spectrum Antiproliferative Activity"],"prefix":"10.3390","volume":"23","author":[{"given":"Beata","family":"Donarska","sequence":"first","affiliation":[{"name":"Department of Chemical Technology and Pharmaceuticals, Faculty of Pharmacy, Collegium Medicum, Nicolaus Copernicus University, Jurasza 2, 85-089 Bydgoszcz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"\u015awitalska","sequence":"additional","affiliation":[{"name":"Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Rudolfa Weigla 12, 53-114 Wroc\u0142aw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4980-6606","authenticated-orcid":false,"given":"Joanna","family":"Wietrzyk","sequence":"additional","affiliation":[{"name":"Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Rudolfa Weigla 12, 53-114 Wroc\u0142aw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wojciech","family":"P\u0142azi\u0144ski","sequence":"additional","affiliation":[{"name":"Jerzy Haber Institute of Catalysis and Surface Chemistry, Polish Academy of Sciences, Niezapominajek 8, 30-239 Cracow, Poland"},{"name":"Department of Biopharmacy, Medical University of Lublin, Chodzki 4a, 20-093 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2364-6181","authenticated-orcid":false,"given":"Magdalena","family":"Mizerska-Kowalska","sequence":"additional","affiliation":[{"name":"Department of Virology and Immunology, Faculty of Biology and Biotechnology, Maria Curie-Sk\u0142odowska University, Akademicka 19 Street, 20-033 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0920-3192","authenticated-orcid":false,"given":"Barbara","family":"Zdzisi\u0144ska","sequence":"additional","affiliation":[{"name":"Department of Virology and Immunology, Faculty of Biology and Biotechnology, Maria Curie-Sk\u0142odowska University, Akademicka 19 Street, 20-033 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2107-2719","authenticated-orcid":false,"given":"Krzysztof Z.","family":"\u0141\u0105czkowski","sequence":"additional","affiliation":[{"name":"Department of Chemical Technology and Pharmaceuticals, Faculty of Pharmacy, Collegium Medicum, Nicolaus Copernicus University, Jurasza 2, 85-089 Bydgoszcz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1164\/ajrccm.164.5.2103040","article-title":"Leukocyte elastase: Physiological functions and role in acute lung injury","volume":"64","author":"Lee","year":"2001","journal-title":"Am. 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