Discovery of New 3,3-Diethylazetidine-2,4-dione Based Thiazoles as Nanomolar Human Neutrophil Elastase Inhibitors with Broad-Spectrum Antiproliferative Activity
A series of 3,3-diethylazetidine-2,4-dione based thiazoles <b>3a</b>–<b>3j</b> were designed and synthesized as new human neutrophil elastase (HNE) inhibitors in nanomolar range. The representative compounds <b>3c</b>, <b>3e</b>, and <b>3h</b&...
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MDPI AG
2022-07-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/14/7566 |
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| author | Beata Donarska Marta Świtalska Joanna Wietrzyk Wojciech Płaziński Magdalena Mizerska-Kowalska Barbara Zdzisińska Krzysztof Z. Łączkowski |
| author_facet | Beata Donarska Marta Świtalska Joanna Wietrzyk Wojciech Płaziński Magdalena Mizerska-Kowalska Barbara Zdzisińska Krzysztof Z. Łączkowski |
| author_sort | Beata Donarska |
| collection | DOAJ |
| description | A series of 3,3-diethylazetidine-2,4-dione based thiazoles <b>3a</b>–<b>3j</b> were designed and synthesized as new human neutrophil elastase (HNE) inhibitors in nanomolar range. The representative compounds <b>3c</b>, <b>3e</b>, and <b>3h</b> exhibit high HNE inhibitory activity with IC<sub>50</sub> values of 35.02–44.59 nM, with mixed mechanism of action. Additionally, the most active compounds <b>3c</b> and <b>3e</b> demonstrate high stability under physiological conditions. The molecular docking study showed good correlation of the binding energies with the IC<sub>50</sub> 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 IC<sub>50</sub> values of 4.59–9.86 μM. Additionally, compounds <b>3c</b> and <b>3e</b> 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. |
| first_indexed | 2024-03-09T10:18:05Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T10:18:05Z |
| publishDate | 2022-07-01 |
| publisher | MDPI AG |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-2ee7c676fe8144598a0b9bff4da9e3632023-12-01T22:14:01ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-07-012314756610.3390/ijms23147566Discovery of New 3,3-Diethylazetidine-2,4-dione Based Thiazoles as Nanomolar Human Neutrophil Elastase Inhibitors with Broad-Spectrum Antiproliferative ActivityBeata Donarska0Marta Świtalska1Joanna Wietrzyk2Wojciech Płaziński3Magdalena Mizerska-Kowalska4Barbara Zdzisińska5Krzysztof Z. Łączkowski6Department of Chemical Technology and Pharmaceuticals, Faculty of Pharmacy, Collegium Medicum, Nicolaus Copernicus University, Jurasza 2, 85-089 Bydgoszcz, PolandHirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Rudolfa Weigla 12, 53-114 Wrocław, PolandHirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Rudolfa Weigla 12, 53-114 Wrocław, PolandJerzy Haber Institute of Catalysis and Surface Chemistry, Polish Academy of Sciences, Niezapominajek 8, 30-239 Cracow, PolandDepartment of Virology and Immunology, Faculty of Biology and Biotechnology, Maria Curie-Skłodowska University, Akademicka 19 Street, 20-033 Lublin, PolandDepartment of Virology and Immunology, Faculty of Biology and Biotechnology, Maria Curie-Skłodowska University, Akademicka 19 Street, 20-033 Lublin, PolandDepartment of Chemical Technology and Pharmaceuticals, Faculty of Pharmacy, Collegium Medicum, Nicolaus Copernicus University, Jurasza 2, 85-089 Bydgoszcz, PolandA series of 3,3-diethylazetidine-2,4-dione based thiazoles <b>3a</b>–<b>3j</b> were designed and synthesized as new human neutrophil elastase (HNE) inhibitors in nanomolar range. The representative compounds <b>3c</b>, <b>3e</b>, and <b>3h</b> exhibit high HNE inhibitory activity with IC<sub>50</sub> values of 35.02–44.59 nM, with mixed mechanism of action. Additionally, the most active compounds <b>3c</b> and <b>3e</b> demonstrate high stability under physiological conditions. The molecular docking study showed good correlation of the binding energies with the IC<sub>50</sub> 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 IC<sub>50</sub> values of 4.59–9.86 μM. Additionally, compounds <b>3c</b> and <b>3e</b> 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.https://www.mdpi.com/1422-0067/23/14/7566human neutrophil elastaseantiproliferative activitythiazolemolecular docking |
| spellingShingle | Beata Donarska Marta Świtalska Joanna Wietrzyk Wojciech Płaziński Magdalena Mizerska-Kowalska Barbara Zdzisińska Krzysztof Z. Łączkowski Discovery of New 3,3-Diethylazetidine-2,4-dione Based Thiazoles as Nanomolar Human Neutrophil Elastase Inhibitors with Broad-Spectrum Antiproliferative Activity International Journal of Molecular Sciences human neutrophil elastase antiproliferative activity thiazole molecular docking |
| title | Discovery of New 3,3-Diethylazetidine-2,4-dione Based Thiazoles as Nanomolar Human Neutrophil Elastase Inhibitors with Broad-Spectrum Antiproliferative Activity |
| title_full | Discovery of New 3,3-Diethylazetidine-2,4-dione Based Thiazoles as Nanomolar Human Neutrophil Elastase Inhibitors with Broad-Spectrum Antiproliferative Activity |
| title_fullStr | Discovery of New 3,3-Diethylazetidine-2,4-dione Based Thiazoles as Nanomolar Human Neutrophil Elastase Inhibitors with Broad-Spectrum Antiproliferative Activity |
| title_full_unstemmed | Discovery of New 3,3-Diethylazetidine-2,4-dione Based Thiazoles as Nanomolar Human Neutrophil Elastase Inhibitors with Broad-Spectrum Antiproliferative Activity |
| title_short | Discovery of New 3,3-Diethylazetidine-2,4-dione Based Thiazoles as Nanomolar Human Neutrophil Elastase Inhibitors with Broad-Spectrum Antiproliferative Activity |
| title_sort | discovery of new 3 3 diethylazetidine 2 4 dione based thiazoles as nanomolar human neutrophil elastase inhibitors with broad spectrum antiproliferative activity |
| topic | human neutrophil elastase antiproliferative activity thiazole molecular docking |
| url | https://www.mdpi.com/1422-0067/23/14/7566 |
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