Synthesis of 4,5-Dihydro-1<i>H</i>-[1,2]dithiolo[3,4-<i>c</i>]quinoline-1-thione Derivatives and Their Application as Protein Kinase Inhibitors
This study represents the design and synthesis of a new set of hybrid and chimeric derivatives of 4,5-dihydro-4,4-dimethyl-1<i>H</i>-[1,2]dithiolo[3,4-<i>c</i>]quinoline-1-thiones, the structure of which the tricyclic fragment linearly bound or/and condensed with another hete...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-06-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/27/13/4033 |
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| author | Svetlana M. Medvedeva Khidmet S. Shikhaliev |
| author_facet | Svetlana M. Medvedeva Khidmet S. Shikhaliev |
| author_sort | Svetlana M. Medvedeva |
| collection | DOAJ |
| description | This study represents the design and synthesis of a new set of hybrid and chimeric derivatives of 4,5-dihydro-4,4-dimethyl-1<i>H</i>-[1,2]dithiolo[3,4-<i>c</i>]quinoline-1-thiones, the structure of which the tricyclic fragment linearly bound or/and condensed with another heterocyclic fragment. Using the PASS Online software, among the previously synthesized and new derivatives of 1,2-dithiolo[3,4-<i>c</i>]quinoline-1-thione we identified 12 substances with pleiotropic activity, including chemoprotective and antitumor activity. All the synthesized derivatives were screened for their inhibitory assessment against a number of kinases. Compounds which exhibited prominent inhibition percentage in cells (>85%) were also examined for their inhibitory efficiency on human kinases via ELISA utilizing sorafenib as a reference standard to estimate their IC<sub>50</sub> values. It was revealed that compounds <b>2a</b>, <b>2b</b>, <b>2c</b>, and <b>2q</b> displayed a significant inhibition JAK3 (IC<sub>50</sub> = 0.36 μM, 0.38 μM, 0.41 μM, and 0.46 μM, respectively); moreover, compounds <b>2a</b> and <b>2b</b> displayed excellent activities against NPM1-ALK (IC<sub>50</sub> = 0.54 μM, 0.25 μM, respectively), against cRAF[Y340D][Y341D], compound <b>2c</b> showed excellent activity, and compound <b>2q</b> showed weak activity (IC<sub>50</sub> = 0.78 μM, 5.34 μM, respectively) (sorafenib IC<sub>50</sub> = 0.78 μM, 0.43 μM, 1.95 μM, respectively). Thus, new promising preferred structures for the creation of drugs for the treatment of cancer and other multifactorial diseases in the future have been found. |
| first_indexed | 2024-03-09T04:01:26Z |
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| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T04:01:26Z |
| publishDate | 2022-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-5fa05e4191ce4cef8d4815657e5405832023-12-03T14:13:02ZengMDPI AGMolecules1420-30492022-06-012713403310.3390/molecules27134033Synthesis of 4,5-Dihydro-1<i>H</i>-[1,2]dithiolo[3,4-<i>c</i>]quinoline-1-thione Derivatives and Their Application as Protein Kinase InhibitorsSvetlana M. Medvedeva0Khidmet S. Shikhaliev1Department of Organic Chemistry, Faculty of Chemistry, Voronezh State University, 1 Universitetskaya Sq., 394018 Voronezh, RussiaDepartment of Organic Chemistry, Faculty of Chemistry, Voronezh State University, 1 Universitetskaya Sq., 394018 Voronezh, RussiaThis study represents the design and synthesis of a new set of hybrid and chimeric derivatives of 4,5-dihydro-4,4-dimethyl-1<i>H</i>-[1,2]dithiolo[3,4-<i>c</i>]quinoline-1-thiones, the structure of which the tricyclic fragment linearly bound or/and condensed with another heterocyclic fragment. Using the PASS Online software, among the previously synthesized and new derivatives of 1,2-dithiolo[3,4-<i>c</i>]quinoline-1-thione we identified 12 substances with pleiotropic activity, including chemoprotective and antitumor activity. All the synthesized derivatives were screened for their inhibitory assessment against a number of kinases. Compounds which exhibited prominent inhibition percentage in cells (>85%) were also examined for their inhibitory efficiency on human kinases via ELISA utilizing sorafenib as a reference standard to estimate their IC<sub>50</sub> values. It was revealed that compounds <b>2a</b>, <b>2b</b>, <b>2c</b>, and <b>2q</b> displayed a significant inhibition JAK3 (IC<sub>50</sub> = 0.36 μM, 0.38 μM, 0.41 μM, and 0.46 μM, respectively); moreover, compounds <b>2a</b> and <b>2b</b> displayed excellent activities against NPM1-ALK (IC<sub>50</sub> = 0.54 μM, 0.25 μM, respectively), against cRAF[Y340D][Y341D], compound <b>2c</b> showed excellent activity, and compound <b>2q</b> showed weak activity (IC<sub>50</sub> = 0.78 μM, 5.34 μM, respectively) (sorafenib IC<sub>50</sub> = 0.78 μM, 0.43 μM, 1.95 μM, respectively). Thus, new promising preferred structures for the creation of drugs for the treatment of cancer and other multifactorial diseases in the future have been found.https://www.mdpi.com/1420-3049/27/13/40331,2-dithiol-3-thione2,2-disubstituted-1,2-dihydroquinolinesdithioloquinolinethionesnon-selective anti-kinase activitybioactivity profiles prediction in silicoPASS online |
| spellingShingle | Svetlana M. Medvedeva Khidmet S. Shikhaliev Synthesis of 4,5-Dihydro-1<i>H</i>-[1,2]dithiolo[3,4-<i>c</i>]quinoline-1-thione Derivatives and Their Application as Protein Kinase Inhibitors Molecules 1,2-dithiol-3-thione 2,2-disubstituted-1,2-dihydroquinolines dithioloquinolinethiones non-selective anti-kinase activity bioactivity profiles prediction in silico PASS online |
| title | Synthesis of 4,5-Dihydro-1<i>H</i>-[1,2]dithiolo[3,4-<i>c</i>]quinoline-1-thione Derivatives and Their Application as Protein Kinase Inhibitors |
| title_full | Synthesis of 4,5-Dihydro-1<i>H</i>-[1,2]dithiolo[3,4-<i>c</i>]quinoline-1-thione Derivatives and Their Application as Protein Kinase Inhibitors |
| title_fullStr | Synthesis of 4,5-Dihydro-1<i>H</i>-[1,2]dithiolo[3,4-<i>c</i>]quinoline-1-thione Derivatives and Their Application as Protein Kinase Inhibitors |
| title_full_unstemmed | Synthesis of 4,5-Dihydro-1<i>H</i>-[1,2]dithiolo[3,4-<i>c</i>]quinoline-1-thione Derivatives and Their Application as Protein Kinase Inhibitors |
| title_short | Synthesis of 4,5-Dihydro-1<i>H</i>-[1,2]dithiolo[3,4-<i>c</i>]quinoline-1-thione Derivatives and Their Application as Protein Kinase Inhibitors |
| title_sort | synthesis of 4 5 dihydro 1 i h i 1 2 dithiolo 3 4 i c i quinoline 1 thione derivatives and their application as protein kinase inhibitors |
| topic | 1,2-dithiol-3-thione 2,2-disubstituted-1,2-dihydroquinolines dithioloquinolinethiones non-selective anti-kinase activity bioactivity profiles prediction in silico PASS online |
| url | https://www.mdpi.com/1420-3049/27/13/4033 |
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