Dual Action of Dipyridothiazine and Quinobenzothiazine Derivatives—Anticancer and Cholinesterase-Inhibiting Activity
The inverse correlation observed between Alzheimer’s disease (AD) and cancer has prompted us to look for cholinesterase-inhibiting activity in phenothiazine derivatives that possess anticancer properties. With the use of in silico and in vitro screening methods, our study found a new biological acti...
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MDPI AG
2020-06-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/25/11/2604 |
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| author | Jakub Jończyk Justyna Godyń Ewelina Stawarska Beata Morak-Młodawska Małgorzata Jeleń Krystian Pluta Barbara Malawska |
| author_facet | Jakub Jończyk Justyna Godyń Ewelina Stawarska Beata Morak-Młodawska Małgorzata Jeleń Krystian Pluta Barbara Malawska |
| author_sort | Jakub Jończyk |
| collection | DOAJ |
| description | The inverse correlation observed between Alzheimer’s disease (AD) and cancer has prompted us to look for cholinesterase-inhibiting activity in phenothiazine derivatives that possess anticancer properties. With the use of in silico and in vitro screening methods, our study found a new biological activity in anticancer polycyclic, tricyclic, and tetracyclic compounds. The virtual screening of a library of 120 ligands, which are the derivatives of azaphenothiazine, led to the identification of 25 compounds that can act as potential inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Biological assays revealed the presence of selective inhibitors of <i>ee</i>AChE (<i>electric eel</i> AChE) or <i>eq</i>BuChE (<i>equine serum</i> BuChE) and nonselective inhibitors of both enzymes among the tested compounds. Their potencies against <i>ee</i>AChE were in a submicromolar-to-micromolar range with IC<sub>50</sub> values from 0.78 to 19.32 μM, while their IC<sub>50</sub> values against <i>eq</i>BuChE ranged from 0.46 to 10.38 μM. The most potent among the compounds tested was the tetracyclic derivative, 6-(4-diethylaminobut-2-ynyl)-9-methylthioquinobenzothiazine <b>24</b>, which was capable of inhibiting both enzymes. 9-Fluoro-6-(1-piperidylethyl)quinobenzothiazine <b>23</b> was found to act as a selective inhibitor of <i>eq</i>BuChE with an IC<sub>50</sub> value of 0.46 μM. Compounds with such a dual antitumor and cholinesterase-inhibitory activity can be considered as a valuable combination for the treatment of both cancer and AD prevention. The results presented in this study might open new directions of research on the group of tricyclic phenothiazine derivatives. |
| first_indexed | 2024-03-10T19:23:30Z |
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| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T19:23:30Z |
| publishDate | 2020-06-01 |
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| spelling | doaj.art-1a61fca694ef43b1a61990b7f12842f82023-11-20T02:45:38ZengMDPI AGMolecules1420-30492020-06-012511260410.3390/molecules25112604Dual Action of Dipyridothiazine and Quinobenzothiazine Derivatives—Anticancer and Cholinesterase-Inhibiting ActivityJakub Jończyk0Justyna Godyń1Ewelina Stawarska2Beata Morak-Młodawska3Małgorzata Jeleń4Krystian Pluta5Barbara Malawska6Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, PolandDepartment of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, PolandDepartment of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, PolandDepartment of Organic Chemistry, Faculty of Pharmaceutical Sciences in Sosnowiec, The Medical University of Silesia in Katowice Jagiellońska 4, 41-200 Sosnowiec, PolandDepartment of Organic Chemistry, Faculty of Pharmaceutical Sciences in Sosnowiec, The Medical University of Silesia in Katowice Jagiellońska 4, 41-200 Sosnowiec, PolandDepartment of Organic Chemistry, Faculty of Pharmaceutical Sciences in Sosnowiec, The Medical University of Silesia in Katowice Jagiellońska 4, 41-200 Sosnowiec, PolandDepartment of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, PolandThe inverse correlation observed between Alzheimer’s disease (AD) and cancer has prompted us to look for cholinesterase-inhibiting activity in phenothiazine derivatives that possess anticancer properties. With the use of in silico and in vitro screening methods, our study found a new biological activity in anticancer polycyclic, tricyclic, and tetracyclic compounds. The virtual screening of a library of 120 ligands, which are the derivatives of azaphenothiazine, led to the identification of 25 compounds that can act as potential inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Biological assays revealed the presence of selective inhibitors of <i>ee</i>AChE (<i>electric eel</i> AChE) or <i>eq</i>BuChE (<i>equine serum</i> BuChE) and nonselective inhibitors of both enzymes among the tested compounds. Their potencies against <i>ee</i>AChE were in a submicromolar-to-micromolar range with IC<sub>50</sub> values from 0.78 to 19.32 μM, while their IC<sub>50</sub> values against <i>eq</i>BuChE ranged from 0.46 to 10.38 μM. The most potent among the compounds tested was the tetracyclic derivative, 6-(4-diethylaminobut-2-ynyl)-9-methylthioquinobenzothiazine <b>24</b>, which was capable of inhibiting both enzymes. 9-Fluoro-6-(1-piperidylethyl)quinobenzothiazine <b>23</b> was found to act as a selective inhibitor of <i>eq</i>BuChE with an IC<sub>50</sub> value of 0.46 μM. Compounds with such a dual antitumor and cholinesterase-inhibitory activity can be considered as a valuable combination for the treatment of both cancer and AD prevention. The results presented in this study might open new directions of research on the group of tricyclic phenothiazine derivatives.https://www.mdpi.com/1420-3049/25/11/2604cholinesterase inhibitorsvirtual screeningAlzheimer’s diseaseanticancer agentsdipyridothiazinesquinobenzothiazine |
| spellingShingle | Jakub Jończyk Justyna Godyń Ewelina Stawarska Beata Morak-Młodawska Małgorzata Jeleń Krystian Pluta Barbara Malawska Dual Action of Dipyridothiazine and Quinobenzothiazine Derivatives—Anticancer and Cholinesterase-Inhibiting Activity Molecules cholinesterase inhibitors virtual screening Alzheimer’s disease anticancer agents dipyridothiazines quinobenzothiazine |
| title | Dual Action of Dipyridothiazine and Quinobenzothiazine Derivatives—Anticancer and Cholinesterase-Inhibiting Activity |
| title_full | Dual Action of Dipyridothiazine and Quinobenzothiazine Derivatives—Anticancer and Cholinesterase-Inhibiting Activity |
| title_fullStr | Dual Action of Dipyridothiazine and Quinobenzothiazine Derivatives—Anticancer and Cholinesterase-Inhibiting Activity |
| title_full_unstemmed | Dual Action of Dipyridothiazine and Quinobenzothiazine Derivatives—Anticancer and Cholinesterase-Inhibiting Activity |
| title_short | Dual Action of Dipyridothiazine and Quinobenzothiazine Derivatives—Anticancer and Cholinesterase-Inhibiting Activity |
| title_sort | dual action of dipyridothiazine and quinobenzothiazine derivatives anticancer and cholinesterase inhibiting activity |
| topic | cholinesterase inhibitors virtual screening Alzheimer’s disease anticancer agents dipyridothiazines quinobenzothiazine |
| url | https://www.mdpi.com/1420-3049/25/11/2604 |
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