Synthesis and Pharmacological Evaluation of Novel 2,3,4,5-tetrahydro[1,3]diazepino[1,2-<i>a</i>]benzimidazole Derivatives as Promising Anxiolytic and Analgesic Agents
A number of novel 2,3,4,5-tetrahydro[1,3]diazepino[1,2-<i>a</i>]benzimidazole derivatives <b>2</b> were obtained by alkylation mainly in the 1<i>H</i>-tautomeric form of 2,3,4,5-tetrahydro[1,3]diazepino[1,2-<i>a</i>]benzimidazole or its 8,9-dimethyl-su...
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| Format: | Article |
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MDPI AG
2021-10-01
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| Online Access: | https://www.mdpi.com/1420-3049/26/19/6049 |
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| author | Dmitriy V. Maltsev Alexander A. Spasov Pavel M. Vassiliev Maria O. Skripka Mikhail V. Miroshnikov Andrey N. Kochetkov Nataliya V. Eliseeva Yuliya V. Lifanova Tatyana A. Kuzmenko Lyudmila N. Divaeva Anatolii S. Morkovnik |
| author_facet | Dmitriy V. Maltsev Alexander A. Spasov Pavel M. Vassiliev Maria O. Skripka Mikhail V. Miroshnikov Andrey N. Kochetkov Nataliya V. Eliseeva Yuliya V. Lifanova Tatyana A. Kuzmenko Lyudmila N. Divaeva Anatolii S. Morkovnik |
| author_sort | Dmitriy V. Maltsev |
| collection | DOAJ |
| description | A number of novel 2,3,4,5-tetrahydro[1,3]diazepino[1,2-<i>a</i>]benzimidazole derivatives <b>2</b> were obtained by alkylation mainly in the 1<i>H</i>-tautomeric form of 2,3,4,5-tetrahydro[1,3]diazepino[1,2-<i>a</i>]benzimidazole or its 8,9-dimethyl-substituted analog 4-chlorobenzyl bromide, 4-chloroacetic acid fluoroanilide, and 4-tert-butylphenacyl bromide in neutral medium. Compounds 3 were cyclized and synthesized earlier with 11-phenacyl-substituted diazepino[1,2-<i>a</i>]benzimidazoles upon heating in conc. HBr. The chemical structures of the compounds were clarified by using the <sup>1</sup>H Nuclear Magnetic Resonance Spectroscopy (<sup>1</sup>H-NMR) technique. Anxiolytic properties were evaluated using the elevated plus maze (EPM) and open field (OF) tests. The analgesic effect of compounds was estimated with the tail flick (TF) and hot plate (HP) methods. Besides, possible the influence of the test compounds on motor activities of the animals was examined by the Grid, Wire, and Rotarod tests. Compounds <b>2d</b> and <b>3b</b> were the most active due to their prominent analgesic and anxiolytic potentials, respectively. The results of the performed in silico analysis showed that the high anxiolytic activity of compound <b>3b</b> is explained by the combination of a pronounced interaction mainly with the benzodiazepine site of the GABA<sub>A</sub> receptor with a prominent interaction with both the specific and allosteric sites of the 5-HT<sub>2A</sub> receptor. |
| first_indexed | 2024-03-10T06:54:20Z |
| format | Article |
| id | doaj.art-b5318cd03f504802b4cf0d7fdff8c827 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T06:54:20Z |
| publishDate | 2021-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-b5318cd03f504802b4cf0d7fdff8c8272023-11-22T16:36:34ZengMDPI AGMolecules1420-30492021-10-012619604910.3390/molecules26196049Synthesis and Pharmacological Evaluation of Novel 2,3,4,5-tetrahydro[1,3]diazepino[1,2-<i>a</i>]benzimidazole Derivatives as Promising Anxiolytic and Analgesic AgentsDmitriy V. Maltsev0Alexander A. Spasov1Pavel M. Vassiliev2Maria O. Skripka3Mikhail V. Miroshnikov4Andrey N. Kochetkov5Nataliya V. Eliseeva6Yuliya V. Lifanova7Tatyana A. Kuzmenko8Lyudmila N. Divaeva9Anatolii S. Morkovnik10Department of Pharmacology and Bioinformatics, Volgograd State Medical University, 400131 Volgograd, RussiaDepartment of Pharmacology and Bioinformatics, Volgograd State Medical University, 400131 Volgograd, RussiaDepartment of Pharmacology and Bioinformatics, Volgograd State Medical University, 400131 Volgograd, RussiaDepartment of Pharmacology and Bioinformatics, Volgograd State Medical University, 400131 Volgograd, RussiaDepartment of Pharmacology and Bioinformatics, Volgograd State Medical University, 400131 Volgograd, RussiaLaboratory for Information Technology in Pharmacology and Computer Modeling of Drugs for Reasearch Center of Innovative Medicines, Volgograd Medical Scientific Center, 400131 Volgograd, RussiaDepartment of Pharmacology and Bioinformatics, Volgograd State Medical University, 400131 Volgograd, RussiaDepartment of Pharmacology and Bioinformatics, Volgograd State Medical University, 400131 Volgograd, RussiaResearch Institute of Physical and Organic Chemistry, Laboratory of organic synthesis, Southern Federal University, 344090 Rostov-on-Don, RussiaResearch Institute of Physical and Organic Chemistry, Laboratory of organic synthesis, Southern Federal University, 344090 Rostov-on-Don, RussiaResearch Institute of Physical and Organic Chemistry, Laboratory of organic synthesis, Southern Federal University, 344090 Rostov-on-Don, RussiaA number of novel 2,3,4,5-tetrahydro[1,3]diazepino[1,2-<i>a</i>]benzimidazole derivatives <b>2</b> were obtained by alkylation mainly in the 1<i>H</i>-tautomeric form of 2,3,4,5-tetrahydro[1,3]diazepino[1,2-<i>a</i>]benzimidazole or its 8,9-dimethyl-substituted analog 4-chlorobenzyl bromide, 4-chloroacetic acid fluoroanilide, and 4-tert-butylphenacyl bromide in neutral medium. Compounds 3 were cyclized and synthesized earlier with 11-phenacyl-substituted diazepino[1,2-<i>a</i>]benzimidazoles upon heating in conc. HBr. The chemical structures of the compounds were clarified by using the <sup>1</sup>H Nuclear Magnetic Resonance Spectroscopy (<sup>1</sup>H-NMR) technique. Anxiolytic properties were evaluated using the elevated plus maze (EPM) and open field (OF) tests. The analgesic effect of compounds was estimated with the tail flick (TF) and hot plate (HP) methods. Besides, possible the influence of the test compounds on motor activities of the animals was examined by the Grid, Wire, and Rotarod tests. Compounds <b>2d</b> and <b>3b</b> were the most active due to their prominent analgesic and anxiolytic potentials, respectively. The results of the performed in silico analysis showed that the high anxiolytic activity of compound <b>3b</b> is explained by the combination of a pronounced interaction mainly with the benzodiazepine site of the GABA<sub>A</sub> receptor with a prominent interaction with both the specific and allosteric sites of the 5-HT<sub>2A</sub> receptor.https://www.mdpi.com/1420-3049/26/19/6049diazepino[1,2-<i>a</i>]benzimidazoletriazabenzo[<i>a</i>]cyclopenta[<i>cd</i>]azuleniumanxiolyticanalgesichot plateopen field |
| spellingShingle | Dmitriy V. Maltsev Alexander A. Spasov Pavel M. Vassiliev Maria O. Skripka Mikhail V. Miroshnikov Andrey N. Kochetkov Nataliya V. Eliseeva Yuliya V. Lifanova Tatyana A. Kuzmenko Lyudmila N. Divaeva Anatolii S. Morkovnik Synthesis and Pharmacological Evaluation of Novel 2,3,4,5-tetrahydro[1,3]diazepino[1,2-<i>a</i>]benzimidazole Derivatives as Promising Anxiolytic and Analgesic Agents Molecules diazepino[1,2-<i>a</i>]benzimidazole triazabenzo[<i>a</i>]cyclopenta[<i>cd</i>]azulenium anxiolytic analgesic hot plate open field |
| title | Synthesis and Pharmacological Evaluation of Novel 2,3,4,5-tetrahydro[1,3]diazepino[1,2-<i>a</i>]benzimidazole Derivatives as Promising Anxiolytic and Analgesic Agents |
| title_full | Synthesis and Pharmacological Evaluation of Novel 2,3,4,5-tetrahydro[1,3]diazepino[1,2-<i>a</i>]benzimidazole Derivatives as Promising Anxiolytic and Analgesic Agents |
| title_fullStr | Synthesis and Pharmacological Evaluation of Novel 2,3,4,5-tetrahydro[1,3]diazepino[1,2-<i>a</i>]benzimidazole Derivatives as Promising Anxiolytic and Analgesic Agents |
| title_full_unstemmed | Synthesis and Pharmacological Evaluation of Novel 2,3,4,5-tetrahydro[1,3]diazepino[1,2-<i>a</i>]benzimidazole Derivatives as Promising Anxiolytic and Analgesic Agents |
| title_short | Synthesis and Pharmacological Evaluation of Novel 2,3,4,5-tetrahydro[1,3]diazepino[1,2-<i>a</i>]benzimidazole Derivatives as Promising Anxiolytic and Analgesic Agents |
| title_sort | synthesis and pharmacological evaluation of novel 2 3 4 5 tetrahydro 1 3 diazepino 1 2 i a i benzimidazole derivatives as promising anxiolytic and analgesic agents |
| topic | diazepino[1,2-<i>a</i>]benzimidazole triazabenzo[<i>a</i>]cyclopenta[<i>cd</i>]azulenium anxiolytic analgesic hot plate open field |
| url | https://www.mdpi.com/1420-3049/26/19/6049 |
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