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
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
Affiliations
Dmitriy V. Maltsev
Department of Pharmacology and Bioinformatics, Volgograd State Medical University, 400131 Volgograd, Russia
Alexander A. Spasov
Department of Pharmacology and Bioinformatics, Volgograd State Medical University, 400131 Volgograd, Russia
Pavel M. Vassiliev
Department of Pharmacology and Bioinformatics, Volgograd State Medical University, 400131 Volgograd, Russia
Maria O. Skripka
Department of Pharmacology and Bioinformatics, Volgograd State Medical University, 400131 Volgograd, Russia
Mikhail V. Miroshnikov
Department of Pharmacology and Bioinformatics, Volgograd State Medical University, 400131 Volgograd, Russia
Andrey N. Kochetkov
Laboratory for Information Technology in Pharmacology and Computer Modeling of Drugs for Reasearch Center of Innovative Medicines, Volgograd Medical Scientific Center, 400131 Volgograd, Russia
Nataliya V. Eliseeva
Department of Pharmacology and Bioinformatics, Volgograd State Medical University, 400131 Volgograd, Russia
Yuliya V. Lifanova
Department of Pharmacology and Bioinformatics, Volgograd State Medical University, 400131 Volgograd, Russia
Tatyana A. Kuzmenko
Research Institute of Physical and Organic Chemistry, Laboratory of organic synthesis, Southern Federal University, 344090 Rostov-on-Don, Russia
Lyudmila N. Divaeva
Research Institute of Physical and Organic Chemistry, Laboratory of organic synthesis, Southern Federal University, 344090 Rostov-on-Don, Russia
Anatolii S. Morkovnik
Research Institute of Physical and Organic Chemistry, Laboratory of organic synthesis, Southern Federal University, 344090 Rostov-on-Don, Russia
A number of novel 2,3,4,5-tetrahydro[1,3]diazepino[1,2-a]benzimidazole derivatives 2 were obtained by alkylation mainly in the 1H-tautomeric form of 2,3,4,5-tetrahydro[1,3]diazepino[1,2-a]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-a]benzimidazoles upon heating in conc. HBr. The chemical structures of the compounds were clarified by using the 1H Nuclear Magnetic Resonance Spectroscopy (1H-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 2d and 3b 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 3b is explained by the combination of a pronounced interaction mainly with the benzodiazepine site of the GABAA receptor with a prominent interaction with both the specific and allosteric sites of the 5-HT2A receptor.
