Maria О. Maltseva, Kristina I. Adzhienko, Raul I. Musaev, Alexander A. Spasov, Vahid A. Mamedov, Natalia A. Zhukova, Sevil V. Mamedova, Nalatalia V. Eliseeva, Karina R. Magomedova, Dmitriy V. Maltsev

Anxiolytic, antidepressant and analgesic activities of novel derivatives of 1-(3-phenylpyrrol-2-yl)-1,3-dihydro-2H-benzimidazol-2-one

Introduction

Anxiolytic, antidepressant and analgesic activities of novel derivatives of 1-(3-phenylpyrrol-2-yl)-1,3-dihydro-2h-benzimidazol-2-one. Explore novel benzimidazole derivatives exhibiting anxiolytic, antidepressant, and analgesic properties. In vivo studies reveal promising neuropsychotropic potential & structure-activity relationships.

Abstract

Introduction: Benzimidazole (1,3-benzodiazole) derivatives hold an important place in the field of medicinal chemistry, since they have a wide spectrum of pharmacological activity, as well as high variability of the mechanisms of action: GABA-, serotonin-, dopamine-, adrenaline-, angiotensin-, adenosine-, and glutamatergic. In view of the diversity of the ways of influence of benzimidazole derivatives on neurotransmitter systems, as well as the pharmacological effects of these compounds, the synthesis of highly effective neurotropic drugs with an improved safety profile on their basis is ofinterest for study. The aim of this study was to investigate the neuropsychotropic potential of new derivatives of 1-(3-phenylpyrrol-2-yl)-1,3-dihydro-2H-benzimidazole-2-one in vivo. Materials and Methods: The study was conducted on 258 white outbred male mice weighing 25-30 g. The work was carried out in several stages. At the first stage, the safety of the compounds was studied by in silico methods using the PASS-online program with a preliminary calculation of LD50. At the second stage, animals were tested under the influence of the compounds in the Open Field and Light-Dark Box tests. Etifoxine (50 mg/kg) and phenazepam (0.1 mg/kg) were chosen as comparison drugs. At the third stage, the behavior of rodents was studied in Porsolt test, with amitriptyline (10 mg/kg) and fluoxetine (10 mg/kg) used as reference drugs. At the fourth stage, the analgesic properties of the compounds were assessed in the Tail-flick and Hot Plate tests in comparison with morphine (5 mg/kg). Results and Discussion: Based on the obtained results, it can be noted that the phenyl-containing compound CHS-Bi-46 has anxiolytic activity with an antidepressant component. Compounds containing pyridin-3-yl (CHS-Bi-48) and 2-bromophenyl (CHS-Bi-52) are characterized by antidepressant properties, and CHS-Bi-52 also showed a weak analgesic effect in the Hot plate test. For the substance with a pyridin-4-yl fragment CHS-Bi-47, no significant effects were registered according to the results of the tests, but this substance may have other pharmacological activities. 4-Chlorophenyl substance coded CHS-Bi-50 exhibits antinociceptive activity at the spinal level, which is equal to the reference drug morphine at a dose of 5 mg/kg. The 4-bromophenyl-containing compound CHS-Bi-51 is characterized by a moderate combined spinal and supraspinal analgesic property. It can be noted that the most suitable structure for the manifestation of anxiolytic and antidepressant properties of compounds is the presence of a phenyl substituent in the 5 position of the pyrrole ring, and the severity of the analgesic effects of substances is affected by the presence of Cl atoms in the phenyl radical in position 4 for spinal effects and Br – in positions 2 and 4 for supraspinal effects. Conclusion: The obtained data indicate the prospects of further study of 1-(3-phenylpyrrol-2-yl)-1,3-dihydro-2H-benzimidazole-2-one derivatives in order to search for substances with neuropsychotropic activity.

Review

This study presents a thorough *in vivo* investigation into the anxiolytic, antidepressant, and analgesic activities of novel 1-(3-phenylpyrrol-2-yl)-1,3-dihydro-2H-benzimidazol-2-one derivatives. Utilizing a battery of well-established behavioral tests in mice, including Open Field, Light-Dark Box, Porsolt test, Tail-flick, and Hot Plate assays, the researchers aimed to identify compounds with neuropsychotropic potential. The work began with an *in silico* safety assessment, preceding the systematic evaluation of several derivatives against relevant reference drugs. Overall, the research successfully identified specific compounds exhibiting distinct pharmacological profiles, alongside providing initial insights into their structure-activity relationships. A significant strength of this research is its comprehensive *in vivo* screening approach, which explored a broad spectrum of neuropsychotropic activities. The selection of appropriate animal models and the inclusion of multiple gold-standard reference drugs (Etifoxine, phenazepam, amitriptyline, fluoxetine, morphine) bolster the reliability and comparability of the findings. The identification of several promising compounds, such as CHS-Bi-46 with combined anxiolytic and antidepressant properties, CHS-Bi-50 with potent spinal antinociceptive effects, and CHS-Bi-51 demonstrating both spinal and supraspinal analgesia, represents a valuable contribution to medicinal chemistry. Crucially, the preliminary elucidation of structure-activity relationships, linking specific substituents (e.g., phenyl, chloro-, and bromo-phenyl) to the observed pharmacological effects, provides a strong foundation for rational drug design and optimization in future studies. While the study effectively demonstrates the neuropsychotropic potential of these novel derivatives, several areas warrant further exploration to fully characterize their therapeutic utility. A key limitation is the absence of detailed investigation into the precise molecular mechanisms underlying the observed effects; elucidating these pathways would significantly enhance our understanding and guide targeted drug development. Additionally, while reference drug dosages are provided, the abstract does not specify the doses at which the novel compounds were tested, making it difficult to assess their relative potencies. Future studies should focus on dose-response relationships, chronic toxicity, and evaluation in female animals, given that only male mice were utilized. Despite these areas for expansion, this research offers a robust initial screening and lays promising groundwork for the continued development of these benzimidazole derivatives as potential therapeutic agents for neurological and psychiatric disorders.

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