Antidiabetogenic Features of Benzimidazoles

Literature data on the insulinogenic effect of 2-aminobenzimidazole prompted us to investigate its novel derivatives, particularly those containing an additional fused cycle in C1,2-α position, including imidazole, dihydroimidazole, or tetrahydropyrimidine ring. Consensus analysis of the hypoglycemic effect of these compounds performed with IT Microcosm and PASS system revealed that activity is mostly characteristic for N9-2,3-dihydroimidazo[1,2-a]benzimidazole derivatives. Substructural analysis of hypoglycemic activity identified substituents that determine the greatest pharmacological effect. According to the in silico assessment of the ADME properties, RU-254 was nominated as a lead compound due to the most optimal calculated and experimental activity and pharmacokinetic parameters. Preclinical studies have shown that identified compound has a pronounced insulinogenic effect and hypoglycemic effect, both in intact animals and in animals with experimental diabetes mellitus. RU-254 also reduces the level of glycated hemoglobin upon chronic administration, slightly decreases the activity of DPP-4, and increases the average number of Langerhans islets in the pancreas. Pharmaceutical drug formulation of RU-254 was developed and investigated for pharmacokinetic, pharmacodynamic, and toxicological properties. The dosage form of the drug under the name limiglidol (compound RU-254, diabenol) was evaluated in the full cycle of clinical studies that confirmed the safety, tolerability, and prominent antidiabetic properties of the drug

Condensed Benzimidazoles Are a Novel Scaffold for Antioxidant Agents’ Search and Development

Taking into account that the imidazole ring has π-electron redundancy, condensed benzimidazole derivatives have attracted our attention as a promising class for the search for antioxidant substances. Synthesis was carried out, and information on the antioxidant activity of imidazo- and tetrahydropyrimido benzimidazoles was provided. Highly active antioxidant substance enoxifol has been revealed. The data on the synthesis and study of the pharmacodynamic, pharmacokinetic, and toxicological properties of the new antioxidant compound enoxifol are presented. The antioxidant activity of the compound is due to its ability to inactivate superoxide, hydroxyl, and peroxyl radicals, thereby reducing the overall oxidation rate due to a decrease in the total initiation rate. It has been shown that enoxifol has hepatoprotector, antihypoxic, cerebroprotective, nootropic, stress-protective, neuropsychotropic, actoprotective, cardioprotective, antiaggregant, and antithrombogenic properties and is able to prevent rheological disorders in diabetes mellitus

Deep learning-based i-EEG classification with convolutional neural networks for drug-target interaction prediction

Drug-target interaction (DTI) prediction has become a foundational task in drug repositioning, polypharmacology, drug discovery, as well as drug resistance and side-effect prediction. DTI identification using machine learning is gaining popularity in these research areas. Through the years, numerous deep learning methods have been proposed for DTI prediction. Nevertheless, prediction accuracy and efficiency remain key challenges. Pharmaco-electroencephalogram (pharmaco-EEG) is considered valuable in the development of central nervous system-active drugs. Quantitative EEG analysis demonstrates high reliability in studying the effects of drugs on the brain. Earlier preclinical pharmaco-EEG studies showed that different types of drugs can be classified according to their mechanism of action on neural activity. Here, we propose a convolutional neural network for EEG-mediated DTI prediction. This new approach can explain the mechanisms underlying complicated drug actions, as it allows the identification of similarities in the mechanisms of action and effects of psychotropic drugs

Aversion-related effects of kappa-opioid agonist U-50488 on neural activity and functional connectivity between amygdala, ventral tegmental area, prefrontal cortex, hippocampus, and nucleus accumbens

Introduction: Among the various receptor systems in the brain, the opioid receptors have been the subject of extensive research due to their integral role in pain modulation, reward processing, and emotional regulation. The kappa-opioid receptor (KOR) system, in particular, stands apart due to its unique contribution to stress response, aversive behaviors, and dysphoric states. This paper aims to provide an understanding of the neural activity underlying the aversion-associated effects of the KOR agonist U-50488. Materials and Methods: Rats underwent stereotaxic surgery to implant electrodes into the amygdala, ventral tegmental area, prefrontal cortex, hippocampus, and nucleus accumbens. The rats were subjected to conditioned place preference test to measure aversion to U-50488. After that, local field potential (LFP) recordings were made. LFP data were processed and analyzed using spectral and coherence analysis methods. A stepwise multiple linear regression was employed to identify the LFP features most significantly correlated with aversion to U-50488. Results: The administration of U-50488 resulted in significant changes in LFP signals across multiple brain regions. These changes were particularly notable in the theta, gamma, and delta bands of brain waves (p<0.05). Theta and gamma activities were especially sensitive to the effects of U-50488. Connectivity calculations revealed shifts in coherence between brain regions, particularly highlighting the amygdala's involvement. While changes were also observed in the ventral tegmental area, prefrontal cortex, hippocampus, and nucleus accumbens (p<0.05), they contributed less to aversion. Using the stepwise multiple linear regression method, we established a final model with the 3 most significant variables: (1) coherence between the amygdala and medial prefrontal cortex, (2) coherence between the amygdala and hippocampus, and (3) theta power in the amygdala. Conclusion: Overall, the data provided insights into how electrical neural activity mediates aversion in response to KOR activation. The results showed that the severity of aversion can be reasonably predicted (r = 0.72±0.02, p = 0.0099) using LFP band power and functional connectivity data. We concluded that the amygdala is a brain region that contributes the most to the KOR agonist-induced aversion

Search for compounds with antioxidant and antiradical activity among N9-substituted 2-(biphenyl-4-yl)imidazo[1,2-a]benzimidazoles

Introduction: Biphenyl and imidazobenzimidazole derivatives attract ongoing attention as a combination of these two privileged substructures with promising pharmacological activities. The aim of this study was to synthesize and investigate in vitro antioxidant activity of promising novel compounds: 2-(biphenyl-4-yl)imidazo[1,2-a]benzimidazoles. Materials and methods: The newly synthesized compounds were characterized by IR, 1H NMR and CHBr(Cl)NO analyses. All newly synthesized compounds were screened for their in vitro antioxidant activity: inhibition of lipid peroxidation (LPO), 2,2’-azino-bis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS•+) radical cation decolorization and inhibition of hemoglobin (Hb)-H2O2-induced luminol chemiluminescence. Results and discussion: 2-Amino-3-[(2-biphenyl-4-yl)-2-oxo-ethyl)]-1-R-1Н-benzimidazolium bromides were synthesized, and their cyclization into functionalized imidazo[1,2-a]benzimidazole derivatives was studied. The resulting compounds showed LPO inhibitory activity comparable to that of dibunol. Compounds 1a and 1d (see graphical abstract), containing a methyl or dimethylaminoethyl substituent in the N9 position also proved to be equally highly active in the Hb-H2O2-induced luminol chemiluminescence model, while compound 1a was somewhat more active than 1d in the ABTS• radical scavenging assay. Conclusion: The study showed that compounds 1a and 1d have the highest antioxidant activity. Thus, this new class of 2-(biphenyl-4-yl)imidazo[1,2-a]benzimidazole derivatives represents a valuable leading series with great potential for use as antioxidants and as promising candidates for further efficacy evaluation. Graphical abstract

Antiplatelet activity of new derivatives of benzimidazole containing sterically hindered phenolic group in their structure

Introduction: Cardiovascular diseases are currently the leading cause of global disability and mortality. According to the centers for disease control and prevention, the average life expectancy of a person would be 10 years longer but for a high prevalence of cardiovascular diseases, and if antiplatelet drugs and special therapy were used. Materials and methods: Antiplatelet activity of the novel benzimidazole derivatives containing a sterically hindered phenolic group in their structure has been investigated in vitro, using a model of ADP-induced platelet aggregation of rabbit’s plasma. The compounds exhibiting high antiplatelet activity and acetylsalicylic acid, as a reference drug, were examined for antioxidant properties in an ascorbate-dependent model of lipid peroxidation. Results: It was established that the compounds with high antiplatelet activity demonstrated the pronounced antioxidant action. The compound RU-1144 (1-(3,5-ditretbutyl-4-hydroxyphenyl) -1-hydroxypropyl)-phenyl-pyrimidobenzimidazole hydrochloride), in in vitro experiments, had a pronounced antiplatelet activity, surpassing the reference drug acetylsalicylic acid by 21.8 times; in the study of antioxidant activity, the leader compound was inferior to the reference drug dibunol by 1.7 times. By inhibiting intravascular platelet aggregation in vivo, this compound exceeded acetylsalicylic acid by 1.5 times and was slightly inferior to clopidogrel by 1.4 times. Discussion: Benzimidazole derivatives with a hindered phenolic substituent in their structure exhibited antiplatelet and antioxidant properties. It was established that the compounds with high antiplatelet activity demonstrated the pronounced antioxidant action. Conclusion: The chemical class of benzimidazole derivatives with a hindered phenolic substituent in their structure is promising for the search for new antiaggregant and antioxidant drugs

Antiplatelet activity of new derivatives of benzimidazole containing sterically hindered phenolic group in their structure

Introduction: Cardiovascular diseases are currently the leading cause of global disability and mortality. According to the centers for disease control and prevention, the average life expectancy of a person would be 10 years longer but for a high prevalence of cardiovascular diseases, and if antiplatelet drugs and special therapy were used. Materials and methods: Antiplatelet activity of the novel benzimidazole derivatives containing a sterically hindered phenolic group in their structure has been investigated in vitro, using a model of ADP-induced platelet aggregation of rabbit’s plasma. The compounds exhibiting high antiplatelet activity and acetylsalicylic acid, as a reference drug, were examined for antioxidant properties in an ascorbate-dependent model of lipid peroxidation. Results: It was established that the compounds with high antiplatelet activity demonstrated the pronounced antioxidant action. The compound RU-1144 (1-(3,5-ditretbutyl-4-hydroxyphenyl) -1-hydroxypropyl)-phenyl-pyrimidobenzimidazole hydrochloride), in in vitro experiments, had a pronounced antiplatelet activity, surpassing the reference drug acetylsalicylic acid by 21.8 times; in the study of antioxidant activity, the leader compound was inferior to the reference drug dibunol by 1.7 times. By inhibiting intravascular platelet aggregation in vivo, this compound exceeded acetylsalicylic acid by 1.5 times and was slightly inferior to clopidogrel by 1.4 times. Discussion: Benzimidazole derivatives with a hindered phenolic substituent in their structure exhibited antiplatelet and antioxidant properties. It was established that the compounds with high antiplatelet activity demonstrated the pronounced antioxidant action. Conclusion: The chemical class of benzimidazole derivatives with a hindered phenolic substituent in their structure is promising for the search for new antiaggregant and antioxidant drugs

Relationship between intraocular pressure lowering effect and chemical structure of imidazo[1,2-a]benzimidazole and pyrimido[1,2-a]benzimidazole derivatives

This article contains data that relate to the study carried out in the work of Marcus et al. (2018) [1]. Data represent an information about pharmacophore analysis of imidazo[1,2-a]benzimidazole and pyrimido[1,2-a]benzimidazole derivatives and results of construction of the relationship between intraocular pressure (IOP) lowering activity and hypotensive activity of imidazo[1,2-a]benzimidazole and pyrimido[1,2-a]benzimidazole derivatives using a multilayer perceptron artificial neural network. In particular, they include the ones listed in this article: 1) table of all pharmacophores of imidazo[1,2-a]benzimidazole and pyrimido[1,2-a]benzimidazole derivatives that showed IOP lowering activity; 2) table of all pharmacophores of the compounds that showed absence of IOP lowering activity; 3) table of initial data for artificial neural network analysis of relationship between IOP activity and hypotensive activity of this chemical series; 4) graphical representation of the best neural network model of this dependence; 5) original txt-file of results of pharmacophore analysis; 6) xls-file of initial data for neural network modeling; 7) original stw-file of results of neural network modeling; 8) original xml-file of the best neural network model of dependence between IOP lowering activity and hypotensive activity of these azole derivatives. The data may be useful for researchers interested in designing new drug substances and will contribute to understanding of the mechanisms of IOP lowering activity. Keywords: QSAR, In silico drug design, Intraocular pressure;, Intraocular pressure lowering activity, Hypotensive activity;, Imidazo[1,2-a]benzimidazoles, Pyrimido[1,2-a]benzimidazoles, Pharmacophore analysis, Artificial neural network modelin