Consensus Ensemble Multitarget Neural Network Model of Anxiolytic Activity of Chemical Compounds and Its Use for Multitarget Pharmacophore Design.

A classification consensus ensemble multitarget neural network model of the dependence of the anxiolytic activity of chemical compounds on the energy of their docking in 17 biotargets was developed. The training set included compounds thathadalready been tested for anxiolytic activity and were structurally similar to the 15 studied nitrogen-containing heterocyclic chemotypes. Seventeen biotargets relevant to anxiolytic activity were selected, taking into account the possible effect on them of the derivatives of these chemotypes. The generated model consistedof three ensembles of artificial neural networks for predicting three levels of anxiolytic activity, with sevenneural networks in each ensemble. A sensitive analysis of neurons in an ensemble of neural networks for a high level of activity made it possible to identify four biotargets ADRA1B, ADRA2A, AGTR1, and NMDA-Glut, which were the most significant for the manifestation of the anxiolytic effect. For these four key biotargets for 2,3,4,5-tetrahydro-11H-[1,3]diazepino[1,2-a]benzimidazole and [1,2,4]triazolo[3,4-a][2,3]benzodiazepine derivatives, eight monotarget pharmacophores of high anxiolytic activity were built. Superposition of monotarget pharmacophores built two multitarget pharmacophores of high anxiolytic activity, reflecting the universal features of interaction 2,3,4,5-tetrahydro-11H-[1,3]diazepino[1,2-a]benzimidazole and [1,2,4]triazolo[3,4-a][2,3]benzodiazepine derivatives with the most significant biotargets ADRA1B, ADRA2A, AGTR1, and NMDA-Glut.

Amino Derivatives of Diaryl Pyrimidines and Azolopyrimidines as Protective Agents against LPS-Induced Acute Lung Injury.

The problem of lung damage originating from excessive inflammation and cytokine release during various types of infections remains relevant and stimulates the search for highly effective and safe drugs. The biological activity of the latter may be associated with the regulation of hyperactivation of certain immune cells and enzymes. Here, we propose the design and synthesis of amino derivatives of 4,6- and 5,7-diaryl substituted pyrimidines and [1,2,4]triazolo[1,5-a]pyrimidines as promising double-acting pharmacophores inhibiting IL-6 and NO. The anti-inflammatory activity of 14 target compounds was studied on isolated primary murine macrophages after LPS stimulation. Seven compounds were identified to inhibit the synthesis of nitric oxide and interleukin 6 at a concentration of 100 µM. The most active compounds are micromolar inhibitors of IL-6 secretion and NO synthesis, showing a minimal impact on innate immunity, unlike the reference drug dexamethasone, along with acceptable cytotoxicity. Evaluation in an animal model of acute lung injury proved the protective activity of compound 6e, which was supported by biochemical, cytological and morphological markers.

Design, Synthesis and Pharmacological Evaluation of Novel C2,C3-Quinoxaline Derivatives as Promising Anxiolytic Agents.

A new series of quinoxaline derivatives, 2a-4b, were synthesized and their anxiolytic potential was evaluated in vivo using elevated plus maze (EPM), open field (OF) and light-dark box (LDB) techniques. According to the results of the EPM, four active compounds were found in 2a, 2b, 2c, 4b. Their anxiolytic properties were confirmed in terms of LDB and the most active was compound 2b. In the OF, only 2c had an influence on the locomotor activity of the rodents. Thus, the most promising substance was determined; this was 2b, which has the structure of 2-(2-{[3-(4-tert-butylphenyl)quinoxaline-2-yl]methyl}-4,5-dimethoxyphenyl)-N-methylethan-1-amine hydrochloride. The obtained data were analyzed with the pharmacophore feature prediction approach, which made it possible to compare the structures of the studied compounds with the reference drug diazepam, and to determine the contribution of pharmacophores to the manifestation of the activity under study. ADMET analysis was carried out for compound 2b and the acute oral toxicity of this substance was also tested in vivo. As a result of the study, a promising compound with a high anxiolytic effect and low level of toxicity 2b was found, which is of interest for further preclinical study of its properties.

Synthesis and Pharmacological Evaluation of Novel 2,3,4,5-tetrahydro[1,3]diazepino[1,2-a]benzimidazole Derivatives as Promising Anxiolytic and Analgesic Agents.

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.

Searching for new anxiolytic agents among derivatives of 11-dialkylaminoethyl-2,3,4,5-tetrahydrodiazepino[1,2-a]benzimidazole.

A study on the anxiolytic activity of the new derivatives of 11-dialkylaminoethyl-2,3,4,5-tetrahydrodiazepino[1,2-a]benzimidazole, containing privileged scaffolds of benzodiazepine and benzimidazole in their structure, was conducted. The cytotoxic properties of low levels of six compounds were preliminary determined in vitro using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide test. The screening of these substances for anxiolytic activity was conducted using elevated plus maze (EPM) test in vivo, and DAB-21 was found to be the most active compound. The acute toxicity of DAB-21 was determined as less toxic than that of diazepam. The dose-dependent effect of the most active compound revealed a minimum dose of 1.26 mg/kg, which resulted in the maximum counterphobic effect. The effect of DAB-21 was superior in a number of tests compared with that of diazepam, which indicated a high level of tranquilizing activity for DAB-21. The results of in silico docking analysis suggest that DAB-21 should have a slightly lower anxiolytic activity than diazepam, but should exhibit greater specific affinity for the benzodiazepine site of the GABAA receptor, in comparison with its GABA-binding site. The interaction between DAB-21 and flumazenil in terms of EPM verifies the GABAergic mechanism of action of DAB-21. Our results highlight the potential of 11-dialkylaminomethyl-2,3,4,5-tetrahydrodiazepino[1,2-a]benzimidazoles as promising compounds in the search for new highly effective anxiolytics.