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The cytotoxic effect of several synthetic nitrogen-containing heterocyclic compounds on cultures of tumour and normal cells and the calculation of their ADME, QSAR, and DFT pharmacological properties The aim. The purpose of our work was to investigate the cytotoxic influence of some synthetic nitrogen-containing heterocyclic compounds, namely imidazole, aurones, and triazole on the culture of tumour cells of melanoma mouse B16, human glioma U251 and normal HEK293 and their ADME, QSAR, and DFT pharmacological properties calculation. Materials and methods. The estimation of cell viability in the conditions of influence of the investigated drugs was carried out by MTT. ADME data screening was performed by the SWISSADME server. QSAR calculations were performed on Way2Drug servers (cancerogenicity was predicted with ROSC-Pred, metabolism -- with RA, side effects of drugs were investigated using AdverPred server, LD50 were predicted with Gusar software). The calculation of the functional density (DFT) was carried out using B3LYP and the functional of the exchange-correlation with the base set of 6-31 G (D, P) in the MMFF94 force field in the Avogadro program. The results. It was found that compounds 1 and 2 are toxic for normal cells HEK293, compounds 3, 4, 6 and 7 are low-toxic, and 5 does not inhibit cell growth at all. Our study has demonstrated that in the case of tumour cell line U251 compounds 2, 3 and 7 are non-toxic in general, and substances 1, 4, 5, 6 and 7 have significant toxicity. In a case of cancer cell line B16, compounds 1, 2, 4, 5, and 6 are toxic, and compound 7 is cytotoxic at any concentration. The test compounds (1-7) possess drug-like properties. All compounds meet Lipinski's "rule of five" criteria. The BOILED-Egg model demonstrates that compound 3 may penetrate blood-brain barrier, all compounds except 1 can be absorbed in the intestine, 2 and 5 can be cleaved in the gastrointestinal tract and 3, 4, 6, and 7 have resistance to digestive enzymes. The analysis of metabolism showed that these compounds can mainly be metabolized by mechanisms of N- and O-glucuronidation and C-oxidation. The obtained data indicate that the smallest toxic effect is achieved with intravenously introduced compounds, and the largest toxicity is achieved with oral administration for compounds 3, 4, 5 and 6. The compounds 1 and 3 are completely noncarcinogenic, the other compounds can affect thyroid glands and hematopoietic system. This result requires further research when introduced into practical application. DFT calculations have shown that all investigated compounds are stable and reactive. Conclusions. Differences in the sensitivity of cell lines and dose-dependent effects of compounds detected during the study should be considered when calculating the optimal working concentrations of drugs. The results of the study are necessary to understand toxic effects on the cell lines B16, HEK293, and U251 and their further use for preclinical studies [ABSTRACT FROM AUTHOR]

Apoptosis signal-regulating kinase 1 (ASK1) has recently emerged as an attractive molecular target for pharmaceutical intervention. Several classes of small-molecular ASK1 inhibitors have been identified. In this article, we analysed the binding of small-molecular inhibitors from different chemotypes with ASK1 using molecular dynamic simulations. The umbrella sampling technique was used to calculate the binding free energy (ΔG) for these compounds with ASK1 ATP-binding pocket. According to the obtained results, umbrella sampling gave correct ranking of the binding affinities for investigated inhibitors relative to their experimental pIC50 values and can be useful for further structure-based design of ASK1 inhibitors to accelerate lead optimisation. Trial registration: ClinicalTrials.gov identifier: NCT02466516.. [ABSTRACT FROM AUTHOR]

Staphylococcus aureus (S. aureus) is a causative agent of many hospital- and community-acquired infections with the tendency to develop resistance to all known antibiotics. Therefore, the development of novel antistaphylococcal agents is of urgent need. Sortase A is considered a promising molecular target for the development of antistaphylococcal agents. The main aim of this study was to identify novel sortase A inhibitors. In order to find novel antistaphylococcal agents, we performed phenotypic screening of a library containing 15512 compounds against S. aureus ATCC43300. The molecular docking of hits was performed using the DOCK program and 10 compounds were selected for in vitro enzymatic activity inhibition assay. Two inhibitors were identified, N,N-diethyl-N′-(5-nitro-2-(quinazolin-2-yl)phenyl)propane-1,3-diamine (1) and acridin-9-yl-(1H-benzoimidazol-5-yl)-amine (2), which decrease sortase A activity with IC50 values of 160.3 µM and 207.01 µM, respectively. It was found that compounds 1 and 2 possess antibacterial activity toward 29 tested multidrug resistant S. aureus strains with MIC values ranging from 78.12 to 312.5 mg/L. These compounds can be used for further structural optimization and biological research. [ABSTRACT FROM AUTHOR]