Vasyl S. Vdovin

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

Aurone derivatives possessing a wide range of biological activities are of high interest in medicinal chemistry. Carboxylated aurones were found previously to inhibit xanthine oxidase, which is a potential target for treatment of hyperuricemia and gout. In this paper, a series of B-ring nitro-substituted aurone derivatives were studied in vitro as inhibitors of this enzyme. The introduction of hydroxyl group into the B-ring of nitro-functionalized aurones resulted in significant increase of their inhibitory potency. At the same time, aurones chlorinated at ring A and containing nitro and hydroxyl groups at ring B showed only slightly increased inhibition effect. The kinetic studies and molecular docking calculations were carried out to explain the inhibition mechanism of xanthine oxidase by the nitro-substituted aurone derivatives

Background. Serine/threonine protein kinase CK2 is involved in the regulation of a number of cellular functions such as cell growth, proliferation, differentiation and apoptosis. Increased activity of CK2 is associated with the development of different types of cancer, inflammatory response, pain and virus infections. Therefore, protein kinase CK2 is an attractive molecular target for the development of small-molecular inhibitors which can be important compounds for pharmaceutical application. Objective. The main aim of this research is to identify novel chemical class of CK2 inhibitors with good lead-like properties. Method. In order to find novel CK2 inhibitors we have performed virtual screening experiments using Autodock software. Best-scored compounds were tested in vitro using P32 radioactive kinase assay. Results. We have identified small-molecular inhibitors of protein kinase CK2 among the derivatives of 1,3-thiazole-5-carboxylic acid. The most active compound inhibits CK2 with IC50 value of 0.4 µM. Ligand efficiency for studied derivatives of 1,3-thiazole-5-carboxylic acid is in the range from 0.45 to 0.56 kcal/mol/non-hydrogen atom. Conclusion. Considering the fact that the lower limit for ligand efficiency parameter is 0.3, the identified CK2 inhibitors among the derivatives of 1,3-thiazole-5-carboxylic acid are excellent candidates for further lead optimization.