In recent years, researchers have often encountered the significance of the aberrant metabolism of tumor cells in the pathogenesis of malignant neoplasms. This phenomenon, known as the Warburg effect, provides a number of advantages in the survival of neoplastic cells, and its application is considered a potential strategy in the search for antitumor agents. With the aim of developing a promising platform for designing antitumor therapeutics, we synthesized a library of conjugates of 3,5-bis(arylidene)-4-piperidone and sesquiterpene lactones. To gain insight into the determinants of the biological activity of the prepared compounds, we showed that the conjugates of 3,5-bis(arylidene)-4-piperidone and sesquiterpene lactones, which are cytotoxic agents, demonstrate selective activity toward a number of tumor cell lines with glycolysis-inhibiting ability. Moreover, the results of molecular and in silico screening allowed us to identify these compounds as potential inhibitors of the pyruvate kinase M2 oncoprotein, which is the rate-determining enzyme of glycolysis. Thus, the results of our work indicate that the synthesized conjugates of 3,5-bis(arylidene)-4-piperidone and sesquiterpene lactones can be considered a promising platform for designing selective cytotoxic agents against the glycolysis process, which opens new possibilities for researchers involved in the search for antitumor therapeutics among compounds containing piperidone platforms.

The era of chemotherapy began in the 1940s, which is the basis of traditional antitumor approaches and, being one of the most high-tech treatment methods, is still widely used to treat various types of cancer. A promising direction in modern medicinal chemistry is currently the creation of hybrid molecules containing several pharmacophore fragments of different structures. This strategy is successfully used to increase the therapeutic efficacy of cytotoxic agents and reduce side effects. In this work, we synthesized 10 1-aryl derivatives of benzimidazole and benzotriazole and 11 hybrids based on them. Among the compounds obtained, the most promising hybrid molecules were diphenylamines, containing an amino group and a benzotriazole cycle in the ortho position to the bridging NH group, which showed significant cytotoxic activity, excellent antioxidant properties and the ability to suppress the migration activity of tumor cells. Taken together, our results demonstrate that substituted diphenylamine-based bipharmacophoric compounds may serve as a promising platform for further optimization to obtain effective antitumor compounds.

An effective method for synthesizing dihalogenated derivatives of condensed benzimidazole diones with a nodal nitrogen atom has been developed. As a result, five new heterocyclic quinones were obtained, which differed in the structure of the heterocycle annelated to imidazole, as well as the nature and arrangement of halogen atoms. A comprehensive analysis of the anticancer potential of new heterocyclic quinones revealed pronounced cytotoxic activity of the molecules against tumor cells. Using in silico methods for predicting activity spectra, it was found that the synthesized compounds are capable of interacting with a number of key targets that play an important role in oncogenesis, with the highest probability of binding to STAT3, the central regulator of cell growth, proliferation and metabolism. Experimental studies have shown that, despite the lack of pronounced ability to induce apoptosis, these substances effectively inhibit the activity of allosteric glycolytic enzymes, disrupting metabolic adaptation and energy balance of tumor cells. The obtained results expand the understanding of the molecular basis of the antitumor action of heterocyclic compounds and lay a solid foundation for their use as promising modulators of tumor cell metabolism.

Condensed benzimidazoledione derivativ es with a nodal nitrogen atom can become the basis for the development of clinical therapeutic agents for the effective treatment of oncological diseases. This requires research that includes the synthesis and study of the antitumor activity of compounds of this group. The aim. Search for new cytotoxic agents from a series of condensed benzimidazole diones with a nodal nitrogen atom. Materials and methods. The cytotoxic profile of the synthesized compound was evaluated using an MTT test based on the reduction reaction of tetrazolium salt (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide) by mitochondrial dehydrogenases of living cells to formazane crystals insoluble in water. The IC50 values of the cytotoxic effect, which are concentrations of a compound leading to the death of 50 % of cells in a sample, were determined as indicators of effectiveness. Result. The cytotoxicity of a new benzimidazole derivative, 7-bromo-8-chloro-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazole-6,9-dione, was demonstrated against two tumor cell lines: lung adenocarcinoma (A549) and breast adenocarcinoma (MCF-7). In turn, for normal human embryonic kidney cells (Hek-293), this compound was approximately 2.5 times less toxic. Conclusions. The r esults indicat e that fused benzimidazole derivatives with a nodal nitrogen atom are a promising class of compounds for the development of new antitumor agents with selective toxicity.