The aim was analysis of 4-thiazolidinones and related heterocyclic systems anticancer activity data and formation of some rational design directions of potential anticancer agents. Synthetic research carried out in Danylo Halytsky Lviv National Medical University (DH LNMU) allowed us to propose a whole number of new molecular design directions of biological active 4-thiazolidinones and related heterocyclic systems, as well as obtain directed library that numbers over 5000 of novel compounds. At the present time in vitro anticancer activity screening was carried out for more than 1000 compounds (US NCI protocol (Developmental Therapeutic Program), among them 167 compounds showed high antitumor activity level. For the purpose of optimization and rational design of highly active molecules with optimal «drug-like» characteristics and discovering of possible mechanism of action SAR, QSAR analysis and molecular docking were carried out. The ultimate aim of the project is creating of innovative synthetic drug with special mechanism of action and sufficient pharmacological and toxicological features. Some aspects of structure–activity relationships were determined and structure design directions were proposed. The series of active compounds with high anticancer activity and/or selectivity levels were selected

The synthesis and evaluation of the anticancer activity of 3′-aryl-5′-arylidene-spiro[3H-indole-3,2′-thiazolidine]-2,4′(1H)-diones and spiro[3H-indole-3,2′-thi-azolidine]-2,4′(1H)-dione-3′-alkanoic acid esters were described. The structure of the compounds was determined by 1H and 13C NMR and their in vitro anticancer activity was tested in the National Cancer Institute. Among the tested compounds, (5′Z)-5′-(benzylidene)-3′-(4-chlorophenyl)spiro[3H-indole-3,2′-thia-zolidine]-2,4′(1H)-dione (IIa) and (5′Z)-3′-(4-chlorophenyl)-5′-[4-(1-methylethyl)-benzylidene]spiro[3H-indole-3,2′-thiazolidine]-2,4′(1H)-dione (IIb) were superior to other related compounds.

The emergence of drug-resistant bacterial strains continues to be one of the major challenges of medicine. For this reason, the importance of searching for novel structures of antibacterial drugs chemically different from the currently known antibiotics is still of great importance. In this study, we synthesized the thiosemicarbazide and 1,3,4-thiadiazole derivatives and tested them for antibacterial activity. In in vitro tests, we examined the activity of the synthesized substances against Gram-positive and Gram-negative bacteria strains. While all 1,3,4-thiadiazoles tested lacked significant activity, the antimicrobial response of the thiosemicarbazides was moderate and it was also dependent on the type and position of the substituent on the phenyl ring. The highest activity towards all Gram-positive bacteria strains was shown by all three linear compounds containing the trifluoromethylphenyl group in the structure. The MIC (minimum inhibitory concentration) values were in the range of 3.9–250 µg/mL. Additionally, we try to explain the mechanism of the antibacterial activity of the tested compounds using the molecular docking to DNA gyrase and topoisomerase IV, following previous reports on the molecular basis of the activity of thiosemicarbazides. Docking simulations allow the purposing dual mechanism of the antibacterial activity of the synthesized compounds through inhibition of topoisomerase IV DNA gyrase with the moderate prevalence of the topoisomerase pathway.

We designed and synthesized the 1,3,4-thiadiazole derivatives differing in the structure of the substituents in C2 and C5 positions. The cytotoxic activity of the obtained compounds was then determined in biological studies using MCF-7 and MDA-MB-231 breast cancer cells and normal cell line (fibroblasts). The results showed that in both breast cancer cell lines, the strongest anti-proliferative activity was exerted by 2-(2-trifluorometylophenylamino)-5-(3-methoxyphenyl)-1,3,4-thiadiazole. The IC50 values of this compound against MCF-7 and MDA-MB-231 breast cancer cells were 49.6 µM and 53.4 µM, respectively. Importantly, all new compounds had weaker cytotoxic activity on normal cell line than on breast cancer cell lines. In silico studies demonstrated a possible multitarget mode of action for the synthesized compounds. The most likely mechanism of action for the new compounds is connected with the activities of Caspase 3 and Caspase 8 and activation of BAX proteins.

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