Cancer is one of the most common causes of death which is also a complex mutilfunctional illness with many factors that determine its occurrence. Therefore intensive research of new active substances is taking place, which could prove to be an effective drug for a variety of cancerous diseases present. Established targets used in the cancer treatment are enzymes from the family of the human DNA topoisomerases which are involved in the introduction of topological changes of the DNA molecule and are crucial for a successful cell division and cell survival. Human DNA topoisomerase IIα with its complex catalytic cycle provides various approaches to enzyme inhibition and consequently stop the growth of cancer cells. Due to serious adverse effects, especially cardiotoxicity, of some of the established topo IIα poisons used in therapy, new research is focused on the development of novel inhibitors that would act through alternative inhibition mechanisms in the complex catalytic cycle of this enzyme.In this work based on the previously performed structure-based design a new series of 3,5-disubstituted 1,2,4-oxodiazole was synthesized to target the ATP binding site on the topo IIα N- terminal domain and act as the human DNA topoisomerase IIα inhibitors. 3-aminobenzonitrile and 4-aminobenzonitrile were selected as starting materials. All synthesized compounds were evaluated using spectroscopic methods and their physicochemical properties were determined. Additionally, 7 commercially available derivatives structurally similar to the designed compounds were obtained. 8 synthesized compounds from this chemical class and commercially available disubstituted 1,2,4-oxadiazoles were tested in the in vitro topo IIα relaxation enzyme test to evaluate their inhibitory activity and obtain first information about the structure-activity relationship that would be important for further development. 5 compounds from the class 1,2,4-oxadiazoles showed initial inhibitory activity with a determined IC50 values below 1000 μM. Compound 4 proved to be the most promising having an IC50 of 140.2 μM. These compounds represent the first described compounds of this chemical class to exhibit an inhibitory effect on topoisomerase IIα. After analysis of the structure–activity relationship (SAR) data it has been found that for the inhibitory effect the most favorable position of the phenyl rings relative to the 1,2,4-oxadiazole skeleton is the meta-meta and that esters exhibited better inhibitory activity than corresponding acids. It was also evaluated which substituents are not favorable for the topo IIα inhibitory activity. The results of our work will be useful in further optimization of the disubstituted 1,2,4-oxodiazoles as a new class of the human topoisomerase IIα inhibitors with potential anticancer activity.
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