The synthesis and study of novel heterocyclic compounds is of ongoing relevance as scientists continuously strive to improve the efficiency and accuracy of drugs. The development of new active substances for drugs is constantly challenged by the need to design a drug that is effective and binds selectively to the drug target. On the other hand, the substance should be as non-toxic as possible to humans and not cause side effects. Although theoretical computational programmes are increasingly being used for this purpose, they are not a sufficient substitute for testing the actual compounds in laboratories. Comparison of the results of theoretically calculated activity with the activity of the compounds actually tested is still very relevant. In this way, knowledge is being built up and algorithms for such calculation programmes are being improved.
It has been observed that derivatives with two or more heterocycles are safer, cause fewer side-effects. The inclusion of target functional groups enables the development of specificity. The aim of this project was to obtain 1,3,4-oxadiazole analogues capable of acting on the enzyme succinate dehydrogenase (SDH). Mutations in succinate dehydrogenase are believed to be responsible for the progression of some cancers, as excessive amounts of succinate accumulate in the cytosol and intracellular fluid of cells leading to tumour formation.
In collaboration with researchers at Palacký University, an initial theoretical library of 2-(heteroaryl)-5-(alkylthio)-1,3,4-oxadiazole derivatives has been developed and a theoretical in-silico study of their interaction with SDH has been performed. The most selective compounds were selected, synthesis of them was performed and in-vitro studies were carried out by Palacký University scientists.
Preliminary results of the bioassays show that a correlation between the theoretical calculations and the experimental results can be observed. In order to reach reliable conclusions, the library of compounds was extended by the synthesis of 2-heteroaryl-5-(acylthio)-1,3,4-oxadiazole derivatives.