Development of efficient di- and multi-component reactions for synthesis of versatile heterocycles and their hybrid compounds with antiparasitic, fungicidal and cytotoxic activities

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The present joint proposed research is aimed at development of novel facile synthetic methods towards new anticancer and antischistosomal agents, since schistosomiasis and cancer are two diseases that pose a challenge to physicians, pharmacists and chemists.At present, cyclic organic peroxides are very promising scaffolds for a wide range of drugs with an unusual mechanism of action. The first objective is, therefore, development of methods for synthesis of stable compounds with an O-O fragment which might provide lead structures with anticancer and antiparasitic activities. We will focus on the following studies: synthesis of structurally novel stable nitrogen-containing peroxides, especially cyclic azaperoxides and acyl peroxides and other peroxides. Most of existing methods for cyclic peroxide synthesis are based on condensation of ketones with hydrogen peroxide or ozonolysis of unsaturated moieties. In this project, new methods for synthesis of organic peroxides based on discovered free-radical reactions employing photoredox and electrochemical approaches will be proposed.Since most of known approved pharmaceuticals contain heterocyclic rings, a great deal of research in heterocyclic chemistry is concerned with development of new frameworks and of new convenient and efficient synthetic methods for their formation. Such synthetic strategies are desirable concerning environmental aspects and with respect to reduction of costs and of potentially hazardous waste. Thus, the second objective of the joint project is development of facile and environmentally friendly multi-step domino reactions towards unprecedented fused quinazoline-thiohydantoin heterocycles with and without quaternary carbon centers, demonstrating anticancer and antischistosomal activities. Chiral Brønsted acid-catalyzed methods will be developed for highly enantioselective formation of quaternary carbon centers. After the discovery that hybrids can be even more effective than monomers, many researchers started to consider hybrids of bioactive agents also to overcome e.g. multidrug resistance. This new concept, inspired by nature itself, constitutes a great opportunity for the fight against different diseases. In this project, hybrids of monomeric drugs (new stable peroxides and fused heterocyclic compounds, preselected through their systematic biological examination) are planned to be synthesized. By hybridisation of selected parent compounds via various linkers, fundamental lead structures for appearance of efficient anti-cancer and antiparasitic drugs are expected to be developed (third objective). Different linkers between monomeric components of hybrid drugs will be investigated to find out which type of linker is more suitable to get the strongest anti-cancer or antiparasitic activities. The range of linkers will reach from ester, ether, amide, triazole and other moieties. We intend to integrate organocatalyzed click-reactions in the synthesis of 1,2,3-triazole linkers.