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

鉴于血吸虫病和癌症是对医生、药剂师和化学家构成挑战的两种疾病，本联合提议的研究旨在开发新的简便合成方法来开发新的抗癌和抗血吸虫药物。目前，环有机过氧化物是非常有前途的多种药物的支架材料，具有不寻常的作用机制。因此，第一个目标是开发合成具有O-O片段的稳定化合物的方法，该方法可能提供具有抗癌和抗寄生虫活性的先导结构。重点研究了以下几个方面的内容：合成结构新颖、稳定的含氮过氧化物，特别是环状氮氧化物和酰基过氧化物等。现有的合成环状过氧化氢的方法大多是基于酮与过氧化氢的缩合或不饱和部分的臭氧分解。在这个项目中，我们将利用光氧化还原和电化学法在已发现的自由基反应的基础上提出合成有机过氧物的新方法。由于大多数已被批准的药物都含有杂环，因此杂环化学的大量研究集中在开发新的骨架和新的方便高效的合成方法上。在环境方面以及在减少成本和潜在危险废物方面，这种综合战略是可取的。因此，该联合项目的第二个目标是开发简便和环境友好的多步多米诺骨牌反应，以合成具有和不具有季碳中心的前所未有的融合喹唑啉-硫代海因杂环，展示抗癌和抗血吸虫活性。手性Brnsted酸催化方法将被开发用于高对映选择性的季碳中心的形成。在发现杂交物甚至比单体更有效后，许多研究人员开始考虑生物活性物质的杂交物也可以克服多药耐药性。这一新概念受到自然本身的启发，构成了与不同疾病作斗争的巨大机会。在这个项目中，计划合成单体药物的杂化化合物(新的稳定的过氧物和稠合杂环化合物，通过其系统的生物学测试预先选择)。通过选择的母体化合物通过不同的连接物进行杂交，有望开发出有效的抗癌和抗寄生虫药物的基本先导结构(第三个目标)。将研究杂交药物单体组分之间的不同连接物，以找出哪种类型的连接物更适合获得最强的抗癌或抗寄生虫活性。连接剂的范围将达到从酯、醚、酰胺、三氮唑和其他部分。我们打算将有机催化的点击反应整合到1，2，3-三氮唑连接物的合成中。

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.