Construction Of Molecular Library Based On C-N/P Bond And Its Application In Drug Discovery

Drug discovery has always been one of the core parts of the long value chain of drug development,and it has undergone profound evolution,with various new methods and technologies emerging constantly.However,synthetic chemistry remains a key factor in drug development.In the past few decades,several scientists have won Nobel Prizes for inventing breakthrough synthetic methods that have had a wide-ranging impact on multiple fields.At the same time,they have also opened up new directions for research in medicinal chemistry.Synthetic chemistry has always been an important tool in the discovery of new drugs,and new synthetic methods can accelerate the synthesis of drug molecules and expand the chemical space of drug molecules.Despite the progress made in synthetic chemistry,the drug development process still relies too much on a few classic reactions due to some synthetic methods having harsh reaction conditions,poor functional group compatibility,environmental pollution,and other objective factors(money,time,etc.),which limit the speed and breadth of molecular design.Therefore,it is necessary and urgent to develop synthetic methods that are mild,environmentally friendly,economically efficient,and beneficial to drug discovery.This paper first outlines the significant role of synthetic chemistry in drug discovery,as well as representative nitrogen-containing heterocyclic and phosphorus-containing drug molecules.It summarizes in detail the research progress on constructing C-N bonds and C-P bonds(Chapter 1).Based on the research foundation of predecessors and aiming at the deficiencies and limitations of current methods,this paper has developed two methods for constructing C-N bonds(Chapter 2)and C-P bonds(Chapter 3)under mild conditions,and has constructed libraries of molecules with‘structural diversity’ and ‘drug-likeness’.From these libraries,lead molecules with potential biological activity were selected,providing a new opportunity for the discovery of new anticancer and antibacterial active molecules.In the C-N bond construction,given the advantageous position of indole and imidazole structures in medicinal chemistry,this thesis developed a simple and efficient sodium hypochlorite-mediated cross-coupling strategy between indole and imidazole derivatives.This method is easy to operate,has mild conditions,and a wide range of substrates,enabling modular coupling of the two advantageous frameworks in a short period of time.Furthermore,by adjusting the types of substrates,diverse product synthesis and post-modification of small molecule drugs and peptides can be achieved.Additionally,through preliminary activity evaluation,lead molecules with potential biological activity were identified.In the method for constructing C-P bonds,this paper uses the Michael addition reaction between dehydroalanine and pentavalent organic phosphorus reagents to synthesize phosphorus-containing non-natural amino acids and phosphorylated modifications of peptides.This method is simple to operate,with inexpensive and readily available substrates,and good chemical selectivity,which produces a variety of phosphorylated oligopeptides at excellent yields.In addition,given the unique properties of the phosphorus element,this paper introduces a phosphate group into antibacterial short peptides and screens out phosphated antibacterial peptides with strong broad-spectrum antibacterial activity.Compared to the parent peptides,the antibacterial activity of the phosphate-containing antibacterial peptides against Gramnegative bacteria increased by 2-8 times,while maintaining almost the same antibacterial activity against Gram-positive bacteria and improving the antibacterial activity against fungi.This method provides a new idea and approach for the construction of phosphorus-containing peptides and the development of new phosphate-containing antibacterial peptides.Finally,the thesis summarizes the current achievements of the above research and provides further prospects for future research based on development trends.