Diversity Oriented Synthesis And Biological Activity Of Natural Product Like Drug Molecules

Natural products widely exist in nature.They have a variety of biological activities,such as anti-bacterial,anti-tumor,etc,which are precious wealth brought by nature to human beings.It is an important method to discover and develop practical drugs by using natural products or their novel structures.Among them,natural-like drug molecules have always been the hot spot of chemical and biological research,Using a Diversity-Oriented Synthesis strategy to efficiently construct a library of natural small molecule drugs to meet the needs of drug screening is an important approach for drug development.In this dissertation,starting with inexpensive,readily available,and highly reactive diversity-oriented synthetic leader molecules,by using efficient,concise,and environmentally friendly synthetic strategies to construct six types of natural product-like drug molecules.While discussing drug background,synthetic methods,and drug activity,the design synthesis strategy is also studied and discussed in detail.This dissertation is divided into seven chapters.In the first chapter,the research background and general situation of natural product drug molecules and natural product-like small molecule drugs are being reviewed,the application background and important role of Diversity-Oriented Synthesis strategy in the research and development of natural product-like drug molecules are introduced,and the selection and application of synthesis leading molecules of this strategy are summarized.In the second chapter,a novel cascade reaction was developed for the synthesis of pyridin-2-one derivatives.Four types of pyridin-2-ones with a novel structure bearing quaternary centers,spiro rings,extra-ring double bond were synthesized by using the readily available substrate 2-cyanoacetamide as synthon and reacting with various ketone via multicomponent one-pot reaction under solvent-free conditions(Scheme 1).The advantages of this approach include no solvents,simple and practical operation,high yields,and the products possess potential biological activity.In the third chapter,a new approach for the construction of functionalized polysubstituted pyridine derivatives using 2-cyano-3-phenylacrylamide as substrate via Ag2CO3-catalyzed [4+2] cyclization strategy under base promotion was established(Scheme 2).The synthesis method can realize the metal-catalyzed [4+2] cyclization reaction only through a non-transition metal catalyst in ethanol,which is green and environmentally friendly.At the same time,the synthesis route is simple and efficient,and the raw materials are cheap and readily available.In the fourth chapter,a series of aryl substituted 2-aminopyridine derivatives were synthesized by the reaction of 1,1-enediamine with ?-,?-unsaturated compounds(Scheme 3).The synthesis method only needs to be performed in the green solvent ethanol,the reaction conditions are mild,the synthesis route is simple and efficient,and it also has high regioselectivity.In the fifth chapter,a method for the synthesis of functional dimerized pyrrolidone derivatives by the reaction of 1,1-enediamine and benzaldehyde was established(Scheme 4).The synthesis of 2-aminopyrrolones 3 was attained by two-component cascade reaction,and was further oxidized by oxygen for highly diastereoselective synthesis of dimerized pyrrolidone derivatives 4 via crystallization in air.This strategy provides an environmentally friendly,atomically economic,efficient,and highly diastereoselective route to construct vicinal quaternary carbons centers through metal-free Csp3-H bond coupling reaction.In the sixth chapter,a series of spirocyclic indanone derivatives with [2.2.2]bridged core skeleton were synthesized by triethylamine promoted domino multicomponent reaction of aromatic aldehydes and 1,3-indanedione(Scheme 5).In this synthetic strategy,the active cyclic diene obtained through the cyclotrimerization of 1,3-indanedione reacts with 2-arylidene-1,3-indanediones as a dienophiles by [4+2]Cycloaddition Diels-Alder reaction.It provides a simple,efficient,and highly diastereoselective approach for the synthesis of indone derivatives with spiro and bridged rings.In the seventh chapter,a method for the construction of a series of polyhalo cyanoarylamine derivatives by a nucleophilic substitution reaction between polyhalo1,3-isophthalonitrilesre and aromatic amines was established(Scheme 6).The antibacterial activity and biomechanism were studied systematically.The antibacterial activity of optimizatio compounds 4b and 4c are orders of magnitude better than that of marketed drugs,and they are a promising antibacterial candidate because their antibacterial mechanism is different from conventional drugs.