Semi-synthesis Of Nosiheptide Analogs Based On Partial Modification Of Dehydroalanine

Natural products and their derivatives have always been an important source of drug development.Their complex and unique structure promotes the development and optimization of various drugs,and plays an important role in the research of anti-cancer,antiviral,antibacterial,antimalarial and insecticide drugs.Natural products refer to the components in animals,plants or microorganisms or their metabolites,as well as many endogenous chemical components in humans and animals.Natural products and their semi-synthetic analogues have been used as the source of new drug candidates with various pharmacological activities and have been extensively studied.In the past 40 years,these two types of compounds accounted for 25% of all approved new drugs.It is also worth noting that semi-synthetic analogs accounted for the main part(21%).Therefore,the rationalization of using semi-synthetic methods to obtain natural product analogs is of great significance to the screening of new drugs and clinical research.As a natural product,Nosiheptide(NOS)has excellent antibacterial activity,so it has been studied and reported by many scientists.NOS has a hydroxypyridine ring center,which is connected by a thiazole ring to form a macrocyclic structure,and it contains an indole acid side ring and a dehydroalanine side chain connected by a thiazole ring.Previous studies have shown that although NOS has good antibacterial activity,due to its insufficient physical and chemical properties,it is difficult to play a role in clinical medicine.Therefore,the relatively active side chains of NOS reaction sites can be semi-synthetically modified to obtain new analogs,in order to improve the poor physical and chemical properties of NOS.First,we screened 15 aniline derivatives as ligands for Michael adducts,and then synthesized 15 NOS analogs: 2a-2e,3a-3e,4a-4e,all analogs have higher The yield.In the early stage of the reaction,when aniline was directly reacted with NOS at 50 ℃ with a mixture of chloroform and methanol(volume ratio = 9:1),no product was obtained.Interestingly,by using triethylamine as the catalyst,the yield of NOS analogs has been improved,and when the strong base catalyst 1,8-Diazabicyclo[5.4.0]undec-7-ene(DBU)is used,NOS broke down.Finally,by using 1,4-Diazabicyclo[2.2.2]octane;triethylenediamine(DABCO)as a catalyst to react with NOS,various Michael adducts can be obtained with a yield of 75%-92%.And it can be understood from the yield that the electronegativity and radius of different substituents on aniline also have different effects on its nucleophilicity.Finally,we obtained a series of pure analogues using column chromatography separation and semi-preparative HPLC separation methods,and confirmed their structures by high-resolution mass spectrometry and nuclear magnetic resonance.In the antibacterial activity test,we use three kinds of gram-positive bacteria:vancomycin-resistant enterococcus(VRE),methicillin-resistant Staphylococcus aureus(MRSA)and Staphylococcus aureus(ATCC 25923)to evaluate the effectiveness of analogs Antibacterial activity.What is exciting is that all our synthetic analogues have not lost their activity.Among them,compound 3c showed the best antibacterial activity.Compared with the parent compound NOS,its antibacterial activity against VRE,MRSA and ATCC25923 were increased by 4 Times,20 times and 2 times.The results show that the use of aromatic amines to modify the side chain of NOS can improve its antibacterial activity to varying degrees,especially for MRSA.Finally,we used the molecular docking method to analyze the binding of NOS and its analogues to the target.The antibacterial mechanism of NOS is that it targets bacterial ribosomes and binds to the 50 S subunit 23 S r RNA-L11 protein complex,thereby inhibiting protein synthesis in bacteria.We use the Meastro software to perform molecular simulation docking of NOS with its analogues and receptor proteins.Interestingly,the results of molecular docking are basically consistent with the results of the antibacterial activity test.Then we analyzed the molecular interaction between the receptor and the ligand 3c.Further analysis showed that hydrophobic interactions,hydrogen bonds,and π-π stacking are the main interactions that promote the binding of 3c to the target,which may be stronger The reason for the antibacterial activity.In summary,from the perspective of semi-synthesis of natural product analogues,this subject modified the dehydroalanine side chain of NOS and obtained a series of analogues with better antibacterial activity.This topic makes our research on NOS more in-depth and lays the foundation for obtaining NOS analogs that can play a role in clinical practice.