Study On The Design And Synthesis Of 1,4-Dihydropyrazine Derivatives

Bacterial resistance rates are rising and there is a lack of effective treatments for common bacterial infections,according to the World Health Organization’s（WHO）2020global drug resistance test data.Clinical manifestations include changes in the concentration of drugs used in the drug combination,leading to toxic side effects,the development of drug resistant strains and other risks.To deal with the problem of drug resistance,it is urgent to development new antibacterial drugs.1,4-dihydropyrazines are an important class of nitrogen heterocyclic compounds,which have good activities in antibacterial and diabetes treatment.More and more researchers use them as an electronic isoarray for structural modification.In order to find new antibacterial drugs,a series of 1,4-dihydropyrazine derivatives with 1,4-dihydropyrazine ring as skeleton were designed in this paper;By docking with PBP3 transpeptidase,16 target compounds were synthesized and their structures were confirmed;The antibacterial activities of target compounds 1h,1k,3e and3f were studied in vitro.44 1,4-diacyl-1,4-dihydropyrazine was designed by changing the p-styrene and intersite substituent on the pyrazine ring and benzoyl chlorophenyl ring,and the molecular docking study was carried out with bacterial PBP3 transpeptidase（4BJQ）.The docking results showed that the compound could fold 120.3-121.2°and embed the GLU340-ALA544 active site of 4BJQ to form the interaction force mainly composed of hydrogen bond,van der Waals force and hydrophobic force,thus achieving high compatibility.Sixteen compounds with good docking effect were selected for synthesis study.By studying the existing synthesis methods of 1,4-dihydropyrazine,the synthesis route was determined and optimized,and the best reaction conditions were obtained.Optimized purification method combined with column chromatography recrystallization.Sixteen derivatives of 1,4-diacyl-1,4-dihydropyrazine were synthesized and isolated,of which 14compounds have not been reported.The product structure was confirmed by ¹H NMR,and¹³C NMR and MS.The in vitro antibacterial activity of the samples as 1h,1k,3e and 3f was determined by double dilution method.The results showed that the MIC values of 1h,1k,3e and 3f against E.coli were all greater than 3.6 mg/m L.This suggest that the antibacterial activity of the samples was weak or no when the concentration was 3.6 mg/m L,which needed to be further studied.