Synthesis And Biological Evaluation Of Azamacrolide Comprising Triazole Moiety As Quorum Sensing Inhibitors Or Fungicides

In this dissertation,novel azamacrolides were synthesized.Azamacrolides comprising triazole moiety urethane,triazole ring and amide structures.The activities of the difference azamacrolides ring(12,13 and 16)was studied.All the compounds were evaluated for their quorum sensing inhibitor activities on the Agrobacterium tumefaciens.It was found the inhibition rate of compound Z12-3 at 200mg/L(0.45 mM)can reach 67%.The antifungal activity of these compounds against Alternaria solani,Botrytis cinerea,Valsa mali,Macrophoma kuwatsukai,Gibberella zeae and Sclerotinia sclerotiorum were evaluated and found that compounds Z13-5 and Z16-10 showed the most prominent antifungal activity comparable to commercial fungicide Carbendazim against at least five of the six fungi.In order to explore the mechanism of the compounds,the potential binding modes between these molecules and the TraR QS receptor was performed by molecular docking.The results showed that the two nitrogen atoms in the triazole ring of Z12-3 formed hydrogen bonds with GLN-2,and the carbonyl group(C=O)in the amide formed hydrogen bonds with water.It was worth noting that the carbonyl group on the macrolides formed hydrogen bonds with the G-106 base in the DNA.These azamacrolides may block quorum sensing expression through key amino acid residues or DNA bases in the TraR QS receptor by hydrogen-bonded.We found that the structure of the carbonyl(C=O)and triazole of the 4 side chain of Z12-3 in combination with the interactions with the amino acids(Trp4,Gln2,His3,Lys7 to TraR)and DNA of the LuxR type protein family.The quorum sensing inhibitors activity of these compounds tested on the Agrobacterium to inhibit the quorum sensing,and found that compounds Z12-(1,3,5,6),Z16-(1,3,5,6)and Z13-(2,4,5)showed significant quorum sensing inhibitors activity,and concluded that if the compound number of atoms on the maternal ring was even(odd)and the side chain substituent carbon chain was odd(even),this one’s inhibition activity would be well,if not,the inhibition activity would be low.In order to study the mechanism of the compounds,we attempted to synthesize a ruthenium-containing compound for the purpose of tracing,and developed an amide-selective reductive deuteration method.A practical and scalable single electron transfer reduction mediated by sodium dispersions have been developed for the reduction and reductive deuteration of tertiary amides.The chemoselectivity of this method highly depends on the nature of the proton donor.The challenging reduction via C-N bond cleavage has been achieved using Na/EtOH,affording alcohol products,while the use of Na/NaOH/H2O leads to the formation of amines via selective C-O scission.Sodium dispersions with high specific surface areas are crucial to obtain high yields and good chemoselectivity.This new method tolerates a broad range of tertiary amides.Moreover,the corresponding reductive deuterations mediated by Na/EtOD-d1 and Na/NaOH/D2O afford useful α,α-dideuterio alcohols and α,α-dideuterio amines with excellent deuterium content.