Synthesis, Antibacterial Evaluation And 3D-QSAR Of Yanglingmycin Derivatives In Vitro

China is a major agriculture country, agriculture is the root of China’s development, and the top priority of agriculture is farming. However, under the side effect of microorganisms,series of morphological, physiological and biochemical changes on the crops will happen,which may hinder the crops themselves and other crops’ normal process of growth and maturity, thus further affecting people’s economic benefit. Bacterial diseases are diseases caused by bacteria-infection, it has become one of the most important problems affecting agricultural production in our country. Therefore, controlling the crop bacterial diseases,thereby improving crops’ yield and quality is particularly significant.A novel antibacterial agent namely Yanglingmycin, was found in 2013 and successfully synthesized in 2014 by the researchers in Shaanxi Province Key Laboratory of Research and Development of Botanic Pesticide of Northwest A & F University. As an efficient and widespectrum antimicrobial, Yanglingmycin presented excellent inhibitory activity to many kinds of agricultural pathogens, such as Pseudomonas syringae pv. actinidiae, Ralstonia solanacearum. Yanglingmycin and its enantiomer were verified to have considerable antimicrobial activity. To find more facile, high-yield and low-cost synthetic route for large-scale preparation of Yanglingmycin racemate, and then further explore the antibacterial activity of these compounds, so it was decided to begin our efforts toward the preparation of the racemate and its 56 derivatives commenced with 2-hydroxybenzonitrile, and then evaluated their antimicrobial activity against eight common pathogen bacteria. The results are as follows:(1) 2-hydroxybenzonitrile used as a starting material in the first route, generated its imido ester trough a Pinner reaction, the imido ester reacted with serinol, then(±)Yanglingmycin was successfully synthesized. In the second route, 2-hydroxybenzonitrile and serinol were used as the reaction raw materials, with Na2CO3 as the base catalyzed the reaction, finally more efficiently synthesized(±)Yanglingmycin.(2)(±)Yanglingmycin was derivatized to 56 derivatives(including its 31 ester derivatives, 19 ether derivatives, a fluorinated derivative, and 5 different benzene substituted analogues of(±)Yanglingmycin), every compound was confirmed by the 1H-NMR, 13C-NMR and DEPT-135, all compounds were new compound.(3) Paper disc method was used to primarily evaluate the antibacterial activity of all compounds, with ampicillin sodium as the positive control, 57 compounds were determined their inhibitory activity against Bacillus cereus, Bacillus subtilis, Staphylococcus aureus,Pseudomonas aeruginosa, Escherichia coli, Pseudomonas syringae pv. actinidiae,Pseudomonas solanacearum, Ralstonia solanacearum under 10 μg drug-loading, derivative Dd3A2, Dd3A3, Dd3B7, Dd3B8 and Dd3C2 showed strong antibacterial activity.(4) Used ampicillin sodium and fosfomycin sodium as positive controls,(±)Yanglingmycin and its derivatives were tested their minimum inhibitory concentration(MIC) against eight kinds of bacteria mentioned above, utilizing micro-dilution method. The MIC values were in the range of 0.98-125 μg/mL, among which Dd3B8 and Dd3C2 presented the strongest inhibition toward Pseudomonas syringae pv. actinidiae and Pseudomonas solanacearum, the MIC values were 0.98 μg/mL, superior than the positive controls.(5) Based on the antibacterial activity data, we worked on 3D-QSAR of the data, and drew conclusions that increased the volume or enhanced the electronegativity on the alcoholic hydroxyl substituents’ corresponding parts of(±)Yanglingmycin, are conducive to improving the antibacterial activity of the derivatives, these findings might guide for the further related synthesis.