Research team of LV Xianhai, associate professor of Anhui Agricultural University: design and synthesis of targeted DNA toposomerase II antibacterial agent

In order to solve the problem of bacterial resistance, people need to use new ideas to find new antibiotics DNA topoisomerase II (DNA topoisomerase II) is a key enzyme in the nucleus It can catalyze the breaking and binding of DNA strand, thus regulating the topological state of DNA and participating in the regulation of DNA super helix structure template Therefore, bacterial DNA topoisomerase II as a target has been widely used in the development of antibacterial drugs Recently, Lu Xianhai, an associate professor of Anhui Agricultural University, has synthesized 70 coumarin derivatives (scheme 1) by using novobiocin as the precursor drug molecular skeleton and introducing a polysubstituted pyrazol ring The preliminary screening results showed that the activity of the new designed compound was better than that of ciprofloxacin and novobiocin This research result was published in EUR J Med Chem (DOI: 10.1016 / j.ejmech 2018.07.059) under the title of "new coumarin pyrazolecarboxamides derivatives as potential toposomerase II investors: design, synthesis and characteristic activity" Scheme 1 Design strategy of target molecular skeleton (source: EUR J Med Chem.) introduction to LV Xianhai, associate professor, Ph.D., associate professor, master tutor He received his bachelor's degree from Huaibei Normal University in 2002, and his master's degree from the Key Laboratory of green pesticide and Agricultural Bioengineering of the Ministry of education of Guizhou University in 2005 He studied with Academician song Bao'an and Professor Tang Wenming In 2017, he obtained a doctor's degree in agronomy from Anhui Agricultural University and studied under Professor Cao haiqun 2011-2012 domestic visiting scholar of National Key Laboratory of pharmaceutical biotechnology, Nanjing University, under the guidance of Professor Zhu Hailiang Since March 2018, he has been a public visiting scholar of Nanyang University of technology in Singapore and studied under Professor LOH Teck Peng Since 2005, he has been teaching in the school of science of Anhui Agricultural University, mainly engaged in the teaching and scientific research of organic chemistry, pharmaceutical chemistry and pesticide chemistry, with the research direction of targeted drug design and synthesis Frontier research achievements: the design and synthesis of targeted DNA topoisomerase II antimicrobial agents coumarins and quinolones, as the two major inhibitors of topoisomerase II, have gradually shown defects, so it is urgent to design and synthesize topoisomerase II inhibitors with new structures In recent years, scientists have found that pyrazofuran in natural pyrazol C-glycosides can be used as an antimicrobial agent targeting at topoisomerase Therefore, based on the structure of coumarins and pyrazoles, the author designed the framework of the target compounds and synthesized 70 compounds, and screened two compounds with excellent antibacterial activity, which have good inhibitory effect on topoisomerase The synthesis route of the target compound is shown as follows (Figure 1) According to different cross combinations of substituents, it is divided into eight series Firstly, coumarin carboxylic acid (4) with different substituents was synthesized by salicylaldehyde (1) with different substituents, and then pyrazole intermediates (6, 7) were obtained by phenylhydrazine with different substituents Finally, the target compound was synthesized in one pot in phosphorus oxychloride / pyridine system Reagentsand conditions: (a) piperidine, acetic acid, EtOH, 25 ℃ (b) reflux, 2 h (c)ethyl ( E )-2-cyano-3-ethoxyacrylate, H 2 O, NaOH, EtOH, 3 h, reflux (d) H 2 O , NaOH, EtOH, 3 h, reflux (e) 2-(ethoxymethyl)malononitrile,H 2 O, NaOH, EtOH, 3 h, reflux (f) POCl 3 , pyridine, Figure 1 Synthesis route of the target compound (source: EUR J Med Chem.) in order to further explore the activity of the compound, the author selected Staphylococcus aureus, Escherichia coli, Listeria and Salmonella, and carried out in vitro antibacterial activity experiments on the 70 compounds The author determined the antibacterial effect of the compound by measuring the minimum inhibitory concentration (MIC), and screened out two compounds with excellent antibacterial effect (Figure 2, 8v-c and 8v-k) The results of structure-activity relationship study show that most of the compounds designed and synthesized have antibacterial activity; when the benzene ring connected with pyrazole ring contains chlorine substituent, the antibacterial activity of the compounds can be greatly increased; when the benzopyran ring contains diethylamino group, the antibacterial activity is better In order to further determine which substituents play an important role in the activity of the compounds, the authors selected three compounds (8iii-k, 8v-c and 8v-k) with better activity in vitro antibacterial experiment to carry out the inhibition experiment of topoisomerase II and IV The experimental results show that when the compounds contain chlorine or diethylamino group, the inhibition effect of bacteria is better After the in vitro biological activity experiment, the author used the discovery Studio software to analyze the three-dimensional quantitative structure-activity relationship (3D-QSAR) and molecular docking of the compounds The results showed that compound 8v-c and 8v-k had the same amino acid residues in the same active site of topoisomerase II, and could closely bind to the target of topoisomerase II (PDB entry: 2xcs) (Figure 2) These results indicate that these compounds can be used as a potential topoisomerase II inhibitor, and provide valuable clues for the structural optimization of topoisomerase II inhibitors in the future Figure 2 Biological activity and molecular docking analysis (source: EUR J Med Chem.): the team designed and synthesized a number of compounds, successfully screened out compounds with excellent antibacterial activity, and provided important clues for the structural optimization of topoisomerase II inhibitors in the future This achievement was recently published on the European Journal of Medical Chemistry (DOI: 10.1016 / j.ejmech 2018.07.059) The thesis was mainly completed by Liu Hao, a graduate student, and LV Xianhai, an associate professor, was the corresponding author of the thesis The project is supported by National Natural Science Foundation of China (2132002), national key R & D project (2017yfd0600805) and Natural Science Foundation of Anhui Provincial Department of Education (kj2018a0162) Nowadays, people and scientific research have been paid more and more attention in the economic life China has ushered in the "node of science and technology explosion" Behind the progress of science and technology is the work of countless scientists In the field of chemistry, in the context of the pursuit of innovation driven, international cooperation has been strengthened, the influence of Returned Scholars in the field of R & D has become increasingly prominent, and many excellent research groups have emerged in China For this reason, CBG information adopts the 1 + X reporting mechanism CBG information, chembeangoapp, chembeango official microblog, CBG wechat subscription number and other platforms jointly launch the column of "people and scientific research", approach the domestic representative research group, pay attention to their research, listen to their stories, record their demeanor, and explore their scientific research spirit.