Recently, Liang Jianhua group of North Institute of technology, chemistry and chemical engineering, combined azithromycin with quinolones, and obtained the first macrolide hybrid antibiotic with dual action mode of ribosome and topoisomerase, Synthesis and structure activity relationships of new 15 membered robots: quinolone / quinoline containing sidechains tethered to the C-6 position of azithromycin acylates, published in the top medical journal of Medical Chemistry (article link: https://doi.org/10.1016/j.ejmech.2020.112222). Drug resistant bacteria infection has become one of the main threats to human health. However, antibiotics are facing the dilemma of rapid development of drug resistance. Macrolides bind to the narrow new peptide channel of bacterial ribosome, thus blocking the protein output. Quinolone acts on topoisomerase to form enzyme DNA quinolone trisomic complex, which interferes with DNA replication. Based on the concept of hybrid antibiotics, we can covalently connect two molecules with different mechanism of action to obtain a hybrid with dual mode of action, so as to overcome the resistance mechanism of one or two drugs, regain antibacterial activity, and significantly reduce the rate of microbial resistance. The difficulty of this study is that ribosome and topoisomerase are two different targets, which have different requirements on the structure of ligands. It is difficult for heterozygotes to act on these two targets at the same time. Liang Jianhua's group, led by azithromycin, combined quinolones on the C-6 site of azithromycin in the form of acylation. After screening, it was found that the heterozygote of azithromycin and ciprofloxacin / gatifloxacin could inhibit bacterial DNA through the way similar to that of fluoroquinolone - poisoning the gyrase To improve the antibacterial activity of the compound against high level resistant bacteria. The results are consistent with the experimental results of DNA super helix inhibition, DNA fragmentation, molecular docking and whole cell growth inhibition. This dual mode of action, which can inhibit both protein synthesis and DNA replication, has laid a foundation for the rational design of new antibiotics against drug-resistant bacteria in the future. The first author of this paper is fan Bingzhi, a master of chemistry and Chemical Engineering College of Beijing University of technology. Liang Jianhua, an associate professor of chemistry and Chemical Engineering College of Beijing University of technology, is the corresponding author. Hiasa, Professor Aldrich of School of medicine of University of Minnesota and Cushman of School of medicine of Purdue University participated in this work. The research was supported by NSFC for a long time (20602002; 81673335), Beijing excellent talents (2013d0090110000002) and Beijing University of technology excellent young teachers (2012yg1606). Brief introduction of the author: Liang Jianhua, associate professor, 1995-2004 Beijing University of technology, Bachelor / doctor; 2004-present Beijing University of technology, lecturer / Associate Professor / doctoral supervisor. The research direction is pharmaceutical chemistry, which is dedicated to the development of innovative drugs related to the treatment of various major diseases. The research interests involve the fields of anti drug resistant bacteria, anti viral infection drugs, anti neurodegenerative drugs and anti diabetes drugs. At present, he has presided over two general projects of the National Natural Science Foundation of China and national key research and development plan projects. He has published more than 20 corresponding author's papers in the mainstream academic journals such as EUR. J. Med. Chem., bioorg. & Med. Chem., Biot. & Med. Chem. Lett., curr. Top. Med. Chem., J. antibiatics, etc., with 7 patents authorized by the first inventor and 3 PCT patents. From Beijing University of Technology
Pfizer's summary of more than 400 drug synthesis routes
Full Score recommendation: necessary app for chemical research
Click to receive free "the most complete 80 functional groups conversion in history"