Synthesis And Evaluation Of The Antibacterial Activities Of Berberine-rhodanine Derivatives

Drug-resistant bacterial infection has become a major threat to human health globally,and the need for new antibiotics with novel structures and clear molecular targets is urgent and growing.Emerging scientific techniques and methods,such as genomics,high-throughput screening,combinatorial chemistry,and computer-aided drug design,have not led antimicrobial discovery approaches to the"golden age".Natural products remain the most important treasure trove for antimicrobial discovery,and their derivatives with antimicrobial activity remain attractive.Berberine has been used for treatment of gastrointestinal infections in China for 2,000 years,additionally,rhodanine derivatives have potential thyroid-promotive,antibacterial,antiviral,anti-ischemia,cardiovascular,anticancer,thrombolytic and other biological activities.Based on the principle of hybridization,this paper designed to synthesize 21 of tetrahydroproberine-rhodanine conjugated derivatives,and the two fragments are linked together by methylidene group,formally constituting N3 and C5 position disubstituted rhodanine derivatives,which is also considered to be the compound with the most antibacterial activity potential.The structures of all compounds were confirmed by ¹HNMR,¹³CNMR and LCMS.The antibacterial activity of all compounds was evaluated in vitro against three Gram-negative bacteria,three Gram-positive bacteria and one fungus.The antibacterial activity in vitro showed that the compounds displayed general antibacterial activity against Gram-positive bacteria,some compounds exhibited a certain degree of antibacterial activity against gram-negative bacteria,and basically all compounds showed relatively weak antibacterial activity against fungi（Candida albicans ATCC 10231）.When Rhodanine N3-position is a medium-length chain alkane substituted for acetic acid,such as n-butyl and isobutyl,it can significantly improve the bacteriostatic activity against gram-positive bacteria,while the 9-position phenolic hydroxyl group of tetrahydroberine fragment is protected（such as methyl）,which helps to enhance the bacteriostatic activity against gram-negative bacteria.Compounds6g,6i,6k,6l,6m,6s showed good antibacterial activity,especially the minimum inhibitory concentration MIC value of 6l-1,6l-2 and 6m against the drug-resistant Staphylococcus aureus（ATCC 43300）was 32μg/m L.Compounds 6g and 6i showed some degree of inhibitory activity against both gram-negative and gram-positive bacteria,and the minimum inhibitory concentrations against Escherichia coli ATCC 25922 and Bacillus subtilis ATCC 6633 were 512μg/m L and 64μg/m L,respectively.The new structures and fragments isolated from natural products are still treasures in the field of antibiotic research and development,and berberine derivatives and rhodanine fragments with antibacterial activity are still valued by pharmaceutical scientists,and the combination and improvement of the two structures still have strong attraction.This project makes a simple attempt on the combination of the two fragments based on the principle of hybridization,and explores some shallow experience,hoping to provide some help for the design and optimization of such compounds in the future.