Design, Synthesis And Antibacterial Activity Of Novel 15-Membered Macrolide Derivatives Against Resistant Bacteria

Macrolides are a class of weak base antibiotics produced by streptomycetes and has been widely used for the treatment of the infections of respiratory system, digestive system and uropoietic system in clinical application. However, with the extensive use of the antibiotics, especially abuse, the increasing incidence of bacterial resistance to macrolides is becoming a major threat to successful treatment of infectious diseases. Therefore, it has attracted extensive attention to develop new potent macrolides against resistant bacteria.The mechanism of macrolide's action indicates that the binding sites of macrolides are located inside the nascent peptide exit tunnel of the ribosomal 50S subunit near the peptidyl transferase center. The macrolides can inhibit bacterial protein synthesis by blocking up the peptide tunnel when they bind to the binding sites, and consequently bring forth antibacterial activity. Unfortunately, resistant bacteria have many mechanisms of resistance to macrolides and the most common one among them is a target-site modification, which is that expression of an erm resistance determinant in bacteria leads to the production of a methyltransferase enzyme which modifies the key nucleotide, A2058 and thereby confers MLS_B resistance to macrolides. Therefore, design and synthesis of new macrolide derivatives against resistant bacteria based on new target sites is an important way to overcome bacterial resistance.Aimed at the defects of macrolides and ketolides against resistant bacteria, new macrolide derivatives could be designed and synthesized based on the nucleotides on the A～P site or A752 as second target sites, which would help to solve the problem of bacterial resistance. Based on the above thoughts, a series of 15-membered macrolide derivatives were designed and synthesized from azithromycin as a lead compound through the introduction of side chains at C-11, C-12 and C-4" positions of its skeleton. Their structures were confirmed by MS, IR, ¹H-NMR and ¹³H-NMR spectra. In addition, the synthetic routes for the four series were successfully established and had such features as high yields, simple operations and mild conditions after optimization of the reaction conditions.In vitro antibacterial activity of the target compounds was determined by using the tube dilution method. The results were as follow: (1) Antibacterial activity against susceptible bacteria: all of target compounds had excellent activity similar to clarithromycin or azithromycin against S. pneumoniae. (2) Antibacterial activity against resistant bacteria: The majority of A, B and C series showed good activity against M-resistant S. pneumoniae A22072 (MIC≦ 0.5μg/mL), and among them, compounds A1, B2, B4, B7, C6 and C11 exhibited the best activity (MIC=0.06μg/mL). All of compounds in C series had potent activity against MLS_B-resistant S. pneumoniae B1 (MIC≦ 0.5μg/mL), and among them, compounds C1～C3,C6～C7 and C9～C11 exhibited the best activity (MIC=0.25μg/mL). In addition, compounds A6, B4, B5, B7and C7 also displayed activity against mixed type-resistant S. pneumoniae (MIC=2μg/mL).Structure activity relationships were summarized as follows: (1) the basic skeletons of macrolides were an essential to activity against susceptible bacteria. The introduction of C-4"carbamate side chains to the skeleton still had excellent activity against susceptible bacteria and the introduction of arylalkyl side chains, especially, had excellent activity against M-resistant bacteria. (2) C-11, C-12 cyclic carbonate and C-4"carbamate side chains introduced simultaneously to the skeleton still has excellent activity against susceptible bacteria and the introduction of arylalkyl side chains, especially, has excellent activity against M-resistant bacteria. (3) C-4" carbamate and C-11 carbamate side chains introduced simultaneously to the skeleton still has excellent activity against susceptible bacteria and exhibits excellent activity against both M-resistant bacteria and MLS_B-resistant bacteria.