Design, Synthesis And Antibacterial Evaluation Of4"-O-(Trans-β-arylacrylamido)Carbamoyl Azithromycin Analogs

As a well-established class, macrolide antibiotics have been clinically accepted for their efficacy and safety. Currently, semi-synthetic modifications of erythromycin A (EMA) play an important role in search for a new generation of macrolide antibiotics to combat bacterial resistance.Mechanistic studies demonstrate macrolides can serve as potent protein synthesis inhibitors and reversibly bind to A2058in domain V of the23S rRNA, hence interfering with elongation of nascent polypeptide chains. Two distinguished mechanisms have accounted for the majority of macrolide resistance:the first being ribosome methylation resistance encoded by the erm gene and the second being efflux resistance encoded by the mef gene.Targeted to peptidyl transferase center (PTC) region, a series of twelve4"-O-(trans-β-arylacrylamido)carbamoyl azithromycin11,12-carbonates (series A) were designed, synthesized and evaluated in vitro. Afterwards, nine compounds with more favorable antibacterial activities were selected from series A for extensive modification, which affored C-4",11modified azithromycin (AZM) analogs of series B to E. C-11arylalkylcarbamoyl groups of these compounds could confer a tertiary interaction with A752in domain Ⅱ of the23S rRNA. Antibacterial activities of all the target compounds were presented as minimum inhibitory concentrations (MICs) produced by the broth microdilution method and summarized as below.1. Activities against susceptible strains.1) A majority of compounds maintained the activity of AZM against susceptible Streptococcus pyogenes. In addition, a majority of compounds of series B-E displayed MICs below the susceptible level (MIC<1μg/mL) against susceptible Staphylococcus aureus and Streptococcus pneumoniae.2) Compound B8exhibited the most potent activities against susceptible S. aureus (MIC=0.5μg/mL), S. pneumoniae (MIC=0.06μg/mL) and S. pyogenes (MIC=0.25μg/mL).2. Activities against resistant strains.1) All the derivatives demonstrated remarkablely improved activities than the references, EMA and AZM, against all the three phenotypes of resistant S. pneumoniae. In addition, a majority of compounds showed better activities than the references against resistant S. pyogenes.2) A3, the most preferable compound (MIC=0.015μg/mL) against resistant S. pneumoniae expressing the mefA gene, exhibited512and256-fold enhanced activity compared to EMA and AZM, respectively. Compounds A1, A6, A7, A9-A12, B2-B7, C1-C6, C8, D1-D8and E2-E8displayed favorable activities, as well, against resistant S. pneumoniae expressing the mefA gene, with MICs between0.03and0.5μg/mL.3) Compounds D3(MIC=0.5μg/mL), D4(MIC=0.25μg/mL) and D5(MIC=0.5μg/mL) demonstrated potent activities against resistant S. pneumoniae expressing the ermB gene, which were256,512and256-fold better than the references, respectively.4) As for resistant S. pneumoniae expressing the ermB and mefA genes, compounds B5and D3-D5shared the identical activity with the MIC value of1μg/mL, which was below the susceptible level and256-fold lower than the references.Structure-activity relationships (SARs) of the4"-O-(trans-β-arylacrylamido)carbamoyl azithromycin analogs were deduced as below.1. As for susceptible strains.1) Compared with C-11,12cyclic carbonate moiety, the introduction of C-11arylalkylcarbamoyl groups were more beneficial for efficacy against susceptible strains.2) The introduction of three or more methoxy groups to the terminal benzene ring of C-4"side chain may lead to the decrease in activity against susceptible strains. The terminal2-furyl group tended to confer a favorable potency against susceptible S. pyogenes.2. As for resistant strains.1) The introduction of C-4" carbamoyl moieties could result in an improved activity against resistant5. pneumoniae and S. pyogenes.2) Compared with C-11,12carbonates, the introduction of C-11arylalkylcarbamoyl groups were more beneficial for potency against resistant S. pneumoniae, which were able to interact with A752, thereby enhancing the activity against resistant5. pneumoniae expressing the ermB gene.3) Among four different C-11arylalkylcarbamoyl moieties reported herein, the p-methoxybenzylcarbamoyl group was optimum for better activities against resistant S. pneumoniae.4) The introduction of three or more methoxy groups to the terminal benzene ring of C-4"side chain may lead to the decrease in activity against resistant strains. The terminal2-thienyl group tended to confer a favorable potency against resistant S. pneumoniae expressing the me/A gene.Above all, targeted to PTC region and A752, five series of464"-O-(trans-β-arylacrylamido)carbamoyl azithromycin analogs were designed, synthesized and evaluated for their in vitro antibacterial activities. Based on this, we deduced SARs of these AZM analogs in the thesis.