Novel Erythromycin Derivatives with Aryl Groups Tethered to the C-6 Position Are Potent Protein Synthesis Inhibitors and Active against Multidrug-Resistant Respiratory Pathogens

Abstract

A novel series of erythromycin derivatives has been discovered with potent activity against key respiratory pathogens, including those resistant to erythromycin. These compounds are characterized by having an aryl group tethered to the C-6 position of the erythronolide skeleton. Extensive structural modification of the C-6 moiety led to the discovery of several promising compounds with potent activity against both mef- and erm-mediated resistant Streptoccoccus pneumoniae. Preliminary mechanistic studies indicated that the new macrolides are potent protein synthesis inhibitors, which interact with methylated ribosomes isolated from resistant organisms. In experimental animal models, these compounds exhibited excellent in vivo efficacy and balanced pharmacokinetic profiles.

Targeting Antibiotic Resistance

“…Interestingly, for solithromycin, weak binding to ribosomes dimethylated at A2058Ec could be detected by chemical probing 71. Key structural features of the ketolides are summarized in Figure 13 (for an example of a ketolide with a 6‐ O ‐attached side chain, see cethromycin) 74, 75…”

Design, synthesis and antibacterial activity of a novel alkylide: 3-O-(3-aryl-propenyl)clarithromycin derivatives

“…This was significantly different from the previous results of allylation at 6-OH. 4 Further study by X-ray crystallography of 9f disclosed that the allylic double bond isomerized from 2-position to 1-position, and the Heck-isomerization to furnish enol concomitantly resulted in Z configuration, as shown in Figure 2. Therefore, with the exception of 9h, the real structure of 9b-9g and 12c-12f should be the 3-O-(3-aryl-Z-prop-1-enyl)clarithromycin derivatives, not the expected 3-O-(3-aryl-E-prop-2-enyl)clarithromycin derivatives.…”

“…1 It is noted that regioselective methylation at 6-OH to yield clarithromycin was not achieved until the introduction of oxime ether in the 9-carbonyl group. 2 Similarly, new emerging cethromycin [3-oxo-6-O-(3-(3¢-quinolyl)-2-propenyl)erythromycin derivative] as the third-generation erythromycin was synthesized by regioselective allylation at 6-OH [3][4][5] to overcome the relatively recent issues associated with the development of bacterial resistance.…”

“…As a result, modification at 3-OH led to the emergence of ketolide, [3][4][5][6] acylide, 7 bicyclolide, 8 anhydrolide, 9 2,3-enol-ether, 10 3-deoxy, 11 3-ether, 12 3,6-ketal 13 and 3,6-ether. 14 Second, an aryl side chain tethered to the erythronolide core is believed to be very important for the improvement of activities against erythromycin-resistant bacteria, due to the interaction with a secondary ribosomal binding site.…”

“…In the search for novel erythromycin derivatives against erythromycin-resistant bacteria, the allyl group was a very important one for various further modifications at 6-OH of erythromycin. 4,5 To the best of our knowledge, the introduction of the allyl group at 3-OH of 14-membered macrolides was not disclosed yet, in addition to the recent modification of 16-membered macrolides, leucomycin. 16 …”