Desmethyl Macrolides: Synthesis and Evaluation of 4-Desmethyl Telithromycin

Abstract

Novel sources of antibiotics are needed to address the serious threat of bacterial resistance. Accordingly, we have launched a structure-based drug design program featuring a desmethylation strategy wherein methyl groups have been replaced with hydrogens. Herein we report the total synthesis, molecular modeling, and biological evaluation of 4-desmethyl telithromycin (6), a novel desmethyl analogue of the third-generation ketolide antibiotic telithromycin (2) and our final analogue in this series. While 4-desmethyl telithromycin (6) was found to be equipotent with telithromycin (2) against wild-type bacteria, it was 4-fold less potent against the A2058G mutant. These findings reveal that strategically replacing the C4-methyl group with hydrogen (i.e., desmethylation) did not address this mechanism of resistance. Throughout the desmethyl series, the sequential addition of methyls to the 14-membered macrolactone resulted in improved bioactivity. Molecular modeling methods indicate that changes in conformational flexibility dominate the increased biological activity; moreover, they reveal 6 adopts a different conformation once bound to the A2058G ribosome, thus impacting noncovalent interactions reflected in a lower MIC value. Finally, fluorescence polarization experiments of 6 with E. coli ribosomes confirmed 6 is indeed binding the ribosome.

Natural Products as Platforms To Overcome Antibiotic Resistance

“…116–118 In the interest of brevity, we outline the culmination of their campaign with the synthesis of 4-desmethyl telithromycin ( 110 ) (Scheme 6). 119 …”

Scaffold Modifications in Erythromycin Macrolide Antibiotics. A Chemical Minireview

“…Scheme 8 shows the preparation of the 4-desmethyl macrolide 28 . The telithromycin intermediate 24 is prepared from the linear hydroxy acid 23 by a macrolactonization reaction to afford 24 in 65% yield [ 16 ]. The hydroxy acid 23 is prepared by a multistep process.…”

“…Stereoselective glycosylation of 24 with the donor of the desosamine sugar 25 affords the glycoside 26 . The Baker protocol subsequently delivers the macrolactone framework that affords the ketolide 28 [ 16 ].…”

“…Stereoselective glycosylation of 24 with the donor of the desosamine sugar 25 affords the glycoside 26. The Baker protocol subsequently delivers the macrolactone framework that affords the ketolide 28 [16]. Antibacterials: 4-Desmethyl telithromycin is equipotent with telithromycin against wild-type bacteria but is 4-fold less potent against the A2058G mutant.…”

Total Synthesis of Desmethyl Macrolide Antibiotics

“…To simplify the chemical synthesis, we also targeted desmethyl analogues at the C-8 and C-10 positions (i.e., 3-5) to probe the roles of those methyl groups in terms of bioactivity. [11][12][13][14][15] The retrosynthesis of the simplest congener, 4,8,10-tridesmethyl telithromycin (3), is shown in Scheme 1 and is exemplary for the remaining analogues. 11,12 Inspection of 3 and an advanced protected intermediate 7 reveals three topological subgoals: (1) installation of the C-11-C-12 oxazolidinone bearing the butyl-biaryl side chain 9, (2) stereoand site-selective glycosylation at the C-5 hydroxyl position with known D-desosamine donor 10, 16 and (3) preparation of the 14-membered macrolactone ring 11.…”