Desmethyl Macrolides: Synthesis and Evaluation of 4,8-Didesmethyl Telithromycin

Abstract

There is an urgent need for novel sources of antibiotics to address the incessant and inevitable onset of bacterial resistance. To this end, we have initiated a structure-based drug design program that features a desmethylation strategy (i.e., replacing methyl groups with hydrogens). Herein we report the total synthesis, molecular modeling and biological evaluation of 4,8-didesmethyl telithromycin (5), a novel desmethyl analogue of the third-generation ketolide antibiotic telithromycin (2), which is an FDA-approved semisynthetic derivative of erythromycin (1). We found 4,8-didesmethyl telithromycin (5) to be eight times more active than previously prepared 4,8,10-tridesmethyl congener (3) and two times more active than 4,10-didesmethyl regioisomer (4) in MIC assays. While less potent than telithromycin (2) and paralleling the observations made in the previous study of 4,10-didesmethyl analogue (4), the inclusion of a single methyl group improves biological activity thus supporting its role in antibiotic activity.

Natural Products as Platforms To Overcome Antibiotic Resistance

“…Furthermore, the Andrade group designed syntheses to explore the effect of removing the methyl groups at C8 and C10, both of which flank the ketone at C9. 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 …”

Stacking Interactions between 9-Methyladenine and Heterocycles Commonly Found in Pharmaceuticals

“…Interactions of heterocycles with aromatic amino acid side chains and nucleic acids abound in drug binding sites. − For instance, Pyrkov et al analyzed the role of π-stacking interactions in proteins with adenine- and guanine-containing fragments bound. Futhermore, the Andrade group has a long-standing interest in ketolide antibiotics such as telithromycin (TEL) (see Figure a), − which feature an extended heterocyclic alkyl–aryl side chain attached to the macrocycle , and exhibit tighter binding to the ribosome compared with previous classes of macrolides . Despite the excellent activity of TEL against many macrolide-resistant bacteria, the FDA narrowed its approved clinical use because of adverse effects and safety concerns .…”

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.…”

“…The total synthesis of the next desmethyl congener, (-)-4,8-didesmethyl telithromycin (5), presented us with unique challenges. 14 First, the presence of the C-10 methyl group precluded the RCM approach to requisite macroketolactone 81 (Scheme 17, part A). Despite screening a variety of catalysts (e.g., Grubbs I, Grubbs II, Hoveyda-Grubbs II), we were unable to effect the RCM reaction.…”

“…In summary, we prepared didesmethyl analogue 5 in 36 steps overall (26 steps in the longest linear sequence). 14 The 'abiotic' approach not only enabled the synthesis of 5, but it also represented the most step-efficient approach toward the desmethyl analogues of 2.…”