Enhancement of the properties of a drug by mono-deuteriation: reduction of acid-catalysed formation of a gut-motilide enol ether from 8-deuterio-erythromycin B

Abstract

Erythromycin B is structurally very similar to erythromycin A, and also shares its clinically important antibacterial activity. Its potential advantage is that it is much more stable to acid. Both compounds are susceptible to 6-9-enol ether formation, involving loss of a proton from C-8. The enol ethers lack antibacterial activity and can give rise to unpleasant gut motilide side-effects. Our previous work on degradation kinetics revealed that the formation of erythromycin B enol ether from erythromycin B is subject to a large deuterium isotope effect. We therefore synthesized 8-d-erythromycin B (in 87% yield) in the hope that acid-catalysed enol ether formation would be reduced, relative to erythromycin B. In a range of microbiological and biochemical assays, deuteriation did not appear to compromise the efficacy of the drug. Degradation studies showed, however, that incorporation of deuterium into erythromycin B reduces (though does not completely suppress) enol ether formation, providing the possibility of using a facile mono-deuteriation to reduce the gut motilide side-effects of the drug.

Selected Derivatives of Erythromycin B-In Silico and Anti-Malarial Studies

“…None of the global minima for the investigated derivatives of erythromycin B is a typical folded-out conformation. Typical folded-out conformations for erythromycin B and 8-d-erythromycin B were found bound weakly to the bacterial ribosomes [27]; therefore, folded-out conformations were used for the docking analysis as the active conformations of the ligands-investigated derivatives of erythromycin B (erythromycin B 9-oxime, erythromycin B 2 -[3-(morpholinomethyl) benzoate], erythromycin B 2 -[3-(dimethylaminomethyl)benzoate], 5-desosaminyl erythronolide B ethyl succinate, and 8-d-erythromycin B) to the complex consisting of 23S rRNA and L4 protein from the apicoplast ribosome of P. falciparum previously constructed in silico [40]. The typical folded-out conformation (H4-H11 (2.37 Å), H5-H18 (2.58 Å), H15-H16 (2.92 Å)) of erythromycin B 9-oxime was found with the energy 128.73 kJ/mol and erythromycin B 2 -[3-(morpholinomethyl) benzoate] with the energy 103.57 kJ/mol (H4-H11 (2.77 Å), H5-H18 (2.54 Å), H15-H16 (3.05 Å)).…”

“…8-d-erythromycin B was made from erythromycin B enol ether under conditions previously described [27]. Chloroquine, pyrimethamine and sulfadoxine-resistant K1 strain of P. falciparum was cultured with RPMI (Roswell Park Memorial Institute) 1640 media containing 25 mM (2-hydroxyethyl) piperazine-N'-(2-ethane-sulfonic acid) (HEPES) and 0.3 g/L L-glutamine (Gibco, Life Technologies, Renfrew, UK).…”

“…The majority of free or commercially available software for molecular docking are either suitable for proteins or RNAs as receptors, but not for complexes which contain both protein and RNA residues. We chose PatchDock for our docking analysis because it relies on different principles-on shape complementarity [26][27][28]-compared to other software.…”

Deuterium as a Tool for Changing the Properties of Pharmaceutical Substances (Review)

“…The deuteration of the erythromycin B molecule is also accompanied by a decrease in the side effects of intestinal motility as a result of suppression of the formation of 6,9-enol ether [60]. In this case, the antibacterial effect of the drug is not violated.…”

The Influence of Deuterium on the Properties of Pharmaceutical Substances (Review)

“…Дейтерирование молекулы эритромицина В также сопровождается снижением побочных эффектов моторики кишечника в результате подавления образования 6,9-енольного эфира [27]. При этом не нарушается антибактериальный эффект лекарства.…”