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.
Subject(s)
Alcohols/chemical synthesis , Anti-Bacterial Agents/chemistry , Erythromycin/analogs & derivatives , Ethers/chemical synthesis , Alcohols/chemistry , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Catalysis , Erythromycin/chemical synthesis , Erythromycin/chemistry , Erythromycin/pharmacology , Ethers/chemistry , Gram-Negative Bacteria/drug effects , Gram-Negative Bacteria/growth & development , Gram-Positive Bacteria/drug effects , Gram-Positive Bacteria/growth & development , Hydrogen-Ion Concentration , Microbial Sensitivity Tests , Molecular Conformation , Oxidation-ReductionABSTRACT
A major drawback of the antibiotic erythromycin A is its extreme acid sensitivity, leading to rapid inactivation in the stomach. The accepted model for degradation in aqueous acidic solution has erythromycin A in equilibrium with erythromycin A enol ether and degrading to anhydroerythromycin A. We report a detailed kinetic study of the acidic degradation of erythromycin A and of erythromycin A 2'-ethyl succinate (the market-leading pediatric prodrug), investigating the reaction rates and degradation products via NMR. This reveals that the accepted mechanism is incorrect and that both the enol ether and the anhydride are in equilibrium with the parent erythromycin. By implication, both the anhydride and enol ether are antibacterially inactive reservoirs for the parent erythromycin. The actual degradation pathway is the slow loss of cladinose from erythromycin A (or erythromycin A 2'-ethyl succinate), which is reported here for the first time in a kinetic study. The kinetic analysis is based on global, nonlinear, simultaneous least-squares fitting of time course concentrations for all species across multiple datasets to integrated rate expressions, to provide robust estimates of the rate constants.
Subject(s)
Erythromycin Ethylsuccinate/chemistry , Erythromycin/chemistry , Anhydrides/chemistry , Catalysis , Chemistry, Pharmaceutical/methods , Hydrogen-Ion Concentration , Models, Chemical , Models, Statistical , Molecular Conformation , Prodrugs , Technology, Pharmaceutical/methods , Temperature , Time Factors , Water/chemistryABSTRACT
The antibiotic erythromycin A is generally administered to children as a suspension of the pro-drug erythromycin A 2'-ethyl succinate. The success of the pro-drug depends on (a) elimination of the unacceptably bitter taste of free erythromycin, (b) its stability against stomach acid, and (c) its smooth (base-catalyzed) hydrolysis in the body to yield active erythromycin. We have investigated the rates and pathways of acid-catalyzed degradation and base-catalyzed hydrolysis of the 2'-ethyl succinates of erythromycins A and B. Esterification does not protect the drugs against acid-catalyzed degradation in solution; however, erythromycin B 2'-ethyl succinate is much more stable than the corresponding erythromycin A ester, degrading nearly 40 times more slowly. The rates of base-catalyzed hydrolysis in conditions mimicking the blood stream are similar for the two pro-drugs. We conclude that erythromycin B 2'-ethyl succinate is an attractive prospect as a pediatric erythromycin pro-drug.
Subject(s)
Anti-Bacterial Agents/chemistry , Erythromycin/analogs & derivatives , Prodrugs/chemistry , Catalysis , Erythromycin/chemistry , Hydrogen-Ion Concentration , Hydrolysis , Kinetics , PediatricsABSTRACT
A series of N-(5-benzylthio-1,3,4-thiadiazol-2-yl) and N-(5-benzylsulfonyl-1,3,4-thiadiazol-2-yl) derivatives of piperazinyl quinolones was synthesized and evaluated for antibacterial activity against Gram-positive and Gram-negative microorganisms. Some of these derivatives exhibit high activity against Gram-positive bacteria; Staphylococcus aureus and Staphylococcus epidermidis, comparable or more potent than their parent N-piperazinyl quinolones norfloxacin and ciprofloxacin as reference drugs. The SAR of this series indicates that both the structure of the benzyl unit and the S or SO(2) linker dramatically impact antibacterial activity.
