Synthesis and biological activities of 4"-deoxy-4"-sulfonamido-oleandomycin derivatives

Bright, G. Michael; English, Arthur R.; Nagel, A.; Retsema, James A.; Sciavolino, Frank C.

doi:10.1128/aac.25.1.113

Cited by 6 publications

(3 citation statements)

References 8 publications

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“…A further 30 4″-ureido-oleandomycin derivatives related to Mac5 were screened from the Pfizer compound collection (synthesis of these compounds is described in Patent US4098993 34 ). These 30 derivatives of Mac5 were first assessed for IFN-augmenting activity using a reporter system (Figure 8 a).…”

Section: Resultsmentioning

confidence: 99%

Identification of novel macrolides with antibacterial, anti-inflammatory and type I and III IFN-augmenting activity in airway epithelium

Porter

Watson

Roberts

et al. 2016

J. Antimicrob. Chemother.

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BackgroundExacerbations of asthma and COPD are triggered by rhinoviruses. Uncontrolled inflammatory pathways, pathogenic bacterial burden and impaired antiviral immunity are thought to be important factors in disease severity and duration. Macrolides including azithromycin are often used to treat the above diseases, but exhibit variable levels of efficacy. Inhaled corticosteroids are also readily used in treatment, but may lack specificity. Ideally, new treatment alternatives should suppress unwanted inflammation, but spare beneficial antiviral immunity.MethodsIn the present study, we screened 225 novel macrolides and tested them for enhanced antiviral activity against rhinovirus, as well as anti-inflammatory activity and activity against Gram-positive and Gram-negative bacteria. Primary bronchial epithelial cells were grown from 10 asthmatic individuals and the effects of macrolides on rhinovirus replication were also examined. Another 30 structurally similar macrolides were also examined.ResultsThe oleandomycin derivative Mac5, compared with azithromycin, showed superior induction (up to 5-fold, EC50 = 5–11 μM) of rhinovirus-induced type I IFNβ, type III IFNλ1 and type III IFNλ2/3 mRNA and the IFN-stimulated genes viperin and MxA, yet had no effect on IL-6 and IL-8 mRNA. Mac5 also suppressed rhinovirus replication at 48 h, proving antiviral activity. Mac5 showed antibacterial activity against Gram-positive Streptococcus pneumoniae; however, it did not have any antibacterial properties compared with azithromycin when used against Gram-negative Escherichia coli (as a model organism) and also the respiratory pathogens Pseudomonas aeruginosa and non-typeable Haemophilus influenzae. Further non-toxic Mac5 derivatives were identified with various anti-inflammatory, antiviral and antibacterial activities.ConclusionsThe data support the idea that macrolides have antiviral properties through a mechanism that is yet to be ascertained. We also provide evidence that macrolides can be developed with anti-inflammatory, antibacterial and antiviral activity and show surprising versatility depending on the clinical need.

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Section: Resultsmentioning

confidence: 99%

Identification of novel macrolides with antibacterial, anti-inflammatory and type I and III IFN-augmenting activity in airway epithelium

Porter

Watson

Roberts

et al. 2016

J. Antimicrob. Chemother.

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“…The three derivatives and oleandomycin were prepared by members of the Department of Medicinal Chemistry in the Central Research Division, Pfizer Inc., Groton, Conn., by previously described methods (1). Erythromycin was purchased from commercial sources.…”

Section: Methodsmentioning

confidence: 99%

“…However, oleandomycin has much greater acid stability than erythromycin base. Because of this key advantage, chemical modification of oleandomycin was initiated in an attempt to increase potency (1). It was found that the substitution of a nitrogen functionality for the C"-4 hydroxyl conferred increased antibacterial potency in the derivatives.…”

mentioning

confidence: 99%

Evaluation of three 4"-deoxy-4"-sulfonamido-oleandomycin derivatives with erythromycin-like antibacterial potency

English¹,

Retsema²,

Girard³

et al. 1984

Antimicrob Agents Chemother

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Three derivatives of oleandomycin in which the C"-4 hydroxyl moiety was replaced for the first time with a nitrogen functionality have been compared with erythromycin base and oleandomycin base. The minimum inhibitory concentrations of these derivatives for 90% of a group of clinical isolates of Staphylococcus aureus were one-half to one-fourth those of erythromycin. The minimum inhibitory concentrations of the experimental macrolides for 50% of a group of S. aureus isolates resistant to greater than 12.5 micrograms of erythromycin per ml ranged from 0.2 to 0.39 micrograms/ml. The activities of these experimental compounds were equivalent to the activities of erythromycin against Staphylococcus epidermidis, Bacteroides fragilis, and Haemophilus influenzae isolates. In general, erythromycin was more active against Streptococcus species. Each experimental macrolide was superior to erythromycin in inhibiting RNA-directed, cell-free polypeptide synthesis. The three experimental compounds were markedly more active than erythromycin base after oral administration to mice infected with S. aureus. The 50% protective doses of the experimental compounds ranged from 27.4 to 45.7 mg/kg; that of erythromycin was approximately 100 mg/kg.

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Biologically Active Thiophene Derivatives Revisited: 1983–1988

Press¹

1991

Chemistry of Heterocyclic Compounds: A Series of Monographs

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Synthesis and biological activities of 4"-deoxy-4"-sulfonamido-oleandomycin derivatives

Cited by 6 publications

References 8 publications

Identification of novel macrolides with antibacterial, anti-inflammatory and type I and III IFN-augmenting activity in airway epithelium

Identification of novel macrolides with antibacterial, anti-inflammatory and type I and III IFN-augmenting activity in airway epithelium

Evaluation of three 4"-deoxy-4"-sulfonamido-oleandomycin derivatives with erythromycin-like antibacterial potency

Biologically Active Thiophene Derivatives Revisited: 1983–1988

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