10,11,12,13-Tetrahydro Derivatives of Tylosin. II. Synthesis, Antibacterial Activity and Tissue Distribution of 4'-Deoxy-10,11,12,13-tetrahydrodesmycosin.

Narandja, Amalia; Kelnerić, Željko; Kolacny-Babic, Lidija; Djokic, S.

doi:10.7164/antibiotics.48.248

Cited by 6 publications

(18 citation statements)

References 6 publications

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“…Acetylation of the resulting 2′,4′diacetate ( 16) with acetic anhydride in the presence of a catalytic amount of (dimethylamino)pyridine (DMAP) and triethylamine proceeded selectively at the C-4′′ position of D-mycinose (5) to yield triacetate (17), the substrate for the oxidation. The site of acetylation was unambiguously assigned by one-and two-dimensional 1 H NMR and 13 C NMR experiments and the usual reactivity found in desmycosin analogues. With the rest of the functionality suitably protected, we were now ready to chemically manipulate the aglycon C-3 alcohol.…”

Section: Chemistrymentioning

confidence: 83%

“…This takes into account that the core structure of a compound class contributes to the pharmacological profile in addition to the effect it mediates by directing the spatial arrangement of the pharmacophoric substituents. Therefore, the following scaffolds were used for the construction of the library: 2‘,4‘,4‘ ‘-tri- O -acetyldesmycosin ( 7 ), − 10,11,12,13-tetrahydrodesmycosin ( 8, THD), 4‘-deoxy-THD ( 9 ), 3- O -acetyldesmycosin ( 10 ), tylosin ( 1 , T), THT ( 11 ), 2,3-anhydrodesmycosin ( 12 ), 2,3-didehydrodesmycosin ( 13 ), and 2,3-didehydro-THD ( 14 , Figure ) . A simple straightforward structure such as 7 should allow optimization of potency, by parallel or classical synthesis, for example, by formation of the ester bond or double bond by classical carboxylic acid−alcohol condensation methods or Wittig reaction, respectively.…”

Section: Chemistrymentioning

confidence: 99%

“…In continuation of our studies, we have used THD ( 8 ), 4‘-deoxy-THD ( 9 ), tylosin ( 1 ), and THT ( 11 ) as substrates for the Horner−Wadsworth−Emmons reaction (Scheme ). 4‘-Deoxy-THD was prepared in six steps according to literature procedure . For a matter of comparison we have prepared enol 14 , a tetrahydro analogue of 13 , according to a published procedure …”

Section: Chemistrymentioning

confidence: 99%

“…Thus, acetylation of desmycosin (2) with acetic anhydride and triethylamine led smoothly to diacetate 21, which was reacted further with acetic anhydride in the presence of a catalytic amount of DMAP to furnish 2′,4′,4′′-tri-O-acetyldesmycosin (7) in 80% overall yield after chromatographic purification. 10,11 The Pfitzner-Moffat oxidation of 7 provided 2′,4′,4′′-tri-O-acetyl-2,3didehydrodesmycosin (22), whose 13 C NMR spectrum in CDCl 3 again exhibited a C-3 resonance at ca. 180 ppm, unambiguously indicating that the enol form was present.…”

Section: Chemistrymentioning

confidence: 99%

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Semisynthetic Macrolide Antibacterials Derived from Tylosin. Synthesis and Structure−Activity Relationships of Novel Desmycosin Analogues

et al. 2003

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A series of 20-O-substituted and 3,20-di-O-substituted derivatives of desmycosin were synthesized and their biological properties were evaluated. In particular, we have synthesized numerous side chain modified analogues of desmycosin as well as some analogues possessing a combination of modified side chain and alternative C-3 substituents. Thus, alpha,beta-unsaturated analogues of desmycosin (2), tylosin (1), 10,11,12,13-tetrahydrotylosin (11), and 2,3-didehydrodesmycosin (13) were prepared from the corresponding aldehydes by a Wittig reaction with the stabilized ylides (a-d), generating a trans-double bond, followed by modified Pfitzner-Moffat oxidation of the C-3 hydroxyl group. To evaluate the importance of the C-3 position of desmycosin for biological activity, the C-3 substituted derivatives were synthesized by a standard sequence of protective group chemistry followed by Wittig reaction and esterification as the key steps. For the attachment of the C-3 ester functionality, a mixed anhydride protocol was adopted. Reaction proceeded smoothly to give corresponding esters in yields ranging from 70 to 80%. Base- and acid-catalyzed rearrangement products including desmycosin 8,20-aldols (24a and 24b) and desmycosin 3,19-aldol (25) are also described. Parallel array synthesis and purification techniques allowed for the rapid exploration of structure-activity relationships within this class and for the improvement in potency. In vitro evaluation of these derivatives demonstrated good antimicrobial activity against Gram-positive bacteria for most of the compounds. The present derivatives of 16-membered macrolides were active against MLS(B)-resistant strains that were inducibly resistant, but not those constitutively resistant to erythromycin.

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Section: Chemistrymentioning

confidence: 83%

Section: Chemistrymentioning

confidence: 99%

Section: Chemistrymentioning

confidence: 99%

Section: Chemistrymentioning

confidence: 99%

See 2 more Smart Citations

Semisynthetic Macrolide Antibacterials Derived from Tylosin. Synthesis and Structure−Activity Relationships of Novel Desmycosin Analogues

et al. 2003

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“…Researchers at PLIVA have prepared many polyhydro-derivatives of tylosin and desmycosin [108], among them 4Ј-deoxy-10,11,12,13-tetrahydro-desmycosin, which showed better antibacterial activity than tylosin [109]. Oximes of tylosin, especially desmycosin (158) and their polyhydro-derivatives (159) were prepared [110].…”

Section: -Membered Azalidesmentioning

confidence: 99%

Azalides from Azithromycin to New Azalide Derivatives

Mutak

2007

J Antibiot

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Azalides are semi-synthetic macrolides, in which a nitrogen atom is introduced into a macrolactone ring via a Beckmann rearrangement. Starting from erythromycin, oximes, depending on the reaction conditions lactams, or bicyclic-imino-ethers were formed, which were further reduced to aminolactones. The cyclic amine 9a-became the precursor for novel, significantly more active derivatives, especially for 9-dihydro-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A with the generic name azithromycin. It showed a broad spectrum of antibacterial activity covering all significant bacteria causing respiratory tract infections. The greatest advantages of azithromycin are its unusual pharmacokinetics (high tissue distribution), metabolic stability and high tolerability. These properties have led in recent years to the widespread use of the azalide scaffold for the synthesis of new compounds with advantageous pharmacokinetics.The azalide scaffold possesses an amino and several hydroxyl groups, which could be substituted or transformed to obtain new compounds. Different derivatives were obtained by substitution on the nitrogen but a large variety of derivatives, such as ethers, esters and carbamates, were made by reactions with various hydroxyl groups. Substitutions on both nitrogen and hydroxyl or two hydroxyl groups yielded new, bridged compounds. The 4Љ-hydroxy group was oxidized to 4-oxo-, which was transformed via the oxime to 4-amino, or via epoxide to 4Љ-methylamino compounds. Cleavage of the cladinose sugar and further transformations gave 3-acyl or 3-oxo compounds, which were less active than 14-membered acylides or ketolides. Beckmann rearrangement of some 16-membered macrolide oximes yielded only 17-membered lactams, which were less active than starting macrolides, and could not be reduced to amines.Intramolecular rearrangement of azalide imino-ethers yielded 13-membered azalides. Some new 11a-azalides were obtained after oxidative cleavage of some 16-membered macrolides and additional cyclisation.

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Antibiotics, Macrolides

Kirst

2001

Kirk-Othmer Encyclopedia of Chemical Technology

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Macrolide antibiotics are well‐established antimicrobial agents in clinical and veterinary medicine. These agents can be administered orally and are generally used to treat infections in the respiratory tract, skin and soft tissues, and genital tract caused by gram‐positive organisms, Mycoplasma species, and certain susceptible gram‐negative and anaerobic bacteria. The macrolide class is large and structurally diverse. Macrolides are produced by fermentation of soil microorganisms. Additionally, structural modifications using both chemical and microbiological means have yielded biologically active semisynthetic derivatives. The term macrolide was introduced to denote the class of substances produced by Streptomyces species containing a macrocyclic lactone. Traditional macrolide antibiotics are divided into three families according to the size of the aglycone, which can be a 12‐, 14‐, or 16‐membered ring. Naturally occurring 14‐membered macrolides include erythromycin A and erythromycin B, as well as others. Erythromycin has been the principal subject of modification of 14‐membered macrolides; its semisynthetic derivatives include erythromycin ethyl succinate, roxithromycin, clarithromycin, azithromycin, dirithromycin, and others. More recently, the ketolide family has been discovered that exhibits activity against certain macrolide‐resistant strains, from which telithromycin and ABT‐773 are in clinical trials. The 16‐membered macrolides are divided into leucomycin‐ and tylosin‐related groups, which differ in the substitution pattern of their aglycones. Natural products include josamycin (leucomycin A 3 ), spiramycin, and others. The most prominent member of the second group is tylosin, an important veterinary antibiotic. Semisynthetic 16‐membered macrolides include miokamycin, rokitamycin, AIV‐tylosin, and tilmicosin. The advent of molecular biology has opened new possibilities for producing novel macrolides by genetic manipulations of biosynthetic pathways from macrolide‐producing microorganisms (combinatorial biosynthesis) that complement traditional chemical and microbiological approaches. Macrolides inhibit growth of gram‐positive bacteria, Mycoplasma species, and certain gram‐negative and anaerobic bacteria. Susceptible gram‐positive bacteria include many species of Staphylococcus and Streptococcus ; susceptible gram‐negative bacteria include Bordetella pertussis, Legionella pneumophila, Moraxella catarrhalis , Campylobacter sp., Chlamydia sp., and Helicobacter pylori . Some derivatives have shown promising activity against non‐tuberculous mycobacteria. Macrolides inhibit growth of bacteria by inhibiting protein synthesis on ribosomes. Bacterial resistance to macrolides is often accompanied by cross‐resistance to lincosamide and streptogramin B antibiotics (MLS‐resistance). Bacterial resistance to antibiotics usually results from modification of a target site, enzymatic inactivation, or reduced uptake into or increased efflux from bacterial cells. The principal side effects of macrolides are gastrointestinal problems, such as pain, indigestion, diarrhea, nausea, and vomiting. Macrolide antibiotics are used clinically to treat infections resulting from susceptible organisms in the upper and lower respiratory tract, skin and soft tissues, and genital tract. They are generally used orally, although they can be given intravenously. Macrolides are regarded as among the safest of antibiotics. A few macrolides are used in veterinary medicine, such as tylosin and tilmicosin which are used to control respiratory diseases and other infections in poultry, pigs, and cattle.

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10,11,12,13-Tetrahydro Derivatives of Tylosin. II. Synthesis, Antibacterial Activity and Tissue Distribution of 4'-Deoxy-10,11,12,13-tetrahydrodesmycosin.

Cited by 6 publications

References 6 publications

Semisynthetic Macrolide Antibacterials Derived from Tylosin. Synthesis and Structure−Activity Relationships of Novel Desmycosin Analogues

Semisynthetic Macrolide Antibacterials Derived from Tylosin. Synthesis and Structure−Activity Relationships of Novel Desmycosin Analogues

Azalides from Azithromycin to New Azalide Derivatives

Antibiotics, Macrolides

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