Unprecedented Epimerization of an Azithromycin Analogue: Synthesis, Structure and Biological Activity of 2'-Dehydroxy-5″-Epi-Azithromycin.

Certain macrolide antibiotics, azithromycin included, possess anti-inflammatory properties that are considered fundamental for their efficacy in the treatment of chronic inflammatory diseases, such as diffuse pan-bronchiolitis and cystic fibrosis. In this study, we disclose a novel azithromycin analog obtained via Barton-McCombie oxidation during which an unprecedented epimerization on the cladinose sugar occurs. Its structure was thoroughly investigated using NMR spectroscopy and compared to the natural epimer, revealing how the change in configuration of one single stereocenter (out of 16) profoundly diminished the antimicrobial activity through spatial manipulation of ribosome binding epitopes. At the same time, the anti-inflammatory properties of parent macrolide were retained, as demonstrated by inhibition of LPS- and cigarette-smoke-induced pulmonary inflammation. Not surprisingly, the compound has promising developable properties including good oral bioavailability and a half-life that supports once-daily dosing. This novel anti-inflammatory candidate has significant potential to fill the gap in existing anti-inflammatory agents and broaden treatment possibilities.

Design, synthesis and antibacterial evaluation of novel 3-O-substituted 15-membered azalides possessing 1,2,3-triazole side chains.

The acquired and intrinsic resistance of bacteria to macrolide antibiotics limits the clinical application of these agents, and thus it is particularly important to discover novel macrolide antibiotics that can be administered to counteract the prevalence of bacterial resistance. In this study, we introduced some active 1,2,3-triazole side chains into the azithromycin at position 3-O, thereby obtaining a number of 3-O-substituted 15-membered azalides. Determination of the minimum inhibitory concentration (MIC) of these target compounds revealed that the compound 9g possessed the strongest antibacterial activity (MIC = 8-16 µg/mL) against drug-resistant strains and was generally 16- to 32-fold more active than the azithromycin (MIC ≥ 256 µg/mL). Combined analysis of the results of antibacterial activity together with theoretically calculated lipid/water partition coefficients (ClogP) indicated the importance of the chemical nature of the alkyl groups attached to the 1,2,3-triazole side chain in conferring promising antibacterial activity. The findings of molecular docking analyses indicated that compound 9g may bind to the A752 base of 23S rRNA in bacterial ribosome via hydrophobic or electrostatic interactions, resulting in the excellent antibacterial activity of this compound. Furthermore, the data of minimum bactericidal concentration revealed that compounds 9e, 9f, 9g and 9h are excellent bacteriostatic agents. In addition, the study of bactericidal kinetics confirmed that compound 9g is a time- and concentration-dependent agent.

Combining Powder Formulations of Drugs with Food and Beverages to Improve Palatability.

The taste of medicines can significantly affect patient adherence. Pediatric patients often cannot take powder medicines because of their unpleasant taste. Therefore, patients' parents and health care professionals, including pharmacists, often combine medicines with food or beverages to make them easier for pediatric patients to consume because this can reduce their unpleasant taste. The purpose of this study was to evaluate the palatability of powder formulations of azithromycin and carbocysteine and explore their combination with food or beverages to improve palatability for pediatric patients. We quantitatively evaluated the palatability of powder formulations by performing the gustatory sensation test using the visual analog scale score. The gustatory sensation tests were performed on 16 healthy adult volunteers (age 23.0 ± 2.6 years) and indicated that some food and beverages improved the palatability of the powder formulations of azithromycin and carbocysteine. The results of this study indicate that ice cream improves the palatability of azithromycin, while yogurt improves the palatability of carbocysteine. Moreover, the subjects recommended these same combinations for pediatric patients. This study suggests that some foods and beverages improve the palatability of powder formulations, thereby decreasing the possibility that pediatric patients will refuse medications because of their unpleasant taste.

Synthesis and evaluation of biological activity for dual-acting antibiotics on the basis of azithromycin and glycopeptides.

One of the promising directions of the combined approach is the design of dual-acting antibiotics - heterodimeric structures on the basis of antimicrobial agents of different classes. In this study a novel series of azithromycin-glycopeptide conjugates were designed and synthesized. The structures of the obtained compounds were confirmed using NMR spectroscopy and mass spectrometry data including MS/MS analysis. All novel hybrid antibiotics were found to be either as active as azithromycin and vancomycin against Gram-positive bacterial strains or have superior activity in comparison with their parent antibiotics. One compound, eremomycin-azithromycin conjugate 16, demonstrated moderate activity against Enterococcus faecium and Enterococcus faecalis strains resistant to vancomycin, and equal to vancomycin's activity for the treatment of mice with Staphylococcus aureus sepsis.

Synthesis and evaluation of biological activity of benzoxaborole derivatives of azithromycin.

Novel benzoxaborole derivatives of azithromycin in which benzoxaborole residue is attached to the 4″-hydroxy-group of azithromycin have been synthesized. Antibacterial activity of synthesized derivatives in comparison with azithromycin was tested on a panel of Gram-positive and Gram-negative bacterial strains. All the investigated compounds demonstrated broad spectrum of antibacterial activity being in general more active against Gram-positive strains. New benzoxaborole derivatives of azithromycin demonstrated high activity against Streptococcus pyogenes ATCC 19615 and Propionibacterium acnes ATCC 6919 strains. Some of the new compounds were more active than azithromycin against Streptococcus pneumoniae ATCC 49619 strain or Enterococcus faecium strains. Using a reporter construct created on the basis of the transcription attenuator region of the Escherichia coli tryptophan operon pRFPCER-TrpL2A it has been demonstrated that the mechanism of action of azithromycin analogs is blocking nascent peptide in ribosome tunnel.

Synthesis and antibacterial activity of novel 4″-O-(1-aralkyl-1,2,3-triazol-4-methyl-carbamoyl) azithromycin analogs.

Three novel structural series of 4″-O-(1-aralkyl-1,2,3-triazol-4-methyl-carbamoyl) azithromycin analogs were designed, synthesized and evaluated for their in vitro antibacterial activity. All the target compounds exhibited excellent activity against erythromycin-susceptible Streptococcus pyogenes, and significantly improved activity against three phenotypes of erythromycin-resistant Streptococcus pneumoniae compared with clarithromycin and azithromycin. Among the three series of azithromycin analogs, the novel series of 11,4″-disubstituted azithromycin analogs 9a-k exhibited the most effective and balanced activity against susceptible and resistant bacteria. Among them, compound 9j showed the most potent activity against Staphylococcus aureus ATCC25923 (0.008µg/mL) and Streptococcus pyogenes R2 (1µg/mL). Besides, all the 11,4″-disubstituted azithromycin analogs 9a-k except 9f shared the identical activity with the MIC value <0.002µg/mL against Streptococcus pyogenes S2. Furthermore, compounds 9g, 9h, 9j and 9k displayed significantly improved activity compared with the references against all the three phenotypes of resistant S. pneumoniae. Particularly, compound 9k was the most effective (0.06, 0.03 and 0.125µg/mL) against all the erythromycin-resistant S. pneumoniae expressing the erm gene, the mef gene and the erm and mef genes, exhibiting 2133, 133 and 2048-fold more potent activity than azithromycin, respectively.

Actividad in vitro de azitromicina en aislados fecales de Aeromonas hydrophila / In-vitro activity of azithromycin in faecal isolates of Aeromonas hydrophila

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Synthesis and antibacterial activity of novel 3-O-descladinosylazithromycin derivatives.

Novel series of novel 3-O-arylalkylcarbamoyl descladinosylazithromycin derivatives with the 2'-O-acetyl and 11,12-cyclic carbonate groups, the 11,12-cyclic carbonate group and the 11-O-arylalkylcarbamoyl side chain, and 2'-O-arylalkylcarbamoyl descladinosylazithromycin with the 11,12-cyclic carbonate group were designed, synthesized and evaluated for their antibacterial activity using broth microdilution method. The results showed that the majority of the target compounds showed moderate to favorable activity against six kinds of susceptible strains and almost all of them displayed significantly improved activity compared with references against three erythromycin-resistant strains of S. pneumoniae B1 expressing the ermB gene, S. pneumoniae AB11 expressing the ermB and mefA genes, and S. pyogenes R1. In particular, compound 6h exhibited the most potent activity against susceptible B. subtilis ATCC9372 (0.5 µg/mL), penicillin-resistant S. epidermidis (0.125 µg/mL), and erythromycin-resistant S. pneumoniae B1 (1 µg/mL) and S. pneumoniae AB11 (1 µg/mL), which were 2-, 2-, 256-, 256-fold better activity than azithromycin, respectively. Additionally, compounds 6f (0.5 µg/mL) and 6g (0.25 µg/mL) were the most active against S. pneumoniae A22072, which were 8- and 16-fold better activity than azithromycin (4 µg/mL). As for erythromycin-resistant S. pyogenes R1, compound 5a presented the most excellent activity (8 µg/mL), showing 32- and 32-fold higher activity than azithromycin (256 µg/mL) and clarithromycin (256 µg/mL).

Synthesis and antibacterial evaluation of novel 4″-glycyl linked quinolyl-azithromycins with potent activity against macrolide-resistant pathogens.

A new azithromycin-based series of antibacterial macrolones is reported, which features the use of a 4″-ester linked glycin for tethering the quinolone side chain to the macrolide scaffold. Among the analogs prepared, compounds 9e and 22f with a quinolon-6-yl moiety were found to have potent and well-balanced activity against clinically important respiratory tract pathogens, including erythromycin-susceptible and MLSB resistant strains of Streptococcus pneumoniae, Streptococcus pyogenes, and Haemophilus influenzae. In addition, potential lead compounds 9e and 22f demonstrated outstanding levels of activity against Moraxella catarrhalis and inducibly MLSB resistant Staphylococcus aureus. The best member of this series 22f rivals or exceeds, in potency, some of the most active ketolide antibacterial agents known today, such as telithromycin and cethromycin.

Hybrid Antibiotics Based on Azithromycin and Glycopeptides: Synthesis and Antibacterial Activity.

A series of hybrid antibiotics on the basis of azithromycin and glycopeptides with the glycopeptide molecule attached via the aminoalkylcarbamoyl spacer to 11-position of the macrolide was synthesized. All the synthesized compounds demonstrated equal or superior to azithromycin and vancomycin antibacterial activity against 7 tested strains of grampositive bacteria. The new hybrid antibiotics were more active than azithromycin or vancomycin against S.pneumoniae ATCC 49619. Some of the compounds were active against E.faecium and E.faecalis strains resistant to vancomycin.

In Vitro Anti-inflammatory and Antimicrobial Activities of Azithromycin After Loaded in Chitosan- and Tween 20-Based Oil-in-Water Macroemulsion for Acne Management.

The objectives of the current investigation are (1) to prepare and characterize (particle size, surface charge (potential zeta), surface morphology by transmission electron microscopy, drug content, and drug release) the azithromycin (AZM, 100 mg)-loaded oil-in-water (o/w) macroemulsion, (2) to assess the toxicity of macroemulsion with or without AZM using RBC lysis test in comparison with AZM in phosphate buffer solution of pH 7.4, (3) to compare the in vitro antimicrobial activity (in Escherichia coli using zone inhibition assay) of AZM-loaded macroemulsion with its aqueous solution, and (4) to assess the in vitro anti-inflammatory effect (using egg albumin denaturation bioassay) of the AZM-loaded macroemulsion in comparison with diclofenac sodium in phosphate buffer solution of pH 7.4. The AZM-loaded macroemulsion possessed the dispersed oil droplets with a mean diameter value of 52.40 ± 1.55 µm. A reversal in the zeta potential value from negative (-2.16 ± 0.75 mV) to positive (+6.52 ± 0.96 mV) was noticed when AZM was added into the macroemulsion. At a 1:5 dilution ratio, 2.06 ± 0.03 mg of drug was released from macroemulsion followed by 1.01 ± 0.01 and 0.25 ± 0.08 mg, respectively, for 1:10 and 1:40 dilution ratios. Antimicrobial activity maintenance and significant reduction of RBC lysis property were noticed for AZM after loaded in the macroemulsion. However, an increment in the absorbance values for emulsion-treated samples in comparison to the control samples was noticed in the anti-inflammatory test. This speculates the potential of the AZM-loaded emulsion to manage inflammatory conditions produced at Acne vulgaris.

Design, synthesis and biological evaluation of azithromycin glycosyl derivatives as potential antibacterial agents.

A series of 11,12-cyclic carbonate azithromycin-4″-O-carbamoyl glycosyl derivatives were designed, synthesized, and evaluated as antibacterial agents to search for target compounds with excellent activity. The results of preliminary antibacterial tests against eight strains in vitro revealed that all of the title compounds exhibited improved activities with broad spectrum compared with the parent compound. The glycosylated side chains may be the pharmacophores responsible for the improved activity.

Synthesis and antibacterial evaluation of novel 11,4″-disubstituted azithromycin analogs with greatly improved activity against erythromycin-resistant bacteria.

A series of novel 11,4″-disubstituted azithromycin analogs were synthesized and evaluated for their antibacterial activity. All the 11,4″-disubstituted analogs exhibited excellent activity (0.03-0.12 µg/ml) against erythromycin-susceptible Streptococcus pneumoniae, and significantly improved activity against three phenotypes of erythromycin-resistant S. pneumoniae compared with erythromycin A, clarithromycin or azithromycin. Among them, compounds 26-28 showed the most potent activity (0.25, 0.03 and 2 µg/ml) against S. pneumoniae expressing the erm gene, the mef gene and the erm and mef genes, respectively. In addition, compound 28 was the most effective (0.03 and 0.12 µg/ml) against erythromycin-susceptible S. pneumoniae and Staphylococcus aureus as well. It is noteworthy that the most active compounds described above possess the same terminal 3,5-dinitrophenyl groups on their C-4″ bisamide side chains.

Synthesis and activity of new macrolones: conjugates between 6(7)-(2'-aminoethyl)-amino-1-cyclopropyl-3-carboxylic acid (2'-hydroxyethyl) amides and 4″-propenoyl-azithromycin.

A set of novel macrolones containing the flexible C8 basic linker and quinolone 3-(2'-hydroxyethyl)carboxamido group has been prepared and structurally characterized by NMR and IR spectroscopy, mass spectrometry and molecular modeling. The new compounds were evaluated in vitro against a panel of erythromycin-susceptible and erythromycin-resistant Gram-positive and Gram-negative bacterial strains. Compared to azithromycin, most of the compounds exhibited improved in vitro potency against the key respiratory pathogens.

Novel C-4'' modified azithromycin analogs with remarkably enhanced activity against erythromycin-resistant Streptococcus pneumoniae: the synthesis and antimicrobial evaluation.

Three novel structural series of C-4'' modified azithromycin analogs with two amide groups, which were connected by different alkyl linkage, were designed, prepared and evaluated for their in vitro antibacterial activity against seven phenotypes of respiratory pathogens. Among them, 7d, 8j and 9j, as representatives of corresponding series, exhibited remarkably improved activity against erythromycin-resistant Streptococcus pneumoniae expressing the erm gene, the mef gene, and the erm and mef genes. In addition, 7a-c, 7f-h, 7j, 8d, 8g, 8i, 9a-b and 9i displayed favorable efficacy against erythromycin-resistant S. pneumoniae A22072 expressing the mef gene.

Synthesis, activity and pharmacokinetics of novel antibacterial 15-membered ring macrolones.

Synthesis, antibacterial activity and pharmacokinetic properties of a novel class of macrolide antibiotics-macrolones-derived from azithromycin, comprising oxygen atom(s) in the linker and either free or esterified quinolone 3-carboxylic group, are reported. Selected compounds showed excellent antibacterial potency towards key erythromycin resistant respiratory pathogens. However, the majority of compounds lacked good bioavailability. The isopropyl ester, compound 35, and a macrolone derivative with an elongated linker 29 showed the best oral bioavailability in rats, both accompanied with an excellent overall microbiology profile addressing inducible and constitutive MLSb as well as efflux mediated macrolide resistance in streptococci, while compound 29 is more potent against staphylococci.

Synthesis and antibacterial activity of novel 3-O-carbamoyl derivatives of clarithromycin and 11,12-cyclic carbonate azithromycin.

Two series of novel 3-O-carbamoyl derivatives of clarithromycin and 11,12-cyclic carbonate azithromycin were designed, synthesized and evaluated for their in vitro antibacterial activities. Compounds 4j and 4k were the most potent activity against erythromycin-susceptible Staphylococcus aureus, Streptococcus pyogenes and Streptococcus pneumoniae, which were comparable to those of clarithromycin and azithromycin. Compounds 4d, 4h and 4i showed potent activity against erythromycin-resistant S. pneumoniae encoded by the mef gene and compounds 4h and 4i displayed greatly improved activity against erythromycin-resistant S. pneumoniae encoded by the erm gene. Compound 7c exhibited improved activity against erythromycin-resistant S. pneumoniae encoded by the erm and mef genes.

Synthesis and antibacterial activity of novel 11,12-cyclic carbonate azithromycin 4''-O-carbamate derivatives.

A series of novel 11,12-cyclic carbonate azithromycin 4''-O-carbamate derivatives were designed, synthesized and evaluated for their in vitro antibacterial activities. Compounds 7b and 7d were the most effective (0.5 and 0.5 microg ml(-1)) against two strains of erythromycin-resistant Streptococcus pneumoniae whose resistance was encoded by the erm gene and the erm and mef genes, respectively. Compounds 7a, 7e and 7g showed significantly potent activity against erythromycin-susceptible strains such as Staphylococcus aureus and S. pyogenes. These results suggest that the introduction of the prolonged arylalkylcarbamoyl group to the C-4'' position can dramatically enhance the activity against erythromycin-resistant bacteria encoded by the erm gene or the erm and mef genes.

Synthesis and antibacterial activity of novel 15-membered macrolide derivatives: 4''-carbamate, 11,12-cyclic carbonate-4''-carbamate and 11,4''-di-O-arylcarbamoyl analogs of azithromycin.

4''-Carbamate, 11,12-cyclic carbonate-4''-carbamate and 11,4''-di-O-arylcarbamoyl analogs of azithromycin were designed, synthesized and evaluated. The 4''-carbamate analogs retained excellent activity against erythromycin-susceptible Staphylococcus pneumoniae and showed improved activity against erythromycin-resistant Staphylococcus pneumoniae. Compared with 4''-carbamate analogs, 11,12-cyclic carbonate-4''-carbamate analogs exhibited improved activity against erythromycin-resistant Staphylococcus pneumoniae encoded by the mef gene or the erm and mef genes, and 11,4''-di-O-arylalkylcarbamoyl analogs showed greatly improved activity (0.25-0.5 microg/mL) against erythromycin-resistant Staphylococcus pneumoniae encoded by the erm gene. Among them, the novel series of 11,4''-di-O-arylalkylcarbamoyl analogs 7a-k exhibited potent and balanced activity against susceptible and resistant bacteria. In particular, compounds 7f and 7k were the most effective against susceptible bacteria and resistant bacteria encoded by the erm gene or the mef gene.

Synthesis and antibacterial activity of 4'',11-di-O-arylalkylcarbamoyl azithromycin derivatives.

A series of new 4'',11-di-O-arylalkylcarbamoyl azithromycin derivatives were designed, synthesized and evaluated for their in vitro antibacterial activities. Some derivatives exhibited greatly improved activity against erythromycin-resistant bacteria. Among them, compounds 5f and 5k were found to have potent activity against erythromycin-resistant Streptococcus pneumoniae whose resistance was encoded by the erm or mef gene.