Synthesis and Antibacterial Activity of a Novel Class of 15-Membered Macrolide Antibiotics, “11a-Azalides”

Sugimoto, Toshitsugu; Tanikawa, Tetsuya

doi:10.1021/ml100252s

Cited by 9 publications

(3 citation statements)

References 33 publications

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“…Macrocyclic compounds presented in this paper were synthesized using the FideltaMacro approach (Scheme ). The first step is macrocyclic ring opening of A by oxidative cleavage of the 11,12-diol moiety with lead(IV) acetate to afford the seco compound B , which is suitable for further modification of the secondary amino group and insertion of desired motifs, fragments, potential pharmacophores, and hot-spots from protein–protein interactions. Intermediate B still contains the 11C-13C fragment of the macrolide, which serves as a protecting group for the carboxylic acid group on 1C atom.…”

Section: Resultssupporting

confidence: 70%

Macrolide Inspired Macrocycles as Modulators of the IL-17A/IL-17RA Interaction

et al. 2021

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Interleukin 17 (IL-17) cytokines promote inflammatory pathophysiology in many autoimmune diseases, including psoriasis, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. Such broad involvement of IL-17 in various autoimmune diseases makes it an ideal target for drug discovery. Psoriasis is a chronic inflammatory disease characterized by numerous defective components of the immune system. Significantly higher levels of IL-17A have been noticed in lesions of psoriatic patients, if compared to non-lesion parts. Therefore, this paper is focused on the macrolide inspired macrocycles as potential IL-17A/IL-17RA modulators and covers the molecular design, synthesis, and in vitro profiling. Macrocycles are designed to diversify and enrich chemical space through different ring sizes and a variety of three-dimensional shapes. Inhibitors in the nM range were identified in both target-based and phenotypic assays. In vitro ADME as well as in vivo PK properties are reported.

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Section: Resultssupporting

confidence: 70%

Macrolide Inspired Macrocycles as Modulators of the IL-17A/IL-17RA Interaction

et al. 2021

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“…Later, a series of C9-oximes ether ketolides bearing N-aryl-alkyl acetamides were also synthesized, where the length of the alkyl group differed by up to five atoms (Iwaki et al, 2005;Nomura et al, 2005;Nomura et al, 2006). Other structure modifications included the following: modified 5-O-desosamine ketolides (Chen et al, 2012), fluorination at the C2-and/or C12 positions (Denis and Bonnefoy, 2001;Krokidis et al, 2014), variation of the cyclic carbonate and hydrazono-carbamate at 11,12 positions (Hunziker et al, 2004;Andreotti et al, 2007;Zhu et al, 2007) or variation of the aglycon ring (Shaw et al, 2005;Ashley et al, 2006;Sugimoto and Tanikawa, 2010). Lastly, modifications also included replacement of desosamine with different sugars Romero et al, 2005;Chen et al, 2012).…”

Section: Antimicrobial Activity and Chemical Derivatizationmentioning

confidence: 99%

The macrolide antibiotic renaissance

Dinos

2017

British J Pharmacology

311

221

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Macrolides represent a large family of protein synthesis inhibitors of great clinical interest due to their applicability to human medicine. Macrolides are composed of a macrocyclic lactone of different ring sizes, to which one or more deoxy-sugar or amino sugar residues are attached. Macrolides act as antibiotics by binding to bacterial 50S ribosomal subunit and interfering with protein synthesis. The high affinity of macrolides for bacterial ribosomes, together with the highly conserved structure of ribosomes across virtually all of the bacterial species, is consistent with their broad-spectrum activity. Since the discovery of the progenitor macrolide, erythromycin, in 1950, many derivatives have been synthesised, leading to compounds with better bioavailability and acid stability and improved pharmacokinetics. These efforts led to the second generation of macrolides, including well-known members such as azithromycin and clarithromycin. Subsequently, in order to address increasing antibiotic resistance, a third generation of macrolides displaying improved activity against many macrolide resistant strains was developed. However, these improvements were accompanied with serious side effects, leading to disappointment and causing many researchers to stop working on macrolide derivatives, assuming that this procedure had reached the end. In contrast, a recent published breakthrough introduced a new chemical platform for synthesis and discovery of a wide range of diverse macrolide antibiotics. This chemical synthesis revolution, in combination with reduction in the side effects, namely, 'Ketek effects', has led to a macrolide renaissance, increasing the hope for novel and safe therapeutic agents to combat serious human infectious diseases.

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“…A lot of research has been directed at improving the bioavailability and pharmacokinetic and pharmacodynamic properties of the macrolides (Zuckerman et al, 2009;Ma and Ma, 2010), through structural modifications, and this field remains of great interest (Liang et al, 2010;Sugimoto and Tanikawa, 2011).…”

Section: Bioavailabilitymentioning

confidence: 99%

Macrolide Antibiotics

2012

Antibacterial Agents

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Synthesis and Antibacterial Activity of a Novel Class of 15-Membered Macrolide Antibiotics, “11a-Azalides”

Cited by 9 publications

References 33 publications

Macrolide Inspired Macrocycles as Modulators of the IL-17A/IL-17RA Interaction

Macrolide Inspired Macrocycles as Modulators of the IL-17A/IL-17RA Interaction

The macrolide antibiotic renaissance

Macrolide Antibiotics

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