Synthesis and antimicrobial evaluation of 20-deoxo-20(3,5-dimethylpiperidin-1-yl)desmycosin (tilmicosin, EL-870) and related cyclic amino derivatives.

Debono, Manuel; Willard, K. E.; Kirst, Herbert A.; Wind, Julie A.; Crouse, Gary D.; Tao, E. V. P.; Vicenzi, Jeffrey T.; Counter, F. T.; Ott, J. L.; Ose, E. E.; Ōmura, Satoshi

doi:10.7164/antibiotics.42.1253

Cited by 67 publications

(44 citation statements)

References 12 publications

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“…This result indicates that introduction of 4ٞ-N-Fmoc group causes a conformational change that forosamine is close to mycarose, and then the Fmoc group shields around 4Љ-hydroxyl group in mycarose from attack of acylating agents. The formyl group of 6 was treated with a variety of amines in the presence of NaBH(OAc) 3 and AcOH to afford amine compounds 7 in high yields [10]. Finally, deprotection of the Fmoc group with piperidine, followed by methanolysis of the acetyl group provided spiramycin derivatives 3 in good yields.…”

Section: Chemistrymentioning

confidence: 99%

4″′-N-Demethylspiramycin Derivatives: Synthesis and Evaluation of Effectiveness against Drug-resistant Bacteria

et al. 2008

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18-Amino-4Љ-O-benzoyl-4ٞ-N-demethyl-18-deoxospiramycins were designed and synthesized. Synthetic strategy involved selective demethylation of the dimethylamino group in forosamine, benzoylation of the hydroxyl group at the C4Љ position and reductive Namination of the formyl group. Antibacterial characteristics of spiramycin derivatives were tested. The derivatives exhibited promising activity against drug-resistant bacterial strains. Keywords spiramycin, MRSA, demethylation, reductive N-amination IntroductionSpiramycin I (1) is a 16-membered-ring macrolide with two aminosugars, mycaminose and forosamine together with one neutral sugar mycarose (Fig. 1). It shows antibacterial activities against Gram-positive bacteria and mycoplasmas [1]. Our group has continuously studied the synthesis and biological activity of spiramycin derivatives to elucidate their structure-activity relationships [2ϳ7]. Recently, the spiramycin derivatives in our chemical library have been reinvestigated in the course of our screening for antibacterial agents. The spiramycin derivative 2a [4], one of byproducts in the silylacetal formation, was found to show moderate activity for drug-resistant bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), whereas the parent compound 1 is inactive. Structurally, 2a has 3,18-(O-silyl)acetal, 4Љ-O-TBDMS and 4ٞ-methylamino groups. However, the 3,18-(O-silyl)acetal and 4Љ-O-TBDMS groups are not appropriate for medicinal uses because of their lability under acid conditions. Nevertheless, we found that the TBDMS ether 2a can be converted to esters 2b and 2c, which maintain activity against MRSA strains [8]. Moreover, acetylene compound 2c is useful for producing 1,2,3-triazole analogues via click chemistry [9]. If the remaining silylacetal moiety in 2 is converted to other functional groups without reducing activity, it could be a promising lead compound to combat drug-resistant bacteria. Herein, we report the design, synthesis and antibacterial activity of 4ٞ-Ndemethylspiramycin derivatives 3 bearing various amines instead of the 3,18-(O-silyl)acetal moiety found in 2. ChemistrySynthesis of spiramycin derivatives 3 is summarized in Scheme 1. Selective 2Ј-acetylation of 1 with acetic anhydride yielded 2Ј-O-acetylspiramycin 4, which was converted to 4Љ-benzoyl compound 5 in 72% yield through treatment with benzoic acid and DCC in the presence of catalytic DMAP. In this acylation step, the use of benzoic anhydride or benzoyl chloride as acylating agents gave lower yields of 5, accompanied by 3,4Љ-dibenzoyl derivative. Next, we attempted selective N-demethylation of the 4ٞ-dimethylamino group in 5 using our method previously reported [6]. However, N-demethylation with NBS and NaN 3 caused decomposition of 5. After several attempts, the reaction of 5 with FmocCl and NaHCO 3 in EtOAc under reflux smoothly proceeded to provide 4ٞ- Fmoc protected spiramycin 6 in quantitative yield via Ndemethylation of the 4ٞ-dimethylamino group without formation of 3Ј-Fmoc protected spiramycin. The s...

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Section: Chemistrymentioning

confidence: 99%

4″′-N-Demethylspiramycin Derivatives: Synthesis and Evaluation of Effectiveness against Drug-resistant Bacteria

et al. 2008

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“…The second new macrolide, tilmicosin, originated from a SAR study of tylosin derivatives that had exhibited improved oral efficacy and bioavailability [14,15]. Tilmicosin is synthesised from tylosin by sequential hydrolysis of mycarose and reductive amination of the aldehyde in demycarosyltylosin (desmycosin) with 3,5-dimethylpiperidine (G) [16]. This modification enhanced antimicrobial activity against Gram-negative bacteria such as Pasteurella spp.…”

Section: -Membered-ring Macrolide Antibioticsmentioning

confidence: 99%

Macrolide antibiotics in food-animal health

Kirst

1997

Expert Opinion on Investigational Drugs

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Several 14- and 16-membered-ring macrolide antibiotics have acquired important roles in the modern production of food animals. Macrolide antibiotics exhibit many similar antimicrobial properties whether used in veterinary or human medicine. In addition to their direct inhibitory action on micro-organisms, macrolides exert a variety of subinhibitory concentration (sub-MIC) effects that are being increasingly recognised as important factors in the explanation of therapeutic results. Macrolides achieve wide tissue distribution and high intracellular concentrations that contribute prominently to their efficacy. Another important factor governing efficacy is the complex interaction between macrolides, micro-organisms, and phagocytes that may enable the host defence system to enhance the antibiotic's inhibitory action. A potential role for macrolides in modulating inflammatory processes has also been recognised. In both sub-MIC effects and interactions with the host immune system, different macrolides exert different responses that may reinforce or oppose each other. This complexity of responses requires additional studies in appropriate disease states and animal species in order to elucidate a more comprehensive understanding and explanation of in vivo outcomes.

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“…1). Tilmicosin is an important drug developed exclusively for veterinary health, which is synthesized by the introduction of a 3,5-dimethylpiperidine moiety at C-20 of desmycosin via reductive amination [6]. As a result of long half-life, tilmicosin is effective for the treatment of respiratory disease in cattle.…”

Section: Introductionmentioning

confidence: 99%

Fusion PCR-targeted tylCV gene deletion of Streptomyces fradiae for producing desmycosin, the direct precursor of tilmicosin

Min

Lv²,

Zheng

2007

Process Biochemistry

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Synthesis and antimicrobial evaluation of 20-deoxo-20(3,5-dimethylpiperidin-1-yl)desmycosin (tilmicosin, EL-870) and related cyclic amino derivatives.

Cited by 67 publications

References 12 publications

4″′-N-Demethylspiramycin Derivatives: Synthesis and Evaluation of Effectiveness against Drug-resistant Bacteria

4″′-N-Demethylspiramycin Derivatives: Synthesis and Evaluation of Effectiveness against Drug-resistant Bacteria

Macrolide antibiotics in food-animal health

Fusion PCR-targeted tylCV gene deletion of Streptomyces fradiae for producing desmycosin, the direct precursor of tilmicosin

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