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ISSN 1998-9539

Eremomycin Picolylamides and Their Cationic Lipoglycopeptides: Synthesis and Antimicrobial Properties

Elena I. Moiseenko,a Natalia E. Grammatikova,a and Andrey E. Shchekotikhina,b@
aGause Institute of New Antibiotics, 119021 Moscow, Russian Federation
bD.I. Mendeleev University of Chemical Technology of Russia, 125047 Moscow, Russian Federation
@Corresponding author E-mail:
DOI: 10.6060/mhc181216s
In 2017, the World Health Organization (WHO) published a list of pathogens that currently pose the greatest threats to humanity. Vancomycin-resistant Staphylococcus aureus and Enterococcus faecium were included in this list as high-risk pathogens.[1,5] The creation of antibiotics with improved chemotherapeutic properties and toxicological characteristics that act on vancomycin-resistant pathogens remains a priority for the development of new antibacterial agents.[1] This achievement will help to significantly reduce the human mortality rate due to bacterial infections. Eremomycin (2) is a natural glycopeptide antibiotic that exhibits better antibacterial activity against Staphylococci and Enterococci than vancomycin; however, it’s still inactive against antibiotic-resistant Gram-positive bacteria.[6] Therefore, it is important to develop new semi-synthetic eremomycin derivatives, especially a new class of derivatives called cationic lipoglycpeptides.[9] The introduction of a cationic surfactant residue may contribute to the glycopeptide molecule’s ability to anchor to the membrane surface and empower its’ bactericidal action by a multitarget manner.[11,12] Thus, the assessment of the antimicrobial potential of previously unknown eremomycin-based cationic lipoglycopeptides and comparison of their properties with derivatives without the lipophilic cationic group was the main purpose of this study. We describe the synthesis and properties of semisynthetic cationic lipoamides of eremomycin (6a-e) and eremomycin picolylamides (6f-h). To prepare amines for eremomycin modification, a scheme for quaternized picolylamine derivatives synthesis was developed. First, N-tert-butoxycarbonylpicolylamines (4a,b) were obtained by blocking the amino group of 3(4)-picolylamines (3a,b) with the treatment with Boc-anhydride in THF. Next, intermediate 1-alkyl-(tert-butoxycarbonylaminomethyl)pyridinium salts were synthesized via quaternization of the pyridine ring of the N-Boc-picolylamines (4a,b) by boiling in 1,4-dioxane. The maximum yields for the Boc-derivatives of the pyridinium salts, 5a-e (58–65 %), were obtained with 1-alkyl halides in a 1.5-fold excess. A procedure was developed for their purification, including column chromatography on silica gel and subsequent reversed-phase chromatography on C18 silica gel using water–isopropanol. Then, upon removing the Boc protection from the 1-alkyl-N-(tert-butoxycarbonylaminomethyl)pyridinium salts followed by treatment with hydrogen chloride in methanol, quaternized picolylamines 5a-e were obtained. The structures of the quaternized picolylamines 5a-e were confirmed by a combination of 1H and 13C NMR spectra and high-resolution mass spectra (HRMS ESI). Finally, a series of cationic lipoamides of eremomycin (6a-e) with an alkyl chain of altered lengths and positions was synthesized via the condensation of eremomycin (2) with quaternized picolylamines 5a-e. Additionally, to study the effect of the quaternization of the pyridine fragment on the antibacterial properties of lipoamides, previously undescribed eremomycin picolylamides 6f-h were obtained from picolylamines 3a-c. The synthesis of amides 6a-h was performed via condensation of eremomycin (2) with amines in the presence of PyBOP and triethylamine in DMSO. Isolation and purification of the obtained derivatives was performed via re-precipitation of the crude product, followed by reversed phase chromatography on C18 silica gel with gradient elution in a water–isopropanol system. Using the developed method of condensation and purification, target derivatives 6a-h were obtained with acceptable purity (95–98.5 % according to HPLC). The structures of all eremomycin picolylamides were confirmed via high resolution mass spectrometry (HRMS ESI), and the purities and homogeneity of the samples were confirmed using HPLC. Additionally, the structure of compound 6e was confirmed by 1H NMR spectra. A study of their antibacterial properties showed that eremomycin picolylamides 6f-h have significantly greater activities against glycopeptide-sensitive strains of gram-positive pathogens compared with the original eremomycin (2) and compared with the “gold standard”, vancomycin (1). Quaternization of the pyridine fragment with long chain alkyls led to an increase in the activities of derivatives 6a-e against glycopeptide-resistant strains but was accompanied by decreasing activities against sensitive strains. The analysis showed that the cationic lipoglycopeptides are highly active against glycopeptide-resistant strains compared with the picolylamides of eremomycin 6f-h. The most active lipoglycopeptides, 6a and 6c, may be the focus of future in-depth studies of the antibacterial activity, to test their efficacy on in vivo models and to evaluate their toxicological characteristics.


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