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ISSN 1998-9539

Synthesis and Antibacterial Activity of Aminoalkylamides of Eremomycin

Elena I. Moiseenko,a Natalia E. Grammatikova,a and Andrey E. Shchekotikhina,b@
aG.F. Gause 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: shchekotikhin@mail.ru
 
DOI: 10.6060/mhc200812s
Macroheterocycles 2020 13 (3) 298-304
 
Increasing the effectiveness of antimicrobial agents for the treatment of bacteria-resistant infections is one of the urgent chemotherapy problems of the last decades. Macrocyclic glycopeptide vancomycin (1) remains the antibiotic of choice against diseases caused by the resistant-associated strains of gram-positive pathogens. Although its use is strictly regulated, the gradual spread of vancomycin-resistant Staphylococcus and Enterococci strains (GRSA, GISA and VRE) is a serious problem nowadays.[1–3] Along with methicillin-resistant Staphylococcus aureus (MRSA), these bacteria are included by WHO in the priority pathogens list for R&D of new antibiotics.[4] Besides, the use of vancomycin is limited by a number of disadvantages, such as histamine-releasing effects, as well as nephro- and ototoxicity.[5]
Though most new semi-synthetic glycopeptide antibiotics development researches focused on the synthesis of their hydrophobic derivatives, some of them, such as semi-synthetic lipoglycopeptides, have a number of chemotherapeutic advantages over natural glycopeptides.[6–8] A number of works published in recent years shows the promising results of introducing peripheral amino, ammonium, or guanidino groups into the structure of glycopetide antibiotics.[9–14] Additional hydrophilic aminoalkyl groups allow to increase the activity of natural glycopeptide antibiotics, and can be further used as a linker for the conjugation with hydrophobic fragments.[15] Eremomycin (2), structurally similar to vancomycin, is a promising scaffold for the development of new generation of semi-synthetic antibiotics. This glycopeptide has some advantages over vancomycin, in particular, higher antibacterial activity and slightly reduced side effects.[16–18] The most promising directions for modifying eremomycin (2) is an amidation of the C-terminus amino acid. This transformation allows increasing the activity of natural antibiotics and also has a high synthetic and economic efficiency. An application of modern condensation methods gives possibilities for the glycopeptides modification in one stage with minimal by-products formation. A series of eremomycin picolylamides and their quaternized derivatives has been described earlier.[19] Analysis of the biological properties of the obtained derivatives showed that the introduction of a pyridinyl fragment leads to a significant increasing of the antibacterial activity of eremomycin amide 3 for glycopeptide-sensitive strains and bacteria with intermediate resistance. Quaternization of the heterocycle of eremomycin picolylamide 3 by long-chain alkyls leads to an increase of the activity of cationic lipoglycopeptides against resistant strains, but is accompanied by a decrease of the activity against susceptible
strains.[19] Therefore, the aim of this work was to assess the antimicrobial potential of aminoalkyl derivatives of eremomycin amide with different alkyl chain lengths and varying the structure of linker. To achieve this goal, a series of new eremomycin amides was synthesized and the antimicrobial activity comparative study of the obtained compounds was carried out. Condensation of eremomycin sulfate (2) with diamine hydrochlorides was carried out using PyBOP in the presence of DIEA to maintain pH ~ 8, in DMSO. The optimal reagent ratio was accordingly determined as 1:9:13:1.7 (eremomycin sulfate : diamine dihydrochloride : DIEA : PyBOP). Isolation of the obtained derivatives was carried out by reprecipitation, followed by purification by reverse phase chromatography by gradient elution in a water-acetonitrile mixture. The developed method of condensation and purification gives the target aminoalkyl derivatives of eremomycin amide 4a-g with an yield of 48–65 % and acceptable purity (90.0–94.9 % according to HPLC data). The antibacterial activity of the new eremomycin amides 4a-g estimated in comparison with vancomycin (1), eremomycin (2) and its picolylamide 3 on a wide panel of gram-positive pathogens. All synthesized eremomycin aminoalkylamides 4a-g are more active than vancomycin (1), eremomycin (2) and derivative 3 against sensitive and, especially, glycopeptide-resistant bacteria. It has been shown that increase of the alkyl chain length leads to a slight decrease in the activity of the compound, and the carbon atom substitution for the ether group has little effect on the antibiotic activity. Aminoalkylamides 4a,b, that showed the highest antimicrobial activity, are promising for an in-depth study of the antibacterial spectrum, studies of antimicrobial efficacy on in vivo models, and toxicological properties testing. Moreover, the obtained derivatives 4a,b are perspective for the further structure optimization and search for new semi-synthetic glycopeptides with improved pharmacological properties.

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