Please use this identifier to cite or link to this item: http://hdl.handle.net/10995/103077
Title: Stereochemical aspects in the synthesis of novel N-(purin-6-yl)dipeptides as potential antimycobacterial agents
Authors: Musiyak, V. V.
Nizova, I. A.
Chulakov, E. N.
Sadretdinova, L. S.
Tumashov, A. A.
Levit, G. L.
Krasnov, V. P.
Issue Date: 2021
Publisher: Springer
Citation: Stereochemical aspects in the synthesis of novel N-(purin-6-yl)dipeptides as potential antimycobacterial agents / V. V. Musiyak, I. A. Nizova, E. N. Chulakov, et al. — DOI 10.1007/s00726-021-02958-0 // Amino Acids. — 2021. — Vol. 53. — Iss. 3. — P. 407-415.
Abstract: The synthesis of purine conjugates with natural amino acids is one of the promising directions in search for novel therapeutic agents, including antimycobacterial agents. The purpose of this study was to synthesize N-(purin-6-yl)dipeptides containing the terminal fragment of (S)-glutamic acid. To obtain the target compounds, two synthetic routes were tested. The first of them is based on coupling of N-(purin-6-yl)-(S)-amino acids to dimethyl (S)-glutamate in the presence of carbodiimide coupling agent followed by the removal of ester groups. However, it turned out that this coupling process was accompanied by racemization of the chiral center of N-(purin-6-yl)-α-amino acids and in all cases led to mixtures of (S,S)- and (R,S)-diastereomers (6:4). Individual (S,S)-diastereomers were obtained using an alternative approach based on the nucleophilic substitution of chlorine in 6-chloropurine or 2-amino-6-chloropurine with corresponding dipeptides as nucleophiles. The enantiomeric purity of the target compounds was confirmed by chiral HPLC. To test the assumption that racemization of the chiral center of N-(purin-6-yl)-α-amino acids occurs with the participation of nitrogen atoms of the imidazole ring via the stage of formation of a chirally labile intermediate, we obtained such structural analogs of N-(purin-6-yl)-(S)-alanine as N-(9-benzylpurin-6-yl)-(S)-alanine and N-(7-deazapurin-6-yl)-(S)-alanine. It was found that coupling of these compounds to dimethyl (S)-glutamate was also accompanied by racemization. This indicates that the imidazole fragment does not play a crucial role in this process. When testing the antimycobacterial activity of some of the obtained compounds, conjugates with moderate activity against the laboratory Mycobacterium tuberculosis H37Rv strain (MIC 3.1–6.25 μg/mL) were identified. © 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH, AT part of Springer Nature.
Keywords: ANTIMYCOBACTERIAL ACTIVITY
COUPLING
DIPEPTIDES
NUCLEOPHILIC SUBSTITUTION
PURINE
RACEMIZATION
ANTIMYCOBACTERIAL AGENT
CYANAMIDE
GLUTAMIC ACID
N(PURIN 6 YL)ALANINE
N(PURIN 6 YL)DIPEPTIDE
N(PURIN 6 YL)PHENYLALANINE
N(PURIN 6 YL)VALINE
UNCLASSIFIED DRUG
ANTIBACTERIAL ACTIVITY
ANTIMYCOBACTERIAL ACTIVITY
ARTICLE
CHEMICAL REACTION
CONJUGATION
COUPLING PROCESS
DIASTEREOISOMER
DRUG STRUCTURE
DRUG SYNTHESIS
ENANTIOMER
HIGH PERFORMANCE LIQUID CHROMATOGRAPHY
MINIMUM INHIBITORY CONCENTRATION
MYCOBACTERIUM TUBERCULOSIS
NONHUMAN
PRIORITY JOURNAL
RACEMIZATION
STEREOCHEMISTRY
URI: http://hdl.handle.net/10995/103077
Access: info:eu-repo/semantics/openAccess
SCOPUS ID: 85101238737
PURE ID: 21031660
08ce0a5f-8439-4b66-b6f9-91df51d579b6
ISSN: 9394451
DOI: 10.1007/s00726-021-02958-0
metadata.dc.description.sponsorship: The work was financially supported by the Russian Science Foundation (Grant 19-13-00231). We are grateful to Dr. Marionella A. Kravchenko [Ural Research Institute of Phthisiopulmonology (National Medical Research Center, Ministry of Healthcare of the Russian Federation, Ekaterinburg, Russia)] for conducting biological trials. Analytical studies were carried out using equipment of the Centre for Joint Use ?Spectroscopy and Analysis of Organic Compounds? at the Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences.
RSCF project card: 19-13-00231
Appears in Collections:Научные публикации, проиндексированные в SCOPUS и WoS CC

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