Synthesis and antimycobacterial activity of imidazo[1,2-b][1,2,4,5]tetrazines.

Autor: Maslov DA; Laboratory of Bacterial Genetics, Vavilov Institute of General Genetics Russian Academy of Sciences, Moscow, 119333, Russia. Electronic address: maslov_da@vigg.ru., Korotina AV; Laboratory of Heterocyclic Compounds, Postovsky Institute of Organic Synthesis, Ural Branch of RAS, Ekaterinburg, 620990, Russia; Ural Federal University, Ekaterinburg, 620002, Russia. Electronic address: korotina@ios.uran.ru., Shur KV; Laboratory of Bacterial Genetics, Vavilov Institute of General Genetics Russian Academy of Sciences, Moscow, 119333, Russia., Vatlin AA; Laboratory of Bacterial Genetics, Vavilov Institute of General Genetics Russian Academy of Sciences, Moscow, 119333, Russia., Bekker OB; Laboratory of Bacterial Genetics, Vavilov Institute of General Genetics Russian Academy of Sciences, Moscow, 119333, Russia., Tolshchina SG; Laboratory of Heterocyclic Compounds, Postovsky Institute of Organic Synthesis, Ural Branch of RAS, Ekaterinburg, 620990, Russia; Ural Federal University, Ekaterinburg, 620002, Russia., Ishmetova RI; Laboratory of Heterocyclic Compounds, Postovsky Institute of Organic Synthesis, Ural Branch of RAS, Ekaterinburg, 620990, Russia., Ignatenko NK; Laboratory of Heterocyclic Compounds, Postovsky Institute of Organic Synthesis, Ural Branch of RAS, Ekaterinburg, 620990, Russia., Rusinov GL; Laboratory of Heterocyclic Compounds, Postovsky Institute of Organic Synthesis, Ural Branch of RAS, Ekaterinburg, 620990, Russia; Ural Federal University, Ekaterinburg, 620002, Russia., Charushin VN; Laboratory of Heterocyclic Compounds, Postovsky Institute of Organic Synthesis, Ural Branch of RAS, Ekaterinburg, 620990, Russia; Ural Federal University, Ekaterinburg, 620002, Russia., Danilenko VN; Laboratory of Bacterial Genetics, Vavilov Institute of General Genetics Russian Academy of Sciences, Moscow, 119333, Russia.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2019 Sep 15; Vol. 178, pp. 39-47. Date of Electronic Publication: 2019 May 31.
DOI: 10.1016/j.ejmech.2019.05.081
Abstrakt: Tuberculosis (TB) has recently become the leading killer among infectious diseases. Multidrug and extensively drug-resistant Mycobacterium tuberculosis strains urge the need to develop anti-TB drugs with a novel mechanism of action. We describe synthesis of 22 novel imidazo[1,2-b][1,2,4,5]tetrazine derivatives with different substituents at C(3) and C(6) positions, and their antimycobacterial activity in vitro. 8 compounds show activity as potential serine/threonine protein kinase (STPK) inhibitors in M. smegmatis aphVIII+ test-system, which is characteristic for this class. 3 compounds out of 5 most active STPK inhibitors have a prominent minimal inhibitory concentration on M. tuberculosis H37Rv of 1 μg/ml. We were able to obtain M. smegmatis mc2 155 mutants resistant to 4 compounds and show that they do not have cross resistance with other drugs, but have a common mechanism of resistance among these 4 imidazo[1,2-b][1,2,4,5]tetrazines. Compound 3h seems the most promising, combining a predicted STPK inhibitor activity, the lowest MIC on M. tuberculosis and a low frequency of drug resistant mutants' emergence.
(Copyright © 2019 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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