New antibacterial agents: Hybrid bioisoster derivatives as potential E. coli FabH inhibitors.

Autor: Segretti ND; Universidade de São Paulo, Faculdade de Ciências Farmacêuticas, Departamento de Farmácia, Av. Prof. Lineu Prestes, 580, 05508-900 SP, Brazil., Serafim RA; Universidade de São Paulo, Faculdade de Ciências Farmacêuticas, Departamento de Farmácia, Av. Prof. Lineu Prestes, 580, 05508-900 SP, Brazil., Segretti MC; Universidade Estadual de Campinas, Instituto de Química, Cidade Universitária 'Zeferino Vaz', Distrito de Barão Geraldo, 13083-970, Campinas, SP, Brazil., Miyata M; Universidade Estadual Paulista 'Júlio de Mesquita Filho', Faculdade de Ciências Farmacêuticas, Departamento de Ciências Biológicas, Rodovia Araraquara-Jaú km 1, 14801-902 Araraquara, SP, Brazil., Coelho FR; Universidade de São Paulo, Instituto de Química, Departamento de Bioquímica, 748, 05508-000 SP, Brazil., Augusto O; Universidade de São Paulo, Instituto de Química, Departamento de Bioquímica, 748, 05508-000 SP, Brazil., Ferreira EI; Universidade de São Paulo, Faculdade de Ciências Farmacêuticas, Departamento de Farmácia, Av. Prof. Lineu Prestes, 580, 05508-900 SP, Brazil. Electronic address: elizabeth.igne@gmail.com.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2016 Aug 15; Vol. 26 (16), pp. 3988-93. Date of Electronic Publication: 2016 Jun 30.
DOI: 10.1016/j.bmcl.2016.06.089
Abstrakt: The development of resistance to antibiotics by microorganisms is a major problem for the treatment of bacterial infections worldwide, and therefore, it is imperative to study new scaffolds that are potentially useful in the development of new antibiotics. In this regard, we propose the design, synthesis and biological evaluation of hybrid sulfonylhydrazone bioisosters/furoxans with potential antibacterial (Escherichia coli) activity. The most active compound of the series, (E)-3-methyl-4-((2-tosylhydrazono)methyl)-1,2,5-oxadiazole 2-oxide, with a MIC=0.36μM, was not cytotoxic when tested on Vero cells (IC50>100μM). To complement the in vitro screening, we also studied the interaction of the test compounds with β-ketoacyl acyl carrier protein synthase (FabH), the target for the parent compounds, and we observed three important hydrogen-bonding interactions with two important active site residues in the catalytic site of the enzyme, providing complementary evidence to support the target of the new hybrid molecules.
(Copyright © 2016 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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