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

Author(s)

Segretti, Natanael D. ; Serafim, Ricardo A. M. ; Segretti, Mariana C. F. ; Miyata, Marcelo ; Coelho, Fernando R. ; Augusto, Ohara ; Ferreira, Elizabeth I.

• Document type: Journal article
• Source: Bioorganic & Medicinal Chemistry Letters; v. 26, n. 16, p. 3988-3993, AUG 15 2016.
• Web of Science Citations: 5

Abstract

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 = 0.36 mu M, was not cytotoxic when tested on Vero cells (IC50 > 100 mu M). To complement the in vitro screening, we also studied the interaction of the test compounds with beta-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. (C) 2016 Elsevier Ltd. All rights reserved. (AU)

• FAPESP's process: 13/07937-8 - Redoxome - Redox Processes in Biomedicine
• Grantee: Ohara Augusto
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC