title: New antibacterial agents: Hybrid bioisoster derivatives as potential E. coli FabH inhibitors.
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=0.36μM, 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.
authors.affiliation: Universidade de São Paulo, Faculdade de Ciências Farmacêuticas, Departamento de Farmácia, Av. Prof. Lineu Prestes, 580, 05508-900 SP, Brazil.
authors.forename: Natanael D
authors.initials: ND
authors.lastname: Segretti
authors.affiliation: Universidade de São Paulo, Faculdade de Ciências Farmacêuticas, Departamento de Farmácia, Av. Prof. Lineu Prestes, 580, 05508-900 SP, Brazil.
authors.forename: Ricardo A M
authors.initials: RA
authors.lastname: Serafim
authors.affiliation: Universidade Estadual de Campinas, Instituto de Química, Cidade Universitária 'Zeferino Vaz', Distrito de Barão Geraldo, 13083-970, Campinas, SP, Brazil.
authors.forename: Mariana C F
authors.initials: MC
authors.lastname: Segretti
authors.affiliation: 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.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Miyata
authors.affiliation: Universidade de São Paulo, Instituto de Química, Departamento de Bioquímica, 748, 05508-000 SP, Brazil.
authors.forename: Fernando R
authors.initials: FR
authors.lastname: Coelho
authors.affiliation: Universidade de São Paulo, Instituto de Química, Departamento de Bioquímica, 748, 05508-000 SP, Brazil.
authors.forename: Ohara
authors.initials: O
authors.lastname: Augusto
authors.affiliation: 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.
authors.forename: Elizabeth I
authors.initials: EI
authors.lastname: Ferreira
mesh_terms: D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase; D000123:Acetyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D001665:Binding Sites; D002176:Candida albicans / Q000187:drug effects; D020134:Catalytic Domain; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology*; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054889:Fatty Acid Synthase, Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D006860:Hydrogen Bonding; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D055672:Static Electricity; D013329:Structure-Activity Relationship; D014709:Vero Cells
chemical_list: C528141:1,2,5-oxadiazole 2-oxide; D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D029968:Escherichia coli Proteins; D010069:Oxadiazoles; D000123:Acetyltransferases; C557158:fabH protein, E coli; D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase; D054889:Fatty Acid Synthase, Type II
keywords: Docking approach; E. coli FabH potential inhibitors; Furoxan hybrid derivatives; Sulfonylhydrazone derivatives