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 ß-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.
Subject(s)
Acetyltransferases/antagonists & inhibitors , Anti-Bacterial Agents/chemistry , Enzyme Inhibitors/chemistry , Escherichia coli Proteins/antagonists & inhibitors , Escherichia coli/enzymology , 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase , Acetyltransferases/metabolism , Animals , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/toxicity , Binding Sites , Candida albicans/drug effects , Catalytic Domain , Cell Survival/drug effects , Chlorocebus aethiops , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/toxicity , Escherichia coli/drug effects , Escherichia coli Proteins/metabolism , Fatty Acid Synthase, Type II/antagonists & inhibitors , Fatty Acid Synthase, Type II/metabolism , Hydrogen Bonding , Microbial Sensitivity Tests , Molecular Docking Simulation , Oxadiazoles/chemical synthesis , Oxadiazoles/chemistry , Oxadiazoles/toxicity , Static Electricity , Structure-Activity Relationship , Vero CellsABSTRACT
Several new mercaptoacetamides were synthesized and studied as HDAC6 inhibitors. One compound, 2b, bearing an aminoquinoline cap group, was found to show 1.3 nM potency at HDAC6, with >3000-fold selectivity over HDAC1. 2b also showed excellent efficacy at increasing tubulin acetylation in rat primary cortical cultures, inducing a 10-fold increase in acetylated tubulin at 1 µM. To assess possible therapeutic effects, compounds were assayed for their ability to increase T-regulatory (Treg) suppressive function. Some but not all of the compounds increased Treg function, and thereby decreased conventional T cell activation and proliferation in vitro.
