title: Catechol-rhodanine derivatives: Specific and promiscuous inhibitors of Escherichia coli deoxyxylulose phosphate reductoisomerase (DXR).
abstract: To develop more effective inhibitors than fosmidomycin, a natural compound which inhibits the deoxyxylulose 5-phosphate reductoisomerase (DXR), the second enzyme of the MEP pathway, we designed molecules possessing on the one hand a catechol that is able to chelate the magnesium dication and on the other hand a group able to occupy the NADPH recognition site. Catechol-rhodanine derivatives (1-6) were synthesized and their potential inhibition was tested on the DXR of Escherichia coli. For the inhibitors 1 and 2, the presence of detergent in the enzymatic assays led to a dramatic decrease of the inhibition suggesting, that these compounds are rather promiscuous inhibitors. The compounds 4 and 5 kept their inhibition capacity in the presence of Triton X100 and could be considered as specific inhibitors of DXR. Compound 4 showed antimicrobial activity against Escherichia coli. The only partial protection of NADPH against the inhibition suggested that the catechol-rhodanine derivatives did not settle in the coenzyme binding site. This paper points out the necessity to include a detergent in the DXR enzymatic assays to avoid false positive when putative hydrophobic inhibitors are tested and especially when the IC50, are in the micromolar range.
authors.affiliation: Université de Strasbourg/CNRS, Strasbourg, UMR 7177, Institut Le Bel, 4 rue Blaise Pascal, 67081 Strasbourg, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Zinglé
authors.affiliation: Université de Strasbourg/CNRS, Strasbourg, UMR 7177, Institut Le Bel, 4 rue Blaise Pascal, 67081 Strasbourg, France. Electronic address: dtritsch@unistra.fr.
authors.forename: Denis
authors.initials: D
authors.lastname: Tritsch
authors.affiliation: Université de Strasbourg/CNRS, Strasbourg, UMR 7177, Institut Le Bel, 4 rue Blaise Pascal, 67081 Strasbourg, France. Electronic address: grosdemange@unistra.fr.
authors.forename: Catherine
authors.initials: C
authors.lastname: Grosdemange-Billiard
authors.affiliation: Université de Strasbourg/CNRS, Strasbourg, UMR 7177, Institut Le Bel, 4 rue Blaise Pascal, 67081 Strasbourg, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Rohmer
mesh_terms: D019747:Aldose-Ketose Isomerases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002396:Catechols / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D012236:Rhodanine / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D002396:Catechols; D004791:Enzyme Inhibitors; D012236:Rhodanine; C114231:1-deoxy-D-xylulose 5-phosphate reductoisomerase; D019747:Aldose-Ketose Isomerases; C034221:catechol
keywords: Catechol–rhodanines; DXR; False positives; Isoprenoid; Promiscuous inhibitors