Catechol–rhodanine derivatives: Specific and promiscuous inhibitors of Escherichia coli deoxyxylulose phosphate reductoisomerase (DXR)

• Published in: Bioorganic & medicinal chemistry 2014-07, Vol.22 (14), p.3713-3719
• Main Authors: Zinglé, Catherine, Tritsch, Denis, Grosdemange-Billiard, Catherine, Rohmer, Michel
• Format: Article
• Language: English
• Subjects: Aldose-Ketose Isomerases - antagonists & inhibitors; Aldose-Ketose Isomerases - metabolism; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Catechols - chemistry; Catechols - pharmacology; Catechol–rhodanines; Dose-Response Relationship, Drug; DXR; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Escherichia coli; Escherichia coli - drug effects; Escherichia coli - enzymology; Escherichia coli - growth & development; False positives; Isoprenoid; Microbial Sensitivity Tests; Molecular Structure; Promiscuous inhibitors; Rhodanine - chemistry; Rhodanine - pharmacology; Structure-Activity Relationship
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2014.05.004

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.