Inhibitors for the bacterial ectonucleotidase Lp1NTPDase from Legionella pneumophila. Issue 18 (15th September 2016)

• Record Type: Journal Article
• Authors: Fiene, Amelie; Baqi, Younis; Malik, Enas M.; Newton, Patrice; Li, Wenjin; Lee, Sang-Yong; Hartland, Elizabeth L.; Müller, Christa E.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 24:Issue 18(2016)
• Page Start: 4363
• Page End: 4371
• Publication Date: 2016-09-15
• Subjects: Anthraquinone -- Antibacterial drug -- Capillary electrophoresis -- Ecto-5′-nucleotidase -- Legionnaires' disease -- Lpg1905 -- NTPDase -- Reactive Blue 2 -- Structure–activity relationships -- Synthesis; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2016.07.027
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Legionella pneumophila is an aerobic, Gram-negative bacterium of the genus Legionella, which constitutes the major causative agent of Legionnaires' disease. Recently a nucleoside triphosphate diphosphohydrolase (NTPDase) from L. pneumophila was identified and termed Lp1NTPDase; it was found to be a structural and functional homolog of mammalian NTPDases catalyzing the hydrolysis of ATP to ADP and ADP to AMP. Its activity is believed to contribute to the virulence of Legionella pneumophila . Therefore Lp1NTPDase inhibitors are considered as novel antibacterial drugs. However, only weakly potent compounds are available so far. In the present study, a capillary electrophoresis (CE)-based enzyme assay for monitoring the Lp1NTPDase activity was established. The enzymatic reaction was performed in a test tube followed by separation of substrate and products by CE and subsequent quantification by UV analysis. After kinetic characterization of the enzyme, a series of 1-amino-4-ar(alk)ylamino-2-sulfoanthraquinone derivatives structurally related to the anthraquinone dye Reactive Blue 2, a non-selective ecto-NTPDase inhibitor, was investigated for inhibitory activity on Lp1NTPDase using the CE-based enzyme assay. Derivatives bearing a large lipophilic substituent (e.g., fused aromatic rings) in the 4-position of the 1-amino-2-sulfoanthraquinone showed the highest inhibitory activity. Compounds with IC50 values in the low micromolar range were identified. The most potent inhibitor was 1-amino-4-[phenanthrene-9-yl-amino]-9, 10-dioxo-9, 10-dihydroanthracene-2-sulfonate (28, PSB-16131), with an IC50 -value of 4.24 μM. It represents the most potent Lp1NTPDase inhibitor described to date. These findings may serve as a starting point for further optimization. Lp1NTPDase inhibition provides a novel approach for the (immuno)therapy of Legionella infections.