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Design and Synthesis of Fluorescent Acyclic Nucleoside Phosphonates as Potent Inhibitors of Bacterial Adenylate Cyclases.
- Source :
-
ChemMedChem [ChemMedChem] 2016 Nov 21; Vol. 11 (22), pp. 2534-2546. Date of Electronic Publication: 2016 Oct 24. - Publication Year :
- 2016
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Abstract
- Bordetella pertussis adenylate cyclase toxin (ACT) and Bacillus anthracis edema factor (EF) are key virulence factors with adenylate cyclase (AC) activity that substantially contribute to the pathogenesis of whooping cough and anthrax, respectively. There is an urgent need to develop potent and selective inhibitors of bacterial ACs with prospects for the development of potential antibacterial therapeutics and to study their molecular interactions with the target enzymes. Novel fluorescent 5-chloroanthraniloyl-substituted acyclic nucleoside phosphonates (Cl-ANT-ANPs) were designed and synthesized in the form of their diphosphates (Cl-ANT-ANPpp) as competitive ACT and EF inhibitors with sub-micromolar potency (IC <subscript>50</subscript> values: 11-622 nm). Fluorescence experiments indicated that Cl-ANT-ANPpp analogues bind to the ACT active site, and docking studies suggested that the Cl-ANT group interacts with Phe306 and Leu60. Interestingly, the increase in direct fluorescence with Cl-ANT-ANPpp having an ester linker was strictly calmodulin (CaM)-dependent, whereas Cl-ANT-ANPpp analogues with an amide linker, upon binding to ACT, increased the fluorescence even in the absence of CaM. Such a dependence of binding on structural modification could be exploited in the future design of potent inhibitors of bacterial ACs. Furthermore, one Cl-ANT-ANP in the form of a bisamidate prodrug was able to inhibit B. pertussis ACT activity in macrophage cells with IC <subscript>50</subscript> =12 μm.<br /> (© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Subjects :
- Adenylyl Cyclase Inhibitors chemical synthesis
Adenylyl Cyclase Inhibitors chemistry
Animals
Dose-Response Relationship, Drug
Fluorescent Dyes chemical synthesis
Fluorescent Dyes chemistry
Macrophages drug effects
Mice
Molecular Structure
Nucleosides chemical synthesis
Nucleosides chemistry
Organophosphonates chemical synthesis
Organophosphonates chemistry
Structure-Activity Relationship
Adenylyl Cyclase Inhibitors pharmacology
Adenylyl Cyclases metabolism
Bordetella pertussis enzymology
Drug Design
Fluorescent Dyes pharmacology
Nucleosides pharmacology
Organophosphonates pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1860-7187
- Volume :
- 11
- Issue :
- 22
- Database :
- MEDLINE
- Journal :
- ChemMedChem
- Publication Type :
- Academic Journal
- Accession number :
- 27775243
- Full Text :
- https://doi.org/10.1002/cmdc.201600439