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Synthesis and application of a bromomethyl substituted scaffold to be used for efficient optimization of anti-virulence activity

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Title Synthesis and application of a bromomethyl substituted scaffold to be used for
efficient optimization of anti-virulence activity
 
Creator Chorell, E
Bentsson, C
Banchelin, Thomas Sainte-Luce
Das, Pralay
Uvell, H
Sinha, Arun K
Pinkner, Jerome S.
Hultgren, Scott J.
Almqvis, Fredrik
 
Subject Plant sciences
Natural Product Chemistry
 
Description Pilicides are a class of compounds that attenuate virulence in Gram negative bacteria by blocking the
chaperone/usher pathway in Escherichia coli. It has also been shown that compounds derived from the
peptidomimetic scaffold that the pilicides are based on can prevent both Ab aggregation and curli
formation. To facilitate optimizations towards the different targets, a new synthetic platform has been
developed that enables fast and simple introduction of various substituents in position C-7 on the
peptidomimetic scaffold. Importantly, this strategy also enables introduction of previously unattainable
heteroatoms in this position. Pivotal to the synthetic strategy is the synthesis of a C-7 bromomethyl
substituted derivative of the ring-fused dihydrothiazolo 2-pyridone pilicide scaffold. From this versatile
and reactive intermediate various heteroatom-linked substituents could be introduced on the scaffold
including amines, ethers, amides and sulfonamides. In addition, carbon-carbon bonds could be introduced
to the sp3-hybridized bromomethyl substituted scaffold by SuzukieMiyaura cross couplings.
Evaluation of the 24 C-7 substituted compounds in whole-bacterial assays provided important structure
eactivity data and resulted in the identification of a number of new pilicides with activity as good or
better than those developed previously
 
Date 2011
 
Type Article
PeerReviewed
 
Format application/pdf
 
Identifier http://ihbt.csircentral.net/1056/1/78_Synthesis_2011.pdf
Chorell, E and Bentsson, C and Banchelin, Thomas Sainte-Luce and Das, Pralay and Uvell, H and Sinha, Arun K and Pinkner, Jerome S. and Hultgren, Scott J. and Almqvis, Fredrik (2011) Synthesis and application of a bromomethyl substituted scaffold to be used for efficient optimization of anti-virulence activity. European Journal of Medicinal Chemistry, 46. pp. 1103-1116.
 
Relation http://ihbt.csircentral.net/1056/