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.

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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

Item Type: Article
Uncontrolled Keywords: Pilicide Anti-virulence 2-Pyridone peptidomimetic
Subjects: Plant sciences
Natural Product Chemistry
Depositing User: Dr. Aparna Maitra Pati
Date Deposited: 23 Apr 2012 06:31
Last Modified: 23 Apr 2012 06:31

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