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

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 Aβ 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 sp(3)-hybridized bromomethyl substituted scaffold by Suzuki-Miyaura cross couplings. Evaluation of the 24 C-7 substituted compounds in whole-bacterial assays provided important structure-activity data and resulted in the identification of a number of new pilicides with activity as good or better than those developed previously.

MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Infektionsmedicin hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine Infectious Medicine hsv//eng
NATURVETENSKAP Kemi Organisk kemi hsv//swe
NATURAL SCIENCES Chemical Sciences Organic Chemistry hsv//eng
NATURVETENSKAP Kemi Oorganisk kemi hsv//swe
NATURAL SCIENCES Chemical Sciences Inorganic Chemistry hsv//eng
MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper Läkemedelskemi hsv//swe
MEDICAL AND HEALTH SCIENCES Basic Medicine Medicinal Chemistry hsv//eng
Pilicide
Anti-virulence
2-Pyridone
peptidomimetic
Infectious diseases
Infektionssjukdomar
Organic chemistry
Organisk kemi
Bio-inorganic chemistry
Bio-oorganisk kemi
Pharmaceutical chemistry
Läkemedelskemi
Organic synthesis
Organisk syntes
Biorganic Chemistry
bioorganisk kemi
Infectious Diseases
infektionssjukdomar
computational linguistics
datorlingvistik
organisk kemi
Organic Chemistry

Bengtsson, ChristofferUmeå universitet,Kemiska institutionen(Swepub:umu)chrben00 (författare)
Sainte-Luce Banchelin, ThomasUmeå universitet,Kemiska institutionen(Swepub:umu)thsa0024 (författare)
Das, PralayUmeå universitet,Kemiska institutionen (författare)
Uvell, HannaUmeå universitet,Kemiska institutionen(Swepub:umu)hauv0001 (författare)
Sinha, Arun KUmeå universitet,Kemiska institutionen (författare)
Pinkner, Jerome SDepartment of Molecular Microbiology, Washington University, School of Medicine, St. Louis, Missouri 63110, USA (författare)
Hultgren, Scott JDepartment of Molecular Microbiology, Washington University, School of Medicine, St. Louis, Missouri 63110, USA (författare)
Almqvist, FredrikUmeå universitet,Kemiska institutionen(Swepub:umu)fral0001 (författare)
Umeå universitetKemiska institutionen (creator_code:org_t)

Ingår i:European Journal of Medicinal Chemistry: Elsevier Masson SAS46:4, s. 1103-11160223-52341768-3254

Av författaren/redakt...: Chorell, Erik; Bengtsson, Chris ...; Sainte-Luce Banc ...; Das, Pralay; Uvell, Hanna; Sinha, Arun K; visa fler...; Pinkner, Jerome ...; Hultgren, Scott ...; Almqvist, Fredri ...; visa färre...

Om ämnet

MEDICIN OCH HÄLSOVETENSKAP: MEDICIN OCH HÄLS ...; och Klinisk medicin; och Infektionsmedici ...

MEDICIN OCH HÄLSOVETENSKAP: MEDICIN OCH HÄLS ...; och Medicinska och f ...; och Läkemedelskemi

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