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Eur J Med Chem. 2010 Sep;45(9):3752-61. doi: 10.1016/j.ejmech.2010.05.024. Epub 2010 May 20.

Synthesis and structure activity relationship studies of novel Staphylococcus aureus Sortase A inhibitors.

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  • 1Department of Chemistry, University of Alabama at Birmingham, 901, 14th Street South, Birmingham, AL 35294-1240, USA.


Synthetic methods have been developed for lead Sortase A inhibitors identified from previous studies. Several derivatives of the lead inhibitor were synthesized to derive preliminary structure activity relationships (SAR). Different regions of the lead inhibitor that are critical for the enzyme activity have been determined by systematic SAR studies. The E stereochemistry of the lead compound was found to be critical for its activity. Replacement of the E double bond with Z double bond or a rigid triple bond reduced the enzyme inhibitory activity in most cases. Reduction of the double bond to a C-C single bond resulted in complete loss of activity. Amide carbonyl and NH groups were also found to be crucial for the activity of this class of inhibitors, as well. The morpholine ring oxygen atom was also found to be an important factor for the activity of the lead inhibitor. Preliminary SAR studies led to the identification of compounds with improved enzyme inhibition. The most active compound was found to have an IC(50) value of 58 microM against the enzyme.

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