Modifications around the carboxylate group of the tryptophanyl tRNA synthetase inhibitor Chuangxinmycin: Active non-charged analogues and tight sterical constraints

ORGN 553

Dieter W. Hamprecht1, Murray J B Brown2, Martin J. Hibbs3, Richard L. Jarvest3, Lucy Mensah3, Peter J. O'Hanlon3, Andrew J. Pope3, and Christine M. Richardson3. (1) Medicinal Chemistry, Psychiatry CEDD, GlaxoSmithKline, Via Fleming 4, 37135 Verona, Italy, (2) Medicines Research Centre, GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG1 2NY, United Kingdom, (3) GlaxoSmithKline, New Frontiers Science Park, Harlow, United Kingdom

Chuangxinmycin (CXM) is a natural product with antibacterial activity against a number of Gram-positive and Gram-negative bacteria. We recently disclosed the finding that this compound and some synthetic analogues are potent and selective (wrt. ovine WRS) inhibitors of bacterial tRNA synthetase (WRS). Structural information of CXM bound in the active site of the enzyme indicated that interactions of the carboxylic acid group are mediated through water molecules. We here report on the investigation of this interaction using modifications around the carboxylate moiety with the potential to mimic some of the functionality of this group. Alternatively we sought to replace this moiety plus one or two hydrogen bound water molecules. Results indicate that the carboxylate may be replaced by non-charged moieties if those have similar or reduced sterical requirements.

Bioorganic, Molecular Recognition, Asymmetric Reactions and Syntheses 11:00 AM-1:00 PM, Wednesday, September 10, 2003 Javits Convention Center -- Hall 1B/1C, Poster Sci-Mix 8:00 PM-10:00 PM, Monday, September 8, 2003 Javits Convention Center -- North Pavillion, Sci-Mix Division of Organic Chemistry The 226th ACS National Meeting, New York, NY, September 7-11, 2003