Glutamyl-gamma-boronate inhibitors of bacterial Glu-tRNA(Gln) amidotransferase. |
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| Authors: | C P Decicco D J Nelson Y Luo L Shen K Y Horiuchi K M Amsler L A Foster S M Spitz J J Merrill C F Sizemore K C Rogers R A Copeland M R Harpel |
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| Affiliation: | Department of Medicinal Chemistry, DuPont Pharmaceuticals Company, Experimental Station, PO Box 80400, Wilmington, DE 19880, USA. carl.p.decicco@dupontpharma.com |
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| Abstract: | Analogues of glutamyl-gamma-boronate (1) were synthesized as mechanism-based inhibitors of bacterial Glu-tRNA(Gln) amidotransferase (Glu-AdT) and were designed to engage a putative catalytic serine nucleophile required for the glutaminase activity of the enzyme. Although 1 provides potent enzyme inhibition, structure-activity studies revealed a narrow range of tolerated chemical changes that maintained activity. Nonetheless, growth inhibition of organisms that require Glu-AdT by the most potent enzyme inhibitors appears to validate mechanism-based inhibitor design of Glu-AdT as an approach to antimicrobial development. |
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