This paper describes the design and characterization of novel inhibitors of IleRS, whose binding affinity approaches the tightest reported for noncovalent inhibition. Compounds were designed from a binding model for the natural product pseudomonic acid-A (PS-A) together with a detailed understanding of the reaction cycle of IleRS and characterization of the mode of binding of the reaction intermediate IleAMP. The interactions of the compounds with IleRS were characterized by inhibition of aminoacylation of tRNA or PP(i)/ATP exchange at supersaturating substrate concentration and by transient kinetics and calorimetry methods. A detailed understanding of the interaction of a comprehensive series of compounds with IleRS allowed the identification of key features and hence the design of exquisitely potent inhibitors. Predictions based on these results have been recently supported by a docking model based on the crystal structure of IleRS with PS-A [Silvian, L. F., Wang J. M., and Steitz T. A. (1999) Science 285 1074-1077].

The interactions of isoleucyl-tRNA synthetase (IleRS,E

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Structure-activity relationships in a series of (5i?)-6-triazolylmethylene penems with potent /Mactamase inhibitory activity are described. In most cases, their in vitro synergistic activity with amoxycillin is superior to that of clavulanic acid, sulbactam and tazobactam (YTR830). Against an Escherichia coli TEM-1infection in mice, the compoundsshowed a broad range of potencies; an optimum polarity was found, however, which gave maximumpotency.Earlier papers in this series1~4) have described the synthesis and biological properties of a series of racemic 6-(substituted methylene)penems. Of particular interest was the triazolylmethylene penem (5b), and this paper outlines some further work on a series of triazolyl derivatives with a chiral centre at C-5. ChemistryThe (5i?,6Z)penems (5) were prepared using two routes. Route A (Scheme 1) has been described for the preparation of 5b5) and is shown schematically in full elsewhere6): it requires a 1,2,3-triazolecarboxylic Scheme 1.