Antibiotic resistance in bacteria threatens to eradicate many of the gains made against infectious disease in the Twentieth Century. As such, it is imperative that novel strategies to combat pathological bacteria are explored to the fullness of their potential. Our research group has focused on the inhibition of the biosynthetic pathway employed by bacteria to manufacture the essential amino acid tryptophan. Our research targets the fourth step in the sequence of the tryptophan biosynthetic pathway, wherein indole 3-glycerol phosphate synthase (IGPs) converts 1-(o-carboxyphenylamino) 1-deoxyribulose 5-phosphate (CdRP) to indole-3-glycerol phosphate (IGP). As there are no human homologs for IGPs, effective inhibition of the enzyme could serve as the basis for a novel class of antibiotic drugs. Three previous libraries of substituted isoxazolines have been prepared and screened for inhibition of IGPs, and several compounds showed promising results. The goal in the preparation of the current library is to improve upon the previous generation of compounds, enhancing affinity for the active site by means of halogen bonding. The research presented herein will focus on the design and synthesis of isoxazoline compounds that mimic the aromatic and carbohydrate ends of CdRP, with the addition of halogen substituents on the aromatic ring.  <br/>

Design and synthesis of halogen bonding compounds for the inhibition of IGPs

253rd National Meeting (2017)

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