Synthesis of atypically substituted carbapenems and urazoles

Despite the decline in commercial development of new antibacterial agents in recent decades, bacterial antibiotic resistance continues to evolve and disseminate at an accelerating pace. Thus there is an urgent need for the development of new antibiotics to meet this growing challenge. Carbapenems, which represent the most potent members of the β-lactam class, have broad broad-spectrum activity against Gram-positive and Gram-negative pathogens. However, with the growing usage of carbapenems, resistance inevitably develops. This suggests that the development of new carbapanems, which could avoid bacterial resistance factors, would have significant clinical utility. Within this thesis I will present new antibiotics, which are designed and synthesized to potentially present more potent activity against highly resistant Gram-negative pathogens. Specifically, the new carbapenems are designed with modifications on C5 and C6 positions. Also, new synthetic methodology was developed to facilitate the use of urazoles as potential scaffolds for drug discovery

β-Lactamase Inhibition by 7-Alkylidenecephalosporin Sulfones: Allylic Transposition and Formation of An Unprecedented Stabilized Acyl-Enzyme

The inhibition of the class A SHV-1 β-lactamase by 7-(tert-butoxycarbonyl)methylidenecephalosporin sulfone was examined kinetically, spectroscopically, and crystallographically. An 1.14 Å X-ray crystal structure shows that the stable acyl-enzyme, which incorporates an eight-membered ring, is a covalent derivative of Ser70 linked to the 7-carboxy group of 2-H-5,8-dihydro-1,1-dioxo-1,5-thiazocine-4,7-dicarboxylic acid. A cephalosporin-derived enzyme complex of this type is unprecedented, and the rearrangement leading to its formation may offer new possibilities for inhibitor design. The observed acyl-enzyme derives its stability from the resonance stabilization conveyed by the β-aminoacrylate (i.e., vinylogous urethane) functionality as there is relatively little interaction of the eight-membered ring with active site residues. Two mechanistic schemes are proposed, differing in whether, subsequent to acylation of the active site serine and opening of the β-lactam, the resultant dihydrothiazine fragments on its own or is assisted by an adjacent nucleophilic atom, in the form of the carbonyl oxygen of the C7 tert-butyloxycarbonyl group. This compound was also found to be a submicromolar inhibitor of the class C ADC-7 and PDC-3 β-lactamases

β‑Lactamase Inhibition by 7‑Alkylidenecephalosporin Sulfones: Allylic Transposition and Formation of an Unprecedented Stabilized Acyl-Enzyme

The inhibition of the class A SHV-1 β-lactamase by 7-(<i>tert</i>-butoxycarbonyl)­methyl­idene­cephalo­sporin sulfone was examined kinetically, spectroscopically, and crystallographically. An 1.14 Å X-ray crystal structure shows that the stable acyl-enzyme, which incorporates an eight-membered ring, is a covalent derivative of Ser70 linked to the 7-carboxy group of 2-<i>H</i>-5,8-dihydro-1,1-dioxo-1,5-thiazocine-4,7-dicarboxylic acid. A cephalosporin-derived enzyme complex of this type is unprecedented, and the rearrangement leading to its formation may offer new possibilities for inhibitor design. The observed acyl-enzyme derives its stability from the resonance stabilization conveyed by the β-aminoacrylate (i.e., vinylogous urethane) functionality as there is relatively little interaction of the eight-membered ring with active site residues. Two mechanistic schemes are proposed, differing in whether, subsequent to acylation of the active site serine and opening of the β-lactam, the resultant dihydrothiazine fragments on its own or is assisted by an adjacent nucleophilic atom, in the form of the carbonyl oxygen of the C7 <i>tert</i>-butyloxycarbonyl group. This compound was also found to be a submicromolar inhibitor of the class C ADC-7 and PDC-3 β-lactamases