Syntheses and Biological Evaluations of Hydroxamate Containing and N-Methylthiolated β-Lactams as Potential Therapeutic Agents

With our current antibiotic arsenal dwindling, the need for new antibiotics with novel mechanisms is needed. Described herein are the syntheses of sets of hydroxamate containing monobactams, bicyclic β-lactams, and cephalosporins in addition to their biological evaluations.

Chapter 1 provides a general introduction to antibiotics and the β-lactam family with an emphasis on utilizing the β-lactam core for delivery of medicinal agents. The Chapter then concludes with a preview of the present work in addition to key literature precedent. Chapters 2-4 detail studies on the syntheses of monobactams, bicyclic hydroxamate containing β-lactams, and cephalosporins bearing hydroxamate functionality. As reported, a number of compounds exhibited notable antibacterial activity and/or β-lactamase inhibitory activity. Chapter 5 discusses the synthesis of hydroxamate containing β-lactam systems bearing an alkylthio linkage between hydroxamate and β-lactam. Chapter 6 presents the syntheses of an intriguing library of hydroxamate containing, N-methylthiolated monobactams. A number of compounds exhibited significant anti-TB and β-lactamase inhibitory activity, with MIC values in the range of 25 to <0.19 μM against TB, and Ki values in the range of 25-0.03 μM against purified NDM-1 and VIM-1 lysate metallo β-lactamases. Chapter 7 then focuses on the syntheses and biological evaluations of penicillins and cephalosporins possessing O-substituted hydroxamates as alternative “ionizable” groups in place for the carboxylate. Many of these compounds have potent activity against a variety of Gram-positive bacteria. Lastly, Chapter 8 discusses the design, syntheses, and anti-tuberculosis activities for a number of cephalosproin-pBTZ conjugates. These conjugates showed notable anti-tuberculosis activity with MIC values in the range of 4.6 to 1.5 μM.