Anna Blood

Date of Award

2019

Document Type

Thesis

Degree Name

Bachelors

Department

Natural Sciences

First Advisor

Sherman, Suzanne

Area of Concentration

Chemistry

Abstract

Bacteria’s ease of developing resistance and fast rate of reproduction leads to a constant demand for new antibiotics. Since bacterial cell wall biosynthesis is independent of mammalian cell biosynthesis, it is a great antibiotic target. Biosynthesis of the peptidoglycan, a component of the bacterial cell wall, requires D-alanine. By inhibiting alanine racemase and preventing isomerization of L-alanine to D-alanine, the biosynthesis should be disrupted, and the bacteria should die. This thesis contributes to a library of possible alanine racemase inhibitors synthesized from amino heterocycles and amino acids. The inhibitors were designed with the goal of being in equilibrium of neutral and zwitterionic forms in order to efficiently pass through the cell wall of bacteria, and to be small and similar in structure to alanine in order to bind and inhibit alanine racemase. Six tert-butyloxycarbonyl-protected intermediates were synthesized: tert-butyl (2-((1,3,4-thiadiazol-2-yl)amino)-2-oxoethyl)carbamate (60%), tert-butyl (2-oxo-2-(thiazol-2-ylamino)ethyl)carbamate (59%), tert-butyl (1-((1,3,4-thiadiazol-2-yl)amino)-1-oxopropan-2-yl)carbamate (24%), tert-butyl (1-oxo-1-(thiazol-2-ylamino)propan-2-yl)carbamate (6%), tert-butyl (3-((1,3,4-thiadiazol-2-yl)amino)-3-oxopropyl)carbamate (22%), tert-butyl (3-oxo-3-(thiazol-2-ylamino)propyl)carbamate (4%). Four final target inhibitors were synthesized: 2-amino-N-(1,3,4-thiadiazol-2-yl)acetamide, 2-amino-N-(thiazol-2-yl)acetamide, 2-amino-N-(1,3,4-thiadiazol-2-yl)propanamide, and 3-amino-N-(1,3,4-thiadiazol-2-yl)propanamide. The yields for the inhibitors could not be calculated accurately due to their high hygroscopicity. An efficient synthesis for the remaining compounds will be worked towards and their antibacterial properties will be tested.

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