Peptidoglycan is a complex heteropolymer that surrounds the cytoplasmic membrane. It consists of linear polysaccharide chains cross-linked with short peptides. Undecaprenyl diphosphate (UPP) acts as a lipid carrier in peptidoglycan biosynthesis. The enzyme that catalyzes the synthesis of UPP is an undecaprenyl diphosphate synthase (UPPS). Due to its key role in the biosynthesis of bacterial peptidoglycans, UPPS represents an interesting target for drug design.
As part of our master's thesis, we designed and synthesized derivatives of triazole and alpha-cyanocinnamic acid, which were previously discovered by virtual screening, as potential UPPS inhibitors. We used two different multistep synthetic pathways. The synthesis of derivatives of alpha-cyanocinnamic acid included the Williamson ether synthesis, Knoevenagel condensation, ester hydrolysis to carboxylic acid and amide synthesis from anthranilic acid via acid chloride method. On the other hand, the synthesis of triazole derivatives, proceeded via acylhydrazide to the thiol derivative, which can be alkylated with corresponding alkyl bromide to the final product.
We were unable to synthesize the compounds obtained by virtual screening. The main problem was the last step of ester hydrolysis to a carboxylic acid. Nevertheless, in the case of alpha-cyanocinnamic acid derivatives, we were able to develop the synthetic procedure to corresponding esters; further optimization of hydrolysis to carboxylic acids will be a challenge for the future. In the case of triazole derivatives, we could not alkylate the thiol group.
The inhibitory activity of some synthesized compounds on the UPPS enzyme was determined by biochemical evaluation. None of the compounds exhibited any inhibitory activity; however, based on the results obtained from biochemical assay we showed that a free carboxyl group is essential for the inhibitory activity of alpha-cinnamic acid derivatives on the UPPS enzyme.
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