(36) Ruthenium-catalyzed cyclization reactions in pursuit of molecules that inhibit DXP synthase

Objective : DXP synthase is a bacterial enzyme of the non-mevalonate pathway, and is being explored as target for the development of potential antibiotics. The objective is to synthesize synthesize a small library of TPP (enzyme cofactor)-resembling triazole compounds using a diverse set of aromatic or heteroaromatic cores alongside an internal alkyne using ruthenium catalysts. Biological results will also be presented.

Methods: Standard synthetic chemistry methods are employed. A set of aryl or heteroaryl cores (that mimic the enzyme cofactor) were selected. These core bear either a primary alcohol or alkyl halide, which are converted to their corresponding azides. The isolated azides are cyclized in the presence of a specific ruthenium catalyst to yield the corresponding aryl/heteroaryl triazole, which resembles the central ring of the enzyme cofactor, TPP. Product yields of these 8 compounds vary depending upon the type of solvent, catalyst, and temperature used. These compounds will be evaluated in biological assays.

Results: An array of suitable aryl/heteroaryl triazoles (~8-10) have been created using ruthenium catalysts and were then evaluated in cell-based assays to help identify lead compounds or scaffolds towards the inhibition of bacterial DXP synthase.

Conclusions: Ruthenium-based triazole generating reactions are less commonly studied, compared to their more famous metathesis counterparts. Nevertheless, they yield excellent results when traditional copper-based "click" chemistry does not work on internal alkynes. In this study, we demonstrate the utility of this procedure towards the synthesis of suitable enzyme inhibitors.