(366) Copper-catalyzed cyclization reactions in pursuit of molecules that inhibit DXP synthase

Trainee Category: Graduate Student

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

Methods: Standard synthetic chemistry methods are employed. A curated set of aryl or heteroaryl cores (that mimic the enzyme cofactor) were selected based on modeling results. These cores 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 copper catalyst to yield the corresponding aryl/heteroaryl triazole, which resembles the central ring of the enzyme cofactor, TPP. Reaction outcomes varied depending upon the catalyst, solvent, and temperature used. The synthesis of 15 compounds (8 selected azides, 7 triazoles) will be presented. These compounds will be evaluated using MIC assays.

Results: An array of suitable aryl/heteroaryl triazoles were generated from precursor azides using CuAAC chemistry. Product yields vary depending upon the type of solvent, mol % of catalyst (CuI or CuSO4), reaction times (3 to 18 hours) and temperature (25-35 ºC). The triazoles were evaluated in cell-based assays towards lead identification as bacterial DXP synthase inhibitors.

Conclusions: An array of suitable aryl/heteroaryl triazoles were generated from precursor azides using CuAAC chemistry. Product yields vary depending upon the type of solvent, mol % of catalyst (CuI or CuSO4), reaction times (3 to 18 hours) and temperature (25-35 ºC). The triazoles were evaluated in cell-based assays towards lead identification as bacterial DXP synthase inhibitors.