10.1039/b811086g
The research focuses on the development of a method for the parallel synthesis and purification of N-substituted pantothenamides, which are known inhibitors of coenzyme A (CoA) biosynthesis and utilization, particularly by blocking fatty acid metabolism. The purpose of this study was to create a simple and efficient method to synthesize a range of pantothenamides from a single precursor, which could then be evaluated for their potential as antimicrobial agents. The researchers successfully developed a method based on the reactivity of activated thioesters towards amines, using S-phenyl thiopantothenate as a precursor and a variety of amines to produce a diverse library of N-substituted pantothenamides. The synthesized compounds were then purified using either cation exchange chromatography or silica chromatography, depending on the amine used. The biological evaluation of these compounds identified two previously unknown pantothenamides as inhibitors of bacterial growth, demonstrating the potential of this method in discovering new antimicrobials.
10.1021/acs.oprd.6b00059
The study presents an efficient chemoenzymatic synthesis route for coenzyme A (CoASH) and its disulfide, which is scalable to gram quantities using standard laboratory equipment. The key innovation is the use of pantethine, a disulfide derivative of pantetheine, as the biocatalytic precursor. This approach eliminates the need for a sulfhydryl protecting group and prevents sulfur oxidation by-products. The synthesis involves a five-step process starting from ?-alanine, yielding pantethine with a 76% overall yield. The three enzymes of the CoASH salvage pathway—pantetheine kinase (PanK), phosphopantetheine adenyltransferase (PPAT), and dephospho-coenzyme A kinase (DPCK)—are used to convert pantethine into CoA disulfide, a more stable form of the cofactor. The final product, CoA disulfide, can be reduced in situ to free CoASH for biochemical applications. The method avoids chromatography until the final step, facilitating scale-up, and the disulfide form of CoASH is more stable and valuable than the free thiol form.
