The mechanism of action of para-aminosalicylic acid (PAS), a drug used to treat drug-resistant tuberculosis (TB), has been confirmed through the first synthesis and biochemical characterization of its active metabolite 7. The synthesis features the coupling of N2-acetyl-6-formylpterin obtained from the degradation of folic acid and appropriately functionalized arylamines to form Schiff bases. The sequential chemoselective reduction of the imine and pterin ring led to the formation of dihydrofolate analogue 7 and two other dihydropteroate species.
Bibliographical noteFunding Information:
We thank Dr. Bruce Witthuhn of College of Biological Sciences at the University of Minnesota for technical assistant with LC-MS/ MS method development. This work was financially supported by a grant from the University of Minnesota Academic Health Center Faculty Research Development Program to A.D.B. and C.C.A.