Synthesis and Analysis of Bacterial Folate Metabolism Intermediates and Antifolates

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 N-2-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.