Synthesis and Characterization of Naproxen-Salicylate Derivatives as Potential Dual-Targeted Inhibitors of Dihydrofolate Reductase

Abstract

Dihydrofolate reductase (DHFR) is an enzyme that catalyzes the reduction of dihydrofolate (DHF) to tetrahydrofolate (THF). Chemotherapy drugs such as methotrexate help to slow the progression of cancer by limiting the ability of dividing cells to make nucleotides by competitively inhibiting DHFR. Nonsteroidal anti-inflammatory drugs (NSAIDs) have been previously reported to exhibit competitive inhibition of DHFR, in addition to their primary action on cyclooxygenase enzymes. This interaction interferes with the enzymatic reduction of dihydrofolate to tetrahydrofolate, thereby impeding the folate metabolism pathway essential for nucleotide synthesis and cell proliferation.