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A dihydrofolate reductase inhibitor (DHFR inhibitor) is a molecule that inhibits the function of dihydrofolate reductase, and is a type of antifolate.

Since folate is needed by rapidly dividing cells to make thymine, this effect may be used to therapeutic advantage. For example, methotrexate is used as cancer chemotherapy because it can prevent neoplastic cells from dividing. Bacteria also need DHFR to grow and multiply and hence inhibitors selective for bacterial vs. host DHFR have found application as antibacterial agents.

Classes of small-molecules employed as inhibitors of dihydrofolate reductase include diaminoquinazoline and diaminopyrroloquinazoline, Most of the above specified inhibitors are structural analogues of the substrate dihydrofolate and bind to the active site of the enzyme. Further, it has been recently shown that, in E. coli DHFR, allosteric site binders can inhibit the enzyme either uncompetitively or non-competitively. The examples provided below are specific molecules belonging to one of the above-mentioned classes.

• the experimental antimalarial and anti-toxoplasmosis compound JPC-2056
• Oral piritrexim, a treatment for metastatic urothelial cancer.
• Cycloguanil, a metabolite of proguanil (a component of the oral antimalarial atovaquone-proguanil, or Malarone), although this has been called into question (see its article)

References

1. Huennekens FM (1994). "The methotrexate story: a paradigm for development of cancer chemotherapeutic agents". Advances in Enzyme Regulation. 34: 397–419. doi:10.1016/0065-2571(94)90025-6. PMID 7942284.
2. McGuire JJ (2003). "Anticancer antifolates: current status and future directions". Current Pharmaceutical Design. 9 (31): 2593–613. doi:10.2174/1381612033453712. PMID 14529544.
3. Hawser S, Lociuro S, Islam K (March 2006). "Dihydrofolate reductase inhibitors as antibacterial agents". Biochemical Pharmacology. 71 (7): 941–8. doi:10.1016/j.bcp.2005.10.052. PMID 16359642.
4. Mui EJ, Schiehser GA, Milhous WK, Hsu H, Roberts CW, Kirisits M, Muench S, Rice D, Dubey JP, Fowble JW, Rathod PK, Queener SF, Liu SR, Jacobus DP, McLeod R (March 2008). "Novel triazine JPC-2067-B inhibits Toxoplasma gondii in vitro and in vivo". PLOS Neglected Tropical Diseases. 2 (3): e190. doi:10.1371/journal.pntd.0000190. PMC 2254147. PMID 18320016.
5. de Wit R, Kaye SB, Roberts JT, Stoter G, Scott J, Verweij J (February 1993). "Oral piritrexim, an effective treatment for metastatic urothelial cancer". British Journal of Cancer. 67 (2): 388–90. doi:10.1038/bjc.1993.71. PMC 1968166. PMID 8431372.

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