The document discusses dihydrofolate reductase (DHFR) inhibitors. It describes DHFR as an enzyme that converts dihydrofolate to tetrahydrofolate, which is involved in processes like thymidylate and purine synthesis. DHFR inhibitors block this conversion, depleting tetrahydrofolate and disrupting DNA synthesis. Some common DHFR inhibitors mentioned are methotrexate, trimethoprim, pyrimethamine, and proguanil. These are used as cancer chemotherapeutics, antibacterials, and to treat parasites. Side effects can include bone marrow suppression, gastrointestinal issues, and hepatotoxicity.

1. Shakshi Gupta Y17150144. January 7,2021
Dihydrofolate Reductase Inhibitors
Pharmaceutical Medicinal Chemistry III
Submitted to
Dr. Adarsh Sahu
(GUEST FACULTY, DOPS, DHSGU, SAGAR)
Department of Pharmaceutical Sciences
Session 2020-2021

2. Enzyme

3. Dihydrofolate reductase (DHFR)
DHFR is a ubiquitous enzyme that catalyzes the NADPH-dependent conversion of 7,8-dihydrofolate (DHF) to 5,6,7,8-tetrahydrofolate
(THF) (5), which is involved in subsequent metabolic reactions such as thymidylate and purine nucleotide biosynthesis.
•
Fig a . DHFR in folic acid ; Fig b. De Novo pyrimidine synthesis

4. Dihydrofolate reductase inhibitor
A dihydrofolate reductase inhibitor (DHFR inhibitor) is a molecule that inhibits the function of dihydrofolate reductase, and is a
type of antifolate.
Cancer cancer chemotherap
y
Anti fungal and anti protozoan
agent
Antibacterial agent
s
Inhibits urinary tract infection

5. Mechanism of action
• Inhibition of the enzyme dihydrofolate reductase (DHFR) depletes the available tetrahydrofolate
• Blocks the formation of thymidylate, purines, the amino acids methionine and glycine, other cell constituents.
• Lack of thymidylate disrupts DNA synthesis and cell growth ceases.
• Inhibit the enzyme either uncompetitively or non-competitively.

6. DHFR is currently targeted by
•methotrexate (MTX) and trimetrexate (both anticancer),
•trimethoprim (TMP, antibacterial),
•pyrimethamine (PYR, anti-protozoan) ,
•proguanil (antimalarial) and others

7. •Proguanil has been approved by the FDA in a
fi
xed-dose combination with atovaquone for the treatment and
prophylaxis of infections with P. falciparum
.
•DHFR inhibitors used for antiparasitic therapy include pyrimethamine, trimethoprim, proguanil, and
trimetrexate
.
•Pyrimethamine with sulfadiazine is the treatment of choice for toxoplasmosis in most clinical settings
.
•Pyrimethamine has been used with clindamycin in this clinical setting to circumvent HIV-infected patients who
require prolonged therapy for toxoplasmosis
.
•Trimethoprim-sulfamethoxazole, commonly formulated in a 1 : 5 ratio, is the treatment and prophylaxis of
choice for P. jirovecii
.
•Trimethoprim-sulfamethoxazole is the recommended therapy for any patient with Cystoisospora belli infection,
although relapse is common among patients with AIDS.

8. General side effects
•Skin reactions are the most common adverse events of sulfonamides
.
•Proguanil also is associated with oral ulcerations, hair loss, scaling of palms and soles, and urticaria
.
•The toxicity most commonly associated with the DHFR inhibitors is bone marrow suppression,
gastrointestinal tract complaints, and hepatotoxicity which usually can be
alleviated by folinic acid supplementation.