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Proguanil, also known as chlorguanide and chloroguanide, is a medication used to treat and
prevent malaria.[3][4] It is often used together with chloroquine or atovaquone.[4][3] When used with
chloroquine the combination will treat mild chloroquine resistant malaria. [3] It is taken by mouth.[5]
Side effects include diarrhea, constipation, skin rashes, hair loss, and itchiness. [3] Because malaria
tends to be more severe in pregnancy, the benefit typically outweighs the risk.[3] If used during
pregnancy it should be taken with folate.[3] It is likely safe for use during breastfeeding.[3] Proguanil is
converted by the liver to its active metabolite, cycloguanil.[4]
Proguanil has been studied at least since 1945. [6] It is on the World Health Organization's List of
Essential Medicines, the most effective and safe medicines needed in a health system.[7] The
wholesale cost in the developing world is about US$0.10–0.50 per day.[5] In the United States and
Canada it is only available in combination as atovaquone/proguanil.

Mechanism[edit]
When used alone, proguanil functions as a prodrug. Its active metabolite, cycloguanil, is an inhibitor
of dihydrofolate reductase(DHFR).[14] Although both mammals and parasites produce DHFR,
cycloguanil's inhibitory activity is specific for parasitic DHFR. This enzyme is a critical component of
the folic acid cycle. Inhibition of DHFR prevents the parasite from recycling dihydrofolate back
to tetrahydrofolate (THF). THF is required for DNA synthesis, amino acid synthesis, and methylation;
thus, DHFR inhibition shuts down these processes.[15]
Proguanil displays synergism when used in combination with the antimalarial atovaquone. This
mechanism of action differs from when proguanil was used as a singular agent. In this case, it is not
thought to function as a DHFR inhibitor. The addition of proguanil has shown to reduce resistance to
atovaquone and increase the ability of atovaquone to trigger a mitochondrial apoptotic cascade.
[16]
 This is commonly referred to as “collapse of the mitochondrial membrane potential.” [17] Proguanil
lowers the effective concentration of atovaquone needed to increase permeability of the
mitochondrial membrane.[18]
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