Proguanil, also known as chlorguanide and chloroguanide, is a

medication Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to medical diagnosis, diagnose, cure, treat, or preventive medicine, prevent disease. Drug therapy (pharmaco ...

used to treat and prevent

malaria Malaria is a Mosquito-borne disease, mosquito-borne infectious disease that affects vertebrates and ''Anopheles'' mosquitoes. Human malaria causes Signs and symptoms, symptoms that typically include fever, Fatigue (medical), fatigue, vomitin ...

. It is often used together with

chloroquine Chloroquine is an antiparasitic medication that treats malaria. It works by increasing the levels of heme in the blood, a substance toxic to the malarial parasite. This kills the parasite and stops the infection from spreading. Certain types ...

atovaquone Atovaquone, sold under the brand name Mepron, is an antimicrobial medication for the prevention and treatment of ''Pneumocystis jirovecii'' pneumonia (PCP). Atovaquone is a chemical compound that belongs to the class of naphthoquinones. Atova ...

. When used with chloroquine the combination will treat mild chloroquine resistant malaria. It is taken by mouth. Side effects include diarrhea, constipation, skin rashes, hair loss, and itchiness. Because malaria tends to be more severe in

pregnancy Pregnancy is the time during which one or more offspring gestation, gestates inside a woman's uterus. A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Conception (biology), Conception usually occurs ...

, the benefit typically outweighs the risk. If used during pregnancy it should be taken with

folate Folate, also known as vitamin B9 and folacin, is one of the B vitamins. Manufactured folic acid, which is converted into folate by the body, is used as a dietary supplement and in food fortification as it is more stable during processing and ...

. It is likely safe for use during

breastfeeding Breastfeeding, also known as nursing, is the process where breast milk is fed to a child. Infants may suck the milk directly from the breast, or milk may be extracted with a Breast pump, pump and then fed to the infant. The World Health Orga ...

. Proguanil is converted by the liver to its active metabolite, cycloguanil. It is on the

World Health Organization's List of Essential Medicines The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health s ...

. In the United States and Canada it is only available in combination as atovaquone/proguanil.

History

When the

Japanese attack on Pearl Harbor The attack on Pearl HarborAlso known as the Battle of Pearl Harbor was a surprise military strike by the Empire of Japan on the United States Pacific Fleet at its naval base at Pearl Harbor on Oahu, Hawaii, on December 7, 1941. At the tim ...

started

World War II in the Pacific The Pacific War, sometimes called the Asia–Pacific War or the Pacific Theatre, was the Theater (warfare), theatre of World War II fought between the Empire of Japan and the Allies of World War II, Allies in East Asia, East and Southeast As ...

, the US became very interested in

antimalarial medication Antimalarial medications or simply antimalarials are a type of antiparasitic chemical agent, often natural product, naturally derived, that can be used to treat or to prevent malaria, in the latter case, most often aiming at two susceptible target ...

s and funded a large joint US-UK program to find new non-toxic and easy to produce drugs of the type. It was joined by a team led by Frank Rose at the Medical Chemicals Section of

Imperial Chemical Industries Imperial Chemical Industries (ICI) was a British Chemical industry, chemical company. It was, for much of its history, the largest manufacturer in Britain. Its headquarters were at Millbank in London. ICI was listed on the London Stock Exchange ...

(later Pharmaceuticals Division, which ended up demerged into

Zeneca Zeneca (officially Zeneca Group PLC) was a British multinational pharmaceutical company headquartered in London, United Kingdom. It was formed in June 1993 by the demerger of the pharmaceuticals and agrochemicals businesses of Imperial Chemi ...

) at

Blackley Blackley is a suburban area of Manchester, in the county of Greater Manchester, England. Historically in Lancashire, it is approximately north of Manchester city centre, on the River Irk. History The hamlet of Blackley was mentioned in the Do ...

, which earlier developed a way to manufacture

mepacrine Mepacrine, also called quinacrine or by the trade names Atabrine or Atebrin, is a medication with several uses. It is related to chloroquine and mefloquine. Although available from compounding pharmacies, as of August 2020 approved formulations ...

, an antimalarial made exclusively in Germany before the war. Rose and his colleague Frank Curd decided to concentrate on pyrimidines as relatively simple to synthetise, even though the Advisory Panel recommended against that because most antimalarials by then were either

quinoline Quinoline is a heterocyclic aromatic organic compound with the chemical formula C9H7N. It is a colorless hygroscopic liquid with a strong odor. Aged samples, especially if exposed to light, become yellow and later brown. Quinoline is only sl ...

s or

acridine Acridine is an organic compound and a nitrogen heterocycle with the formula C13H9N. Acridines are substituted derivatives of the parent ring. It is a planar molecule that is structurally related to anthracene with one of the central CH groups ...

s. Checking prospective 2,4-diaminopyridine derivatives with a basic side chain and a benzenoid moiety one after another, they noticed a geometric pattern in the effective analogs and wondered if they could reproduce their interesting biologic activity with molecules even simpler, without the pyrimidine ring, and tried

biguanide Biguanide () is the organic compound with the formula HN(C(NH)NH2)2. It is a colorless solid that dissolves in water to give a highly basic solution. These solutions slowly hydrolyse to ammonia and urea. Synthesis Biguanide can be obtained fro ...

s (then called diguanides) with which Rose was familiar due to his earlier sulphonamide research to great effect. The drug was introduced by ICI in 1945.

Medical uses

Proguanil is used for the prevention and treatment of malaria in both adults and children, particularly in areas where

-resistant ''P. falciparum'' malaria has been reported. It is usually taken in combination with

, another antimalarial drug. It is also effective in the treatment of most other multi-drug resistant forms of ''P. falciparum''; the success rate exceeds 93%.

Side effects

Proguanil is generally well tolerated, and most people do not experience side effects. However, common side effects include abdominal pain, nausea, headache, and fever. Taking proguanil with food may lessen these side effects. Proguanil should not be taken by people with severe renal impairment, pregnant women, or women who are breastfeeding children less than 5 kg. There have also been reports of increased levels of liver enzymes, which may remain high for up to 4 weeks after completion of treatment.

Mechanism

When used alone, proguanil functions as a

prodrug A prodrug is a pharmacologically inactive medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be ...

. Its active metabolite, cycloguanil, is an inhibitor of

dihydrofolate reductase Dihydrofolate reductase, or DHFR, is an enzyme that reduces dihydrofolic acid to tetrahydrofolic acid, using NADPH as an electron donor, which can be converted to the kinds of tetrahydrofolate cofactors used in one-carbon transfer chemistry. ...

(DHFR). 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. Proguanil displays

synergism In Christian theology, synergism refers to the cooperative effort between God and humanity in the process of Salvation in Christianity, salvation. Before Augustine of Hippo (354–430), synergism was almost universally endorsed. Later, it came to ...

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. This is commonly referred to as "collapse of the mitochondrial membrane potential." Proguanil lowers the effective concentration of atovaquone needed to increase permeability of the mitochondrial membrane.

References

{{Authority control Antimalarial agents Biguanides 4-Chlorophenyl compounds Drugs developed by AstraZeneca Isopropylamino compounds Prodrugs Protozoal dihydrofolate reductase inhibitors World Health Organization essential medicines Wikipedia medicine articles ready to translate