Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Proguanil: Difference between pages

{{Short description|Chemical compound}}

{{Use dmy dates|date=March 2024}}

{{cs1 config |name-list-style=vanc |display-authors=6}}

| Watchedfields = changed

| verifiedrevid = 464215377

| image = Proguanil.svg

| alt =

| image2 = Proguanil molecule spacefill.png

| alt2 =

<!-- Clinical data -->

| tradename = Paludrine, others

| routes_of_administration = [[Oral administration|By mouth]]

| ATC_prefix = P01

| ATC_suffix = BB01

| ATC_supplemental = {{ATC|P01|BB51}}, {{ATC|P01|BB52}}

| legal_status = Rx-only

<!-- Pharmacokinetic data -->

| protein_bound = 75%

| metabolism = By [[liver]] ([[CYP2C19]])

| elimination_half-life = 12–21 hours<ref>{{cite web|title=Malarone (atovaquone/proguanil) Tablets, Pediatric Tablets. Full Prescribing Information|url=https://www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing_Information/Malarone/pdf/MALARONE.PDF|publisher=GlaxoSmithKline. Research Triangle Park, NC 27709|access-date=14 July 2016|url-status=live|archive-url=https://web.archive.org/web/20160920173748/https://www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing_Information/Malarone/pdf/MALARONE.PDF|archive-date=20 September 2016}}</ref>

| metabolites = [[cycloguanil]] and 4-chlorophenylbiguanide

<!-- Identifiers -->

| ChEBI_Ref = {{ebicite|correct|EBI}}

| synonyms = chlorguanide, chloroguanide<ref>{{cite book| vauthors = Mehlhorn H | chapter = Proguanil |title=Encyclopedia of Parasitology: A-M|date=2008|publisher=Springer Science & Business Media|isbn=9783540489948|page=388| chapter-url =https://books.google.com/books?id=Jpg1ysgVn-AC&pg=PA388|language=en|url-status=live|archive-url=https://web.archive.org/web/20161220074710/https://books.google.ca/books?id=Jpg1ysgVn-AC&pg=PA388|archive-date=20 December 2016}}</ref>

<!-- Chemical data -->

| IUPAC_name = 1-[amino-(4-chloroanilino)methylidene]-2-propan-2-ylguanidine

| C=11 | H=16 | Cl=1 | N=5

| SMILES = Clc1ccc(NC(=N/C(=N/C(C)C)N)N)cc1

| melting_point = 129

<!-- Definition and medical uses -->

'''Proguanil''', also known as '''chlorguanide''' and '''chloroguanide''', is a [[medication]] used to treat and prevent [[malaria]].<ref name=WHO2008/><ref name=AHFS2016/> It is often used together with [[chloroquine]] or [[atovaquone]].<ref name=AHFS2016/><ref name=WHO2008>{{cite book | title = WHO Model Formulary 2008 | year = 2009 | isbn = 9789241547659 | vauthors = ((World Health Organization)) | veditors = Stuart MC, Kouimtzi M, Hill SR | hdl = 10665/44053 | author-link = World Health Organization | publisher = World Health Organization |pages=199, 203 }}</ref> When used with chloroquine the combination will treat mild chloroquine resistant malaria.<ref name=WHO2008/> It is taken by mouth.<ref name=AHFS2016/>

<!-- Side effects and mechanism -->

Side effects include diarrhea, constipation, skin rashes, hair loss, and itchiness.<ref name=WHO2008/> Because malaria tends to be more severe in [[pregnancy]], the benefit typically outweighs the risk.<ref name=WHO2008/> If used during pregnancy it should be taken with [[folate]].<ref name=WHO2008/> It is likely safe for use during [[breastfeeding]].<ref name=WHO2008/> Proguanil is converted by the liver to its active metabolite, [[cycloguanil]].<ref name=AHFS2016>{{cite web|title=Atovaquone and Proguanil Hydrochloride|url=https://www.drugs.com/monograph/atovaquone-and-proguanil-hydrochloride.html|publisher=The American Society of Health-System Pharmacists|access-date=8 December 2016|url-status=live|archive-url=https://web.archive.org/web/20161220223925/https://www.drugs.com/monograph/atovaquone-and-proguanil-hydrochloride.html|archive-date=20 December 2016}}</ref>

It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}</ref> In the United States and Canada it is only available in combination as [[atovaquone/proguanil]].<ref>{{Cite web|url=http://reference.medscape.com/drug/paludrine-proguanil-342692|title=Proguanil|website=www.medscape.com|publisher=Medscape|access-date=8 November 2016|url-status=live|archive-url=https://web.archive.org/web/20161109152802/http://reference.medscape.com/drug/paludrine-proguanil-342692|archive-date=9 November 2016}}</ref>

== History ==

When the [[Japanese attack on Pearl Harbor]] started [[World War II in the Pacific]], the US became very interested in [[antimalarial medication]]s and funded a large joint US-UK program to find new non-toxic and easy to produce drugs of the type.<ref name="Quirke">{{cite journal | url=https://www.academia.edu/7066790 | title=War and Change in the Pharmaceutical Industry: A Comparative Study of Britain and France in the Twentieth Century | journal=Entreprises et Histoire | year=2004 | volume=36 | issue=2 | page=64 | vauthors = Quirke VM | doi=10.3917/eh.036.0064 }}</ref> It was joined by a team led by [[Frank Rose (chemist)|Frank Rose]] at the Medical Chemicals Section of [[Imperial Chemical Industries]] (later Pharmaceuticals Division, which ended up [[Demerger|demerged]] into [[Zeneca]]) at [[Blackley]], which earlier developed a way to manufacture [[mepacrine]], an antimalarial made exclusively in Germany before the war.<ref name="Quirke" />

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]]s or [[acridine]]s. Checking prospective 2,4-diaminopyridine derivatives with a basic side chain and a benzenoid [[Moiety (chemistry)|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]]s (then called diguanides) with which Rose was familiar due to his earlier sulphonamide research to great effect.<ref name="pmid11616178">{{cite journal | vauthors = Suckling CW, Langley BW | title = Francis Leslie Rose: 27 June 1909-3 March 1988 | journal = Biographical Memoirs of Fellows of the Royal Society | volume = 36 | issue = | pages = 491–524 (503-505) | date = 1990 | pmid = 11616178 | doi = 10.1098/rsbm.1990.0041| s2cid = 40302178 | url = https://royalsocietypublishing.org/doi/pdf/10.1098/rsbm.1990.0041 }}</ref> 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 [[chloroquine]]-resistant [[Plasmodium falciparum|''P. falciparum'']] malaria has been reported. It is usually taken in combination with [[atovaquone]], another antimalarial drug.<ref>{{Cite encyclopedia|url=https://medlineplus.gov/ency/article/000621.htm|title=Malaria | encyclopedia = MedlinePlus Medical Encyclopedia | publisher = U.S. National Library of Medicine |access-date=16 November 2016|url-status=live|archive-url= https://web.archive.org/web/20161117064956/https://medlineplus.gov/ency/article/000621.htm |archive-date=17 November 2016}}</ref>

It is also effective in the treatment of most other multi-drug resistant forms of ''P. falciparum''; the success rate exceeds 93%.<ref>{{cite journal | vauthors = Boggild AK, Parise ME, Lewis LS, Kain KC | title = Atovaquone-proguanil: report from the CDC expert meeting on malaria chemoprophylaxis (II) | journal = The American Journal of Tropical Medicine and Hygiene | volume = 76 | issue = 2 | pages = 208–223 | date = February 2007 | pmid = 17297027 | doi = 10.4269/ajtmh.2007.76.208 | doi-access = free }}</ref>

==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.<ref>{{Cite web|url=http://www.mayoclinic.org/drugs-supplements/atovaquone-and-proguanil-oral-route/side-effects/drg-20061484|title=Atovaquone And Proguanil (Oral Route) Side Effects | work = Mayo Clinic |access-date=8 November 2016|url-status=live|archive-url=https://web.archive.org/web/20161109090547/http://www.mayoclinic.org/drugs-supplements/atovaquone-and-proguanil-oral-route/side-effects/drg-20061484|archive-date=9 November 2016}}</ref> Proguanil should not be taken by people with severe renal impairment, pregnant women, or women who are breastfeeding children less than 5&nbsp;kg.<ref>{{Cite web|url=https://www.cdc.gov/malaria/travelers/drugs.html|title=CDC - Malaria - Travelers - Choosing a Drug to Prevent Malaria | work = U.S. Centers for Disease Control and Prevention (CDC) |access-date=8 November 2016|url-status=live|archive-url=https://web.archive.org/web/20161113071230/http://www.cdc.gov/malaria/travelers/drugs.html|archive-date=13 November 2016}}</ref> There have also been reports of increased levels of liver enzymes, which may remain high for up to 4 weeks after completion of treatment.<ref>{{cite journal | vauthors = Looareesuwan S, Wilairatana P, Chalermarut K, Rattanapong Y, Canfield CJ, Hutchinson DB | title = Efficacy and safety of atovaquone/proguanil compared with mefloquine for treatment of acute Plasmodium falciparum malaria in Thailand | journal = The American Journal of Tropical Medicine and Hygiene | volume = 60 | issue = 4 | pages = 526–532 | date = April 1999 | pmid = 10348224 | doi = 10.4269/ajtmh.1999.60.526 | s2cid = 32365159 | doi-access = }}</ref>

==Mechanism==

When used alone, proguanil functions as a [[prodrug]]. Its active metabolite, [[cycloguanil]], is an inhibitor of [[dihydrofolate reductase]] (DHFR).<ref>{{Cite web|url=https://pubchem.ncbi.nlm.nih.gov/compound/proguanil#section=Top|title= Proguanil {{!}} C11H16ClN5 | work = PubChem | publisher = U.S. National Library of Medine |access-date=13 November 2016|url-status=live|archive-url=https://web.archive.org/web/20161114165700/https://pubchem.ncbi.nlm.nih.gov/compound/proguanil#section=Top|archive-date=14 November 2016}}</ref> 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 [[Tetrahydrofolic acid|tetrahydrofolate]] (THF). THF is required for DNA synthesis, amino acid synthesis, and methylation; thus, DHFR inhibition shuts down these processes.<ref>{{cite journal | vauthors = Boggild AK, Parise ME, Lewis LS, Kain KC | title = Atovaquone-proguanil: report from the CDC expert meeting on malaria chemoprophylaxis (II) | journal = The American Journal of Tropical Medicine and Hygiene | volume = 76 | issue = 2 | pages = 208–223 | date = February 2007 | pmid = 17297027 | doi = 10.4269/ajtmh.2007.76.208 | doi-access = free }}</ref>

Proguanil displays [[synergy#Drug synergy|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.<ref>{{cite journal | vauthors = Srivastava IK, Vaidya AB | title = A mechanism for the synergistic antimalarial action of atovaquone and proguanil | journal = Antimicrobial Agents and Chemotherapy | volume = 43 | issue = 6 | pages = 1334–1339 | date = June 1999 | pmid = 10348748 | pmc = 89274 | doi = 10.1128/AAC.43.6.1334 }}</ref> This is commonly referred to as "collapse of the mitochondrial membrane potential."<ref>{{cite journal | vauthors = Srivastava IK, Rottenberg H, Vaidya AB | title = Atovaquone, a broad spectrum antiparasitic drug, collapses mitochondrial membrane potential in a malarial parasite | journal = The Journal of Biological Chemistry | volume = 272 | issue = 7 | pages = 3961–3966 | date = February 1997 | pmid = 9020100 | doi = 10.1074/jbc.272.7.3961 | doi-access = free }}</ref> Proguanil lowers the effective concentration of atovaquone needed to increase permeability of the mitochondrial membrane.<ref>{{cite journal | vauthors = Thapar MM, Gupta S, Spindler C, Wernsdorfer WH, Björkman A | title = Pharmacodynamic interactions among atovaquone, proguanil and cycloguanil against Plasmodium falciparum in vitro | journal = Transactions of the Royal Society of Tropical Medicine and Hygiene | volume = 97 | issue = 3 | pages = 331–337 | date = May 2003 | pmid = 15228254 | doi = 10.1016/S0035-9203(03)90162-3 | doi-access = }}</ref>

== References ==

{{Reflist}}

{{Antimalarials}}

{{Portal bar | Medicine}}

{{Authority control}}

[[Category:Antimalarial agents]]

[[Category:Biguanides]]

[[Category:4-Chlorophenyl compounds]]

[[Category:Drugs developed by AstraZeneca]]

[[Category:Isopropylamino compounds]]

[[Category:Prodrugs]]

[[Category:Protozoal dihydrofolate reductase inhibitors]]

[[Category:World Health Organization essential medicines]]

[[Category:Wikipedia medicine articles ready to translate]]