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{{short description|Chemical compound}}
{{condense|date=June 2012}}
{{no footnotes|date=January 2011}}

{{chembox {{chembox
| Watchedfields = changed
| verifiedrevid = 443424048 | verifiedrevid = 444387711
| ImageFile = Biguanide.svg | ImageFile = Biguanide.svg
| ImageFile_Ref = {{chemboximage|correct|??}} | ImageFile_Ref = {{chemboximage|correct|??}}
| ImageSize = 160 | ImageSize = 160
| ImageName = Skeletal formula of biguanide | ImageName = Skeletal formula of biguanide
| ImageFile1 = Biguanide-3D-balls.png | ImageFile1 = Biguanide-from-xtal-3D-bs-17.png
| ImageFile1_Ref = {{chemboximage|correct|??}} | ImageFile1_Ref = {{chemboximage|correct|??}}
| ImageSize1 = 160 | ImageSize1 = 160
| ImageName1 = Ball and stick model of biguanide | ImageName1 = Ball and stick model of biguanide
| PIN = Imidodicarbonimidic diamide<ref>{{cite book |author=] |date=2014 |title=Nomenclature of Organic Chemistry: IUPAC Recommendations and Preferred Names 2013 |publisher=] |pages=885 |doi=10.1039/9781849733069 |isbn=978-0-85404-182-4}}</ref>
| Section1 = {{chembox Identifiers |Section1={{Chembox Identifiers
| CASNo = 56-03-1
| CASNo_Ref = {{cascite|correct|CAS}} | CASNo = 56-03-1
| CASNo_Ref = {{cascite|correct|CAS}}
| UNII_Ref = {{fdacite|correct|FDA}}
| PubChem = 5939
| UNII = FB4Q52I9K2
| PubChem_Ref = {{pubchemcite|correct|pubchem}}
| ChemSpiderID = 5726 | PubChem = 5939
| ChemSpiderID = 5726
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| EINECS = 200-251-8
| KEGG = C07672 | EINECS = 200-251-8
| KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = C07672
| KEGG_Ref = {{keggcite|correct|kegg}}
| ChEBI = 3095 | ChEBI = 3095
| ChEBI_Ref = {{ebicite|correct|EBI}} | ChEBI_Ref = {{ebicite|correct|EBI}}
| Beilstein = 507183 | Beilstein = 507183
| Gmelin = 240093 | Gmelin = 240093
| SMILES = :c(:)::c(:): | SMILES = N=C(N)NC(=N)N
| StdInChI = 1S/C2H7N5/c3-1(4)7-2(5)6/h(H7,3,4,5,6,7)
| SMILES1 = NC(=N)NC(N)=N
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C2H7N5/c3-1(4)7-2(5)6/h(H7,3,4,5,6,7)
| StdInChIKey = XNCOSPRUTUOJCJ-UHFFFAOYSA-N
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = XNCOSPRUTUOJCJ-UHFFFAOYSA-N
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
}} }}
| Section2 = {{chembox Properties |Section2={{Chembox Properties
| C = 2 | C=2 | H=7 | N=5
| H = 7 | pKa = 3.07, 13.25
| N = 5
}} }}
| Section3 = {{chembox Related |Section3={{Chembox Related
| OtherCompounds =
| OtherCpds = {{unbulleted list|]|]|]|]|]|]|]|]|]|]|]|]|]|]|]|]}}
}} }}
}} }}


'''Biguanide''' ({{IPAc-en|b|aɪ|ˈ|g|w|ɒ|n|aɪ|d}}) is the organic compound with the formula HN(C(NH)NH<sub>2</sub>)<sub>2</sub>. It is a colorless solid that dissolves in water to give a highly basic solution. These solutions slowly hydrolyse to ] and ].<ref name=Ullmann>{{cite book | vauthors = Güthner T, Mertschenk B, Schulz B | chapter = Guanidine and Derivatives | title = Ullmann's Encyclopedia of Industrial Chemistry | date = 2006 | publisher = Wiley-VCH | location = Weinheim | doi = 10.1002/14356007.a12_545.pub2 | isbn = 3527306730 }}</ref>
]]]
]. Note extra ] at bottom right.]]
]. Note extra ] at right.]]
'''Biguanide''' can refer to a molecule, or to a class of drugs based upon this molecule. Biguanides can function as oral antihyperglycemic ]s used for ] or ] treatment. They are also used as ]s.


==Synthesis==
The disinfectant ] (PAPB) features biguanide functional groups.
Biguanide can be obtained from the reaction of ] with ], via a ]-type process.


:<math>\mathrm{C_2H_4N_4 + NH_3 \longrightarrow C_2H_7N_5}</math>
==Examples==

Examples of biguanides:
Biguanide was first synthesized by ] in 1879.<ref>{{cite journal |last1=Rathke |first1=B. |title=Ueber Biguanid |journal=Berichte der Deutschen Chemischen Gesellschaft |date=January 1879 |volume=12 |issue=1 |pages=776–784 |doi=10.1002/cber.187901201219|url=https://zenodo.org/record/2048781 }}</ref>

==Biguanidine drugs==
A variety of ] of biguanide are used as pharmaceutical drugs.

===Antihyperglycemic agents===
The term "biguanidine" often refers specifically to a class of drugs that function as oral antihyperglycemic ]s used for ] or ] treatment.<ref>{{cite book | vauthors = Rang HP, Dale MM, Ritter KM, Moore PK |title=Pharmacology |date=2003 |publisher=Churchill Livingstone |location=Edinburgh |isbn=0-443-07145-4 |edition=5th | page = 388}}</ref>

Examples include:
* ] - widely used in treatment of ] * ] - widely used in treatment of ]
* ] - withdrawn from the market in most countries due to toxic effects * ] - withdrawn from the market in most countries due to toxic effects
* ] - withdrawn from the market due to toxic effects * ] - withdrawn from the market due to toxic effects
* ] - an ].


<gallery caption="bioactive biguanidines" widths="180px" heights="120px" perrow="3">
==History==
File:Metformin.svg|], could be referred to as asymmetric dimethylbiguanidine
'']'' (French lilac) was used for diabetes treatment in traditional medicine for centuries. In the 1920s, ] compounds were discovered in ''Galega'' extracts. Animal studies showed that these compounds lowered blood glucose levels. Some less toxic derivatives, ] A and synthalin B, were used for diabetes treatment, but after the discovery of ] they were forgotten for the next several decades. Biguanides were reintroduced into Type 2 ] treatment in the late 1950s. Initially ] was widely used, but its potential for sometimes fatal ] resulted in its withdrawal from pharmacotherapy in most pharmacopeias (in the U.S. in 1977). Metformin has a much better safety profile, and it is the principal biguanide drug used in pharmacotherapy worldwide.
File:Buformin.svg|]. A ] derivative of biguanidine.
File:Phenformin.svg|]. A phenethylated biguanidine.
</gallery>


==Pharmacotherapy== ====History====
{{details|metformin#History}}
Biguanides do not affect the output of insulin, unlike other ]s such as ]s and ]s. Therefore, not only are they effective in Type 2 diabetics but they can also be effective in Type 1 patients in concert with insulin therapy.
'']'' (French lilac) was used in diabetes treatment for centuries.<ref name = Witters>{{cite journal |author=Witters L |title=The blooming of the French lilac |journal=J Clin Invest |volume=108 |issue=8 |pages=1105–7 |year=2001 |pmid=11602616 |doi=10.1172/JCI14178 |pmc=209536 |url=}}</ref> In the 1920s, ] compounds were discovered in ''Galega'' extracts. Animal studies showed that these compounds lowered blood glucose levels. Some less toxic derivatives, ] A and synthalin B, were used for diabetes treatment, but after the discovery of ], their use declined. Biguanides were reintroduced into Type 2 ] treatment in the late 1950s. Initially ] was widely used, but its potential for sometimes fatal ] resulted in its withdrawal from most pharmacopeias (in the U.S. in 1978).<ref name=Tonascia1986>{{cite book | vauthors = Tonascia S, Meinert CL |title=Clinical trials: design, conduct, and analysis |publisher=Oxford University Press |location=Oxford |year=1986 |pages=53–54, 59 |isbn=0-19-503568-2}}</ref> Metformin has a much better safety profile, and it is the principal biguanide drug used in pharmacotherapy worldwide.


==Mechanism of action== ====Mechanism of action====
The ] of biguanides is not fully understood. Mainly used in Type II Diabetes, Metformin is considered to increase insulin sensitivity in vivo, resulting in reduced plasma glucose concentrations, increased glucose uptake, and decreased gluconeogenesis. The ] of biguanides is not fully understood, and many mechanisms have been proposed for metformin.{{cn|date=January 2024}}


Biguanides do not affect the output of insulin, unlike other ]s such as ]s and ]s. Therefore, they are effective in Type 2 diabetics; and in Type 1 diabetes when used in conjunction with insulin therapy.{{cn|date=January 2024}}
However, in hyperinsulinemia, biguanides can lower fasting levels of insulin in plasma. Their therapeutic uses derive from their tendency to reduce ] in the liver, and, as a result, reduce the level of glucose in the blood. Biguanides also tend to make the cells of the body more willing to absorb glucose already present in the blood stream, and there again reducing the level of glucose in the plasma.


Mainly used in Type II diabetes, metformin is considered to increase insulin sensitivity in vivo, resulting in reduced plasma glucose concentrations, increased glucose uptake, and decreased gluconeogenesis.{{cn|date=January 2024}}
==Side effects and toxicity==
The most common side effect is ] and dyspepsia, occurring in up to 30% of patients. The most important and serious side effect is ], therefore metformin is contraindicated in renal insufficiency. Renal functions should be assessed before starting metformin. Phenformin and buformin are more prone to cause acidosis than metformin; therefore they have been practically replaced by it. However, when metformin is combined with other drugs (combination therapy), ] and other side effects are possible.


However, in hyperinsulinemia, biguanides can lower fasting levels of insulin in plasma. Their therapeutic uses derive from their tendency to reduce ] in the liver, and, as a result, reduce the level of glucose in the blood. Biguanides also tend to make the cells of the body more willing to absorb glucose already present in the bloodstream, and there again reducing the level of glucose in the plasma.{{cn|date=January 2024}}
==References==
{{reflist}}


Biguanides have been shown to interact with copper, specifically in mitochondria, where they interfere with cell metabolism by chelating Copper in its 2+ oxidation state (Cu(II)).<ref>{{cite journal |last1=Solier |first1=Stéphanie |last2=Müller |first2=Sebastian |last3=Tatiana |first3=Cañeque |last4=Antoine |first4=Versini |last5=Arnaud |first5=Mansart |last6=Fabien |first6=Sindikubwabo |last7=Leeroy |first7=Baron |last8=Laila |first8=Emam |last9=Pierre |first9=Gestraud |last10=G. Dan |first10=Pantoș |last11=Vincent |first11=Gandon |last12=Christine |first12=Gaillet |last13=Ting-Di |first13=Wu |last14=Florent |first14=Dingli |last15=Damarys |first15=Loew |last16=Sylvain |first16=Baulande |last17=Sylvère |first17=Durand |last18=Valentin |first18=Sencio |last19=Cyril |first19=Robil |last20=François |first20=Trottein |last21=David |first21=Péricat |last22=Emmanuelle |first22=Näser |last23=Céline |first23=Cougoule |last24=Etienne |first24=Meunier |last25=Anne-Laure |first25=Bègue |last26=Hélène |first26=Salmon |last27=Nicolas |first27=Manel |last28=Alain |first28=Puisieux |last29=Sarah |first29=Watson |last30=Mark A. |first30=Dawson |last31=Nicolas |first31=Servant |last32=Guido |first32=Kroemer |last33=Djillali |first33=Annane |last34=Raphaël |first34=Rodriguez |title=A druggable copper-signalling pathway that drives inflammation |journal=Nature |date=2023 |pages=1-9 |doi=10.1038/s41586-023-06017-4 |pmid=37100912 |url=https://www.nature.com/articles/s41586-023-06017-4|pmc=10131557 }}</ref>
* Rang et al., ''Pharmacology'', 5th Edition, 2003, p 388

====Side effects and toxicity====
The most common side effect is ] and dyspepsia, occurring in up to 30% of patients. The most important and serious side effect is ], therefore metformin is contraindicated in advanced ]. Kidney function should be assessed before starting metformin. Phenformin and buformin are more prone to cause acidosis than metformin; therefore they have been practically replaced by it. However, when metformin is combined with other drugs (combination therapy), ] and other side effects are possible.{{cn|date=January 2024}}

===Antimalarial===
During WWII a British team led by ] discovered (see details there) that some biguanides are useful as ]s. Much later it was demonstrated that they are prodrugs metabolised into active ] derivatives which, until recently, were believed to work by ] ]. Examples include:{{cn|date=January 2024}}
* ] (>])
* ]

===Disinfectants===
{{see also|Bisbiguanide}}
The disinfectants ], ] (PAPB), ], and ] feature biguanide ]s.<ref>{{cite journal | vauthors = Tanzer JM, Slee AM, Kamay BA | title = Structural requirements of guanide, biguanide, and bisbiguanide agents for antiplaque activity | journal = Antimicrobial Agents and Chemotherapy | volume = 12 | issue = 6 | pages = 721–9 | date = December 1977 | pmid = 931371 | pmc = 430011 | doi = 10.1128/aac.12.6.721 }}</ref>

== References ==
{{reflist}}


{{oral hypoglycemics}} {{oral hypoglycemics}}
Line 80: Line 102:


] ]
]
]

Latest revision as of 08:39, 14 July 2024

Chemical compound
Biguanide
Skeletal formula of biguanide
Ball and stick model of biguanide
Names
Preferred IUPAC name Imidodicarbonimidic diamide
Identifiers
CAS Number
3D model (JSmol)
Beilstein Reference 507183
ChEBI
ChemSpider
ECHA InfoCard 100.000.229 Edit this at Wikidata
EC Number
  • 200-251-8
Gmelin Reference 240093
KEGG
PubChem CID
UNII
CompTox Dashboard (EPA)
InChI
  • InChI=1S/C2H7N5/c3-1(4)7-2(5)6/h(H7,3,4,5,6,7)Key: XNCOSPRUTUOJCJ-UHFFFAOYSA-N
SMILES
  • N=C(N)NC(=N)N
Properties
Chemical formula C2H7N5
Molar mass 101.113 g·mol
Acidity (pKa) 3.07, 13.25
Except where otherwise noted, data are given for materials in their standard state (at 25 °C , 100 kPa). checkverify (what is  ?) Infobox references
Chemical compound

Biguanide (/baɪˈɡwɒnaɪd/) 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 from the reaction of dicyandiamide with ammonia, via a Pinner-type process.

C 2 H 4 N 4 + N H 3 C 2 H 7 N 5 {\displaystyle \mathrm {C_{2}H_{4}N_{4}+NH_{3}\longrightarrow C_{2}H_{7}N_{5}} }

Biguanide was first synthesized by Bernhard Rathke in 1879.

Biguanidine drugs

A variety of derivatives of biguanide are used as pharmaceutical drugs.

Antihyperglycemic agents

The term "biguanidine" often refers specifically to a class of drugs that function as oral antihyperglycemic drugs used for diabetes mellitus or prediabetes treatment.

Examples include:

  • bioactive biguanidines
  • Metformin, could be referred to as asymmetric dimethylbiguanidine Metformin, could be referred to as asymmetric dimethylbiguanidine
  • Buformin. A butyl derivative of biguanidine. Buformin. A butyl derivative of biguanidine.
  • Phenformin. A phenethylated biguanidine. Phenformin. A phenethylated biguanidine.

History

Further information: metformin § History

Galega officinalis (French lilac) was used in diabetes treatment for centuries. In the 1920s, guanidine compounds were discovered in Galega extracts. Animal studies showed that these compounds lowered blood glucose levels. Some less toxic derivatives, synthalin A and synthalin B, were used for diabetes treatment, but after the discovery of insulin, their use declined. Biguanides were reintroduced into Type 2 diabetes treatment in the late 1950s. Initially phenformin was widely used, but its potential for sometimes fatal lactic acidosis resulted in its withdrawal from most pharmacopeias (in the U.S. in 1978). Metformin has a much better safety profile, and it is the principal biguanide drug used in pharmacotherapy worldwide.

Mechanism of action

The mechanism of action of biguanides is not fully understood, and many mechanisms have been proposed for metformin.

Biguanides do not affect the output of insulin, unlike other hypoglycemic agents such as sulfonylureas and meglitinides. Therefore, they are effective in Type 2 diabetics; and in Type 1 diabetes when used in conjunction with insulin therapy.

Mainly used in Type II diabetes, metformin is considered to increase insulin sensitivity in vivo, resulting in reduced plasma glucose concentrations, increased glucose uptake, and decreased gluconeogenesis.

However, in hyperinsulinemia, biguanides can lower fasting levels of insulin in plasma. Their therapeutic uses derive from their tendency to reduce gluconeogenesis in the liver, and, as a result, reduce the level of glucose in the blood. Biguanides also tend to make the cells of the body more willing to absorb glucose already present in the bloodstream, and there again reducing the level of glucose in the plasma.

Biguanides have been shown to interact with copper, specifically in mitochondria, where they interfere with cell metabolism by chelating Copper in its 2+ oxidation state (Cu(II)).

Side effects and toxicity

The most common side effect is diarrhea and dyspepsia, occurring in up to 30% of patients. The most important and serious side effect is lactic acidosis, therefore metformin is contraindicated in advanced chronic kidney disease. Kidney function should be assessed before starting metformin. Phenformin and buformin are more prone to cause acidosis than metformin; therefore they have been practically replaced by it. However, when metformin is combined with other drugs (combination therapy), hypoglycemia and other side effects are possible.

Antimalarial

During WWII a British team led by Frank Rose discovered (see details there) that some biguanides are useful as antimalarial drugs. Much later it was demonstrated that they are prodrugs metabolised into active dihydrotriazine derivatives which, until recently, were believed to work by inhibiting dihydrofolate reductase. Examples include:

Disinfectants

See also: Bisbiguanide

The disinfectants chlorhexidine, polyaminopropyl biguanide (PAPB), polihexanide, and alexidine feature biguanide functional groups.

References

  1. International Union of Pure and Applied Chemistry (2014). Nomenclature of Organic Chemistry: IUPAC Recommendations and Preferred Names 2013. The Royal Society of Chemistry. p. 885. doi:10.1039/9781849733069. ISBN 978-0-85404-182-4.
  2. Güthner T, Mertschenk B, Schulz B (2006). "Guanidine and Derivatives". Ullmann's Encyclopedia of Industrial Chemistry. Weinheim: Wiley-VCH. doi:10.1002/14356007.a12_545.pub2. ISBN 3527306730.
  3. Rathke, B. (January 1879). "Ueber Biguanid". Berichte der Deutschen Chemischen Gesellschaft. 12 (1): 776–784. doi:10.1002/cber.187901201219.
  4. Rang HP, Dale MM, Ritter KM, Moore PK (2003). Pharmacology (5th ed.). Edinburgh: Churchill Livingstone. p. 388. ISBN 0-443-07145-4.
  5. Witters L (2001). "The blooming of the French lilac". J Clin Invest. 108 (8): 1105–7. doi:10.1172/JCI14178. PMC 209536. PMID 11602616.
  6. Tonascia S, Meinert CL (1986). Clinical trials: design, conduct, and analysis. Oxford : Oxford University Press. pp. 53–54, 59. ISBN 0-19-503568-2.
  7. Solier, Stéphanie; Müller, Sebastian; Tatiana, Cañeque; Antoine, Versini; Arnaud, Mansart; Fabien, Sindikubwabo; Leeroy, Baron; Laila, Emam; Pierre, Gestraud; G. Dan, Pantoș; Vincent, Gandon; Christine, Gaillet; Ting-Di, Wu; Florent, Dingli; Damarys, Loew; Sylvain, Baulande; Sylvère, Durand; Valentin, Sencio; Cyril, Robil; François, Trottein; David, Péricat; Emmanuelle, Näser; Céline, Cougoule; Etienne, Meunier; Anne-Laure, Bègue; Hélène, Salmon; Nicolas, Manel; Alain, Puisieux; Sarah, Watson; Mark A., Dawson; Nicolas, Servant; Guido, Kroemer; Djillali, Annane; Raphaël, Rodriguez (2023). "A druggable copper-signalling pathway that drives inflammation". Nature: 1–9. doi:10.1038/s41586-023-06017-4. PMC 10131557. PMID 37100912.
  8. Tanzer JM, Slee AM, Kamay BA (December 1977). "Structural requirements of guanide, biguanide, and bisbiguanide agents for antiplaque activity". Antimicrobial Agents and Chemotherapy. 12 (6): 721–9. doi:10.1128/aac.12.6.721. PMC 430011. PMID 931371.
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