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European Journal of Medicinal Chemistry Jul 2021Biguanides are compounds in which two guanidine moieties are fused to form a highly conjugated system. Biguanides are highly basic and hence they are available as salts... (Review)
Review
Biguanides are compounds in which two guanidine moieties are fused to form a highly conjugated system. Biguanides are highly basic and hence they are available as salts mostly hydrochloride salts, these cationic species have been found to exhibit many therapeutic properties. This review covers the research and development carried out on biguanides and accounts the various therapeutic applications of drugs containing biguanide group-such as antimalarial, antidiabetic, antiviral, anticancer, antibacterial, antifungal, anti-tubercular, antifilarial, anti-HIV, as well as other biological activities. The aim of this review is to compile all the medicinal chemistry applications of this class of compounds so as to pave way for the accelerated efforts in finding the drug action mechanisms associated with this class of compounds. Importance has been given to the organic chemistry of these biguanide derivatives also.
Topics: Anti-Infective Agents; Antineoplastic Agents; Biguanides; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Metformin; Polycystic Ovary Syndrome; Proguanil
PubMed: 33857729
DOI: 10.1016/j.ejmech.2021.113378 -
European Journal of Medicinal Chemistry Nov 2021Biguanides have attracted much attention a century ago and showed resurgent interest in recent years after a long period of dormancy. They constitute an important class... (Review)
Review
Biguanides have attracted much attention a century ago and showed resurgent interest in recent years after a long period of dormancy. They constitute an important class of therapeutic agents suitable for the treatment of a wide spectrum of diseases. Therapeutic indications of biguanides include antidiabetic, antimalarial, antiviral, antiplaque, and bactericidal applications. This review presents an extensive overview of the biological activity of biguanides and different mechanisms of action of currently marketed biguanide-containing drugs, as well as their pharmacological properties when applicable. We highlight the recent developments in research on biguanide compounds, with a primary focus on studies on metformin in the field of oncology. We aim to provide a critical overview of all main bioactive biguanide compounds and discuss future perspectives for the design of new drugs based on the biguanide fragment.
Topics: Biguanides; Drug Discovery; Humans; Hypoglycemic Agents; Molecular Structure
PubMed: 34364161
DOI: 10.1016/j.ejmech.2021.113726 -
Diabetologia Sep 2017Metformin (dimethylbiguanide) has become the preferred first-line oral blood glucose-lowering agent to manage type 2 diabetes. Its history is linked to Galega...
Metformin (dimethylbiguanide) has become the preferred first-line oral blood glucose-lowering agent to manage type 2 diabetes. Its history is linked to Galega officinalis (also known as goat's rue), a traditional herbal medicine in Europe, found to be rich in guanidine, which, in 1918, was shown to lower blood glucose. Guanidine derivatives, including metformin, were synthesised and some (not metformin) were used to treat diabetes in the 1920s and 1930s but were discontinued due to toxicity and the increased availability of insulin. Metformin was rediscovered in the search for antimalarial agents in the 1940s and, during clinical tests, proved useful to treat influenza when it sometimes lowered blood glucose. This property was pursued by the French physician Jean Sterne, who first reported the use of metformin to treat diabetes in 1957. However, metformin received limited attention as it was less potent than other glucose-lowering biguanides (phenformin and buformin), which were generally discontinued in the late 1970s due to high risk of lactic acidosis. Metformin's future was precarious, its reputation tarnished by association with other biguanides despite evident differences. The ability of metformin to counter insulin resistance and address adult-onset hyperglycaemia without weight gain or increased risk of hypoglycaemia gradually gathered credence in Europe, and after intensive scrutiny metformin was introduced into the USA in 1995. Long-term cardiovascular benefits of metformin were identified by the UK Prospective Diabetes Study (UKPDS) in 1998, providing a new rationale to adopt metformin as initial therapy to manage hyperglycaemia in type 2 diabetes. Sixty years after its introduction in diabetes treatment, metformin has become the most prescribed glucose-lowering medicine worldwide with the potential for further therapeutic applications.
Topics: Biguanides; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Metformin
PubMed: 28776081
DOI: 10.1007/s00125-017-4318-z -
Journal of Intensive Care Medicine 2019In the 1920s, guanidine, the active component of , was shown to lower glucose levels and used to synthesize several antidiabetic compounds. Metformin (1,1... (Review)
Review
In the 1920s, guanidine, the active component of , was shown to lower glucose levels and used to synthesize several antidiabetic compounds. Metformin (1,1 dimethylbiguanide) is the most well-known and currently the only marketed biguanide in the United States, United Kingdom, Canada, and Australia for the treatment of non-insulin-dependent diabetes mellitus. Although phenformin was removed from the US market in the 1970s, it is still available around the world and can be found in unregulated herbal supplements. Adverse events associated with therapeutic use of biguanides include gastrointestinal upset, vitamin B deficiency, and hemolytic anemia. Although the incidence is low, metformin toxicity can lead to hyperlactatemia and metabolic acidosis. Since metformin is predominantly eliminated from the body by the kidneys, toxicity can occur when metformin accumulates due to poor clearance from renal insufficiency or in the overdose setting. The dominant source of metabolic acidosis associated with hyperlactatemia in metformin toxicity is the rapid cytosolic adenosine triphosphate (ATP) turnover when complex I is inhibited and oxidative phosphorylation cannot adequately recycle the vast quantity of H+ from ATP hydrolysis. Although metabolic acidosis and hyperlactatemia are markers of metformin toxicity, the degree of hyperlactatemia and severity of acidemia have not been shown to be of prognostic value. Regardless of the etiology of toxicity, treatment should include supportive care and consideration for adjunct therapies such as gastrointestinal decontamination, glucose and insulin, alkalinization, extracorporeal techniques to reduce metformin body burden, and metabolic rescue.
Topics: Acidosis; Biguanides; Diabetes Mellitus, Type 2; Humans; Hyperlactatemia; Hypoglycemic Agents; Kidney; Metformin; Renal Insufficiency
PubMed: 30126348
DOI: 10.1177/0885066618793385 -
Acta Medica Portuguesa Sep 1989Biguanides are useful drugs in diabetes but their indications are very precise. The danger of lactic acidosis can be avoided with the use of metformin, the less toxic of... (Review)
Review
Biguanides are useful drugs in diabetes but their indications are very precise. The danger of lactic acidosis can be avoided with the use of metformin, the less toxic of biguanides, and strict respect for contraindications. All biguanides have a similar action, through different pharmacokinetics, and besides their hypoglycemic effect, have a favourable action on blood lipids, which increases their usefulness. Haemorheological effects, recently studied in animal research, may open a new field in the employment of biguanides.
Topics: Acidosis, Lactic; Biguanides; Diabetes Mellitus; Humans; Lipid Metabolism; Metformin
PubMed: 2694769
DOI: No ID Found -
Bioorganic Chemistry Jan 2020Apart from its hypoglycaemic properties, metformin also offers beneficial effects for the cardiovascular system resulting in significant reduction of diabetes-related...
Apart from its hypoglycaemic properties, metformin also offers beneficial effects for the cardiovascular system resulting in significant reduction of diabetes-related death, and all-cause mortality. The aim of this study was to synthesize nine new benzenesulfonamide derivatives of metformin with a halogen substituent, and estimate their influence on selected parameters of plasma and vascular hemostasis. The study describes the synthesis of nine benzenesulfonamide biguanides with o-, m-, and p- chloro-, bromo-, and fluoro substituents. All orto- derivatives (chloro- (1), bromo- (4), and fluoro- (7)) significantly prolong prothrombin time (PT) and partially activated thromboplastin time (APTT). In addition compounds 4 and 7 slow the process of fibrin polymerization, and contribute to increased TT. Multiparametric CL-test revealed that compounds 1, 4, 7 and p-fluorobenzenesulfonamide (9) significantly prolong the onset of clot formation, decrease initial clot formation velocity, and maximum clotting. Analysis of human endothelial cell (HUVECs) and human aortal smooth muscle cell (AoSMCs) viability over the entire tested concentration range (0.001-3.0 μmol/mL) indicated that the examined compounds can undergo further tests up to 1.5 µmol/mL concentration without decreasing cellular viability. Furthermore, none of the synthesized compounds exert an unfavourable effect on erythrocyte integrity, and thus do not interact strongly with the lipid-protein bilayer. In summary, chemical modification of the metformin backbone into benzenesulfonamides containing halogen substituents at the o- position leads to the formation of potential agents with stronger anti-coagulant properties than the parent drug, metformin. Therefore, o-halogenated benzenesulfonamides can be regarded as an initial promising step in the development of novel biguanide-based compounds with anti-coagulant properties.
Topics: Animals; Biguanides; Blood Coagulation; Dose-Response Relationship, Drug; Erythrocytes; Halogenation; Humans; Mice; Molecular Structure; Rats; Structure-Activity Relationship; Sulfonamides
PubMed: 31776031
DOI: 10.1016/j.bioorg.2019.103444 -
Science (New York, N.Y.) Jan 2023The molecular mode of action of biguanides, including the drug metformin, which is widely used in the treatment of diabetes, is incompletely characterized. Here, we...
The molecular mode of action of biguanides, including the drug metformin, which is widely used in the treatment of diabetes, is incompletely characterized. Here, we define the inhibitory drug-target interaction(s) of a model biguanide with mammalian respiratory complex I by combining cryo-electron microscopy and enzyme kinetics. We interpret these data to explain the selectivity of biguanide binding to different enzyme states. The primary inhibitory site is in an amphipathic region of the quinone-binding channel, and an additional binding site is in a pocket on the intermembrane-space side of the enzyme. An independent local chaotropic interaction, not previously described for any drug, displaces a portion of a key helix in the membrane domain. Our data provide a structural basis for biguanide action and enable the rational design of medicinal biguanides.
Topics: Animals; Cryoelectron Microscopy; Electron Transport Complex I; Metformin; Mitochondria; Biguanides
PubMed: 36701435
DOI: 10.1126/science.ade3332 -
Diabete & Metabolisme 1983This review on biguanides gives a general survey of biguanide actions on many metabolic models in vivo and in vitro. It focuses especially on the comparison of the 3... (Review)
Review
This review on biguanides gives a general survey of biguanide actions on many metabolic models in vivo and in vitro. It focuses especially on the comparison of the 3 antidiabetic biguanides, of which metformin is discussed as the only oral antidiabetic biguanide useful in treatment of type-II diabetes with a minimum risk of side effects when applied in a well controlled regime. Pharmacokinetics, pharmacodynamics, hypotheses on the molecular mode of action, and implications for therapy are discussed.
Topics: Animals; Biguanides; Chemical Phenomena; Chemistry; Diabetes Mellitus; Diabetes Mellitus, Experimental; Gluconeogenesis; Glucose; Humans; In Vitro Techniques; Insulin; Intestinal Absorption; Lipid Metabolism; Rats
PubMed: 6352352
DOI: No ID Found -
Current Drug Targets Dec 2012Metformin, a widely used anti-hyperglycemic drug in the biguanide class, is currently under investigation for the prevention of cancer. Surprisingly however, considering... (Review)
Review
A systems pharmacokinetic and pharmacodynamic approach to identify opportunities and pitfalls in energy stress-mediated chemoprevention: the use of metformin and other biguanides.
Metformin, a widely used anti-hyperglycemic drug in the biguanide class, is currently under investigation for the prevention of cancer. Surprisingly however, considering the time and cost of clinical chemoprevention trials and the current scrutiny of cancer chemoprevention, limited attention has been given to integrating available data, identifying the subpopulations most likely to benefit, or to quantitatively understanding the potential pitfalls of biguanide chemoprevention. Herein, a physiologically-based pharmacokinetic (PBPK) and pharmacodynamic framework is proposed for integrating information on physicochemical, cell-based, animal, and human studies of various biguanides to identify gaps in knowledge and to build a systems model that may facilitate the planning of randomized cancer chemoprevention trials of metformin.
Topics: Animals; Biguanides; Chemoprevention; Energy Metabolism; Humans; Hypoglycemic Agents; Metformin; Neoplasms; Oxidative Stress
PubMed: 23140331
DOI: 10.2174/138945012804545614 -
Deutsche Medizinische Wochenschrift... Sep 1978
Topics: Acidosis; Biguanides; Buformin; Humans; Metformin; Phenformin
PubMed: 679851
DOI: No ID Found