Green synthesis for the treatment of type-II diabetes

. Type-II diabetes mellitus (T2DM) is a serious threat to human life as till the year 2019, approximately 463 million individuals of age between 20-79 years are suffering with diabetes and it will rise to 700 million by the year 2045. For the testing and diagnosis of diabetes, The WHO and the ADA are using various clinical and laboratory characteristics. Diabetes is a silent killer which cannot be cured, however by changing the lifestyle, losing fat, using low blood sugar medications, and using metformin (biguanide) which helps in reducing insulin resistance, one can control diabetes to an extent. Metformin is widely used medicine to treat obesity. Various short-and long-term problems including premature death occurs in type-II diabetic patients. Due to the late diagnosis and poor medical facilities for type-II diabetes in countries like Africa, they are susceptible to developing diseases that lead to death. This article mainly discusses type-II diabetes mellitus (T2DM) and the drugs used for its cure. It also gives a green synthesis of one of the diabetes drug done in our lab.


Introduction
Diabetes mellitus (DM) is perhaps the most common disease in the world.In 1936, the differentiation among type-I and type-II diabetes have been laid out.In 1988, Type-II diabetes was first recognized as a component of the insulin resistance syndrome.Type-II diabetes is characterized by low blood sugar, glucose obstruction, as well as relative insulin deficiency.It is the most common sort of diabetes.A combination of hereditary, natural, and conduct factors add to type-II diabetes [1].Diabetes was assessed to influence 366 million individuals in 2011; by 2030, that number will have ascended to 552 million (Shown in figure 1) [2].The predominance of type-II diabetes mellitus (T2DM) is ascending couple with rising corpulence and progressively undesirable ways of life.
As per the World Health Organization, diabetes will influence more than 220 million individuals internationally, with diabetes-related passings expected to rise somewhere in the range of 2005 and 2030 [3].There will be around 80% rise in the cases of type II diabetes of economically weaker nations.In 2011, 4.6 million people death were reported because of DM.Type-II diabetes is anticipated to impact health of 439 million individuals overall by 2030 [4].
Individuals with type-II diabetes are more fragile against various short-and long-term diseases, which frequently lead to an early demise.To accomplish and keep up with ideal metabolic control in diabetes, a balance of way of life changes and pharmacological treatment is vital.Inadequate insulin is the essential physiologic anomaly of T2DM, and high hepatic glucose creation diminishes fringe glucose ingestion by insulin-delicate organs [5].Numerous oral and injectable medicines are currently accessible to treat type-II diabetes mellitus (T2DM).
Drug treatment, incorporates introductory hypoglycemic prescriptions as well as other strengthening ways to deal with keeping up with glycemic command over the long haul, which often involves the usage of numerous specialists with various instruments of activity.Doctors' ought to be comfortable with the different kinds of diabetic medicine which are accessible available and suggest or recommend the ones that are the best, safe, and all-around endured by patients [6].
There have been tremendous changes in the medications used to treat diabetic patients.In 1994, Insulin arrangements and sulfonylureas were the backbones of pharmacotherapy for diabetes.By 2007, diabetes was being treated with a scope of more up-to-date prescription sorts.In 2007 the most usually involved drugs for the treatment of diabetes are Metformin, sulfonylureas, glitazones, insulin, sitagliptin phosphate, and exenatide.Metformin is regularly utilized as the primary treatment in an assortment of treatment plans, and it is remembered to work to a great extent by lessening hepatic glucose creation, which is one of T2DM's significant inadequacies.High hepatic glucose synthesis, diminished fringe glucose retention by insulin-delicate tissues, and inadequate insulin is the major physiologic anomalies of T2DM.Following an investigation of the prescriptions used to treat T2DM, obviously not even one of them focuses on the three basic blemishes of this normal disease [7].Imeglimin is a medicine that is being developed as the 1st of a novel family of oral anti-diabetic drugs which targets both insulin-resistant tissues and pancreatic beta cells.

Type-II Diabetes
Type-II diabetes mellitus (T2DM), also known as non-diabetes Mellitus (NIDM) or adult-onset diabetes, is a metabolic condition due to hyperglycaemia caused by insulin resistance plus relative insulin insufficiency.Type-II diabetes (T2DM) is a common condition that affects greater than 380 million people globally, with estimates that by the 2035, it would impact greater than 590 million people.In the twentieth century, there is a raise in the people affecting with type-II diabetes.Adult cases of type-II diabetes are on the upsurge, particularly in developing countries.Adult diabetes rates, particularly type II diabetes, are predicted to rise over the following twenty years, with more expansion taking place in emerging nations, where most patients are of between 45 and 64 age [8].T2DM is now on the rise throughout the world, the result of rising urbanization, obesity, declining levels of physical exercise and aging populations.
Another factor to the rise in Type-II diabetes mellitus cases is the hazardous environment.Having Type-II diabetes mellitus relatives increases the likelihood of developing T2DM in the community.Atmosphere variables, , 01 nutrition and overweight, play a considerable impact in the development of Type-II diabetes mellitus, regardless of hereditary component.Obesity has been a major contributor to the T2DM epidemic in the United States and Europe.Obesity is believed to be the cause of 70-90 percent of T2DM in adult community in North America and the European Union [9].The majority of adverse diabetes consequences are caused by vascular problems, including macrovascular and microvascular.Macrovascular diseases are much more frequent; approximately 80% of type-II diabetes patients will develop and eventually die from the macrovascular disease, and the expenses for treatment of macrovascular disease are exponentially higher than that of microvascular disease.The significance of controlling type-II diabetes macrovascular problems has gained more attention.
Since diabetes is determined by blood sugar levels, hyperglycaemia treatment receives a lot of importance in diabetes care [10].Many studies have looked at the benefits of treating common risk factors like hypertension.People with type-II diabetes are more likely to develop hypertension, which affects up to 60% of them, and there is an increasing multiplicity of pharmacological therapy choices.The glucose levels will be increased on two occasions and are defined by the WHO as T2DM: fasting plasma glucose ≥≥7.0 mmol/L or a glucose tolerance test two hours after an oral dosage with plasma glucose of 11.1 mmol/L.T2DM can be avoided by following a healthy diet and exercising regularly [11].Drugs that are used include non-sulfonylurea secretagogues, alpha-glucosidase inhibitors, insulin, and thiazolidinediones.Glucagon-like peptide 1 analogy: insulin-releasing glucokinase activators, glucagon-receptor antagonists, sodium-glucose cotransporter 2 inhibitors, and Pancreatic-G-protein-coupled fatty-acid-receptor agonists, dipeptidyl peptidase-IV inhibitors, and 11ß-hydroxysteroid dehydrogenase 1 inhibitor Pancreatic-Gprotein-coupled.Treating type-II diabetes mellitus would be a big problem in the next decades due to 2 reasons.The first is that its worldwide occurrence is increasing at an exponential rate.The second is the disease's pathogenetic complexity, which demands various treatment approaches.The drugs employed for the cure of T2DM will be discussed further, along with the synthesis of the drug [12].3 Pharmacological agents for type-II diabetes mellitus

Sulfonylureas
Many recommendations for patients with type-II diabetes mellitus still prescribe sulfonylureas as a first-line medication.Sulfonylureas were utilized in just 34% to 37% of treatment visits in 2007.This trend was somewhat slower (60 percent) between 1994 and 1999, although it has lately increased.Sulfonylureas and other combination medicines were available around 2000 [13].Glipizide was the most popular noncombination sulfonylurea in 2007, while glyburide (with metformin) and glimepiride (with glitazones) were the most popular combination drugs.These are typically well taken, although they can cause hypoglycemia because they enhance endogenous insulin secretion.When compared to younger patients with diabetes treated with sulfonylureas, elderly individuals with DM had a 36% higher risk of hypoglycemia.In older people with diabetes, long-acting sulfonylureas like glyburide should be avoided, and short-acting glipizide must be used instead [14].

Synthesis of sulfonylureas
The synthesis of sulfonylureas can be done in a simple and environmentally friendly way in two steps Step 1: In this step by using diphenyl carbonate in an aqueous solution of water and tetrahydro furan which is taken in a ratio of 90:10(i.e;H2O: THF, 90: 10), different alkyl/aralkyl amines are converted into phenylcarbamate derivatives [15].
Step 2: The activated carbamates were heated by adding organic bases like Et3N or DBU to generate the intermediate of isocynate, it swiftly intercepted sulfonamides into sulfonylureas [15].1: Green synthesis of sulfonylureas

Metformin
Metformin, which is a biguanide compound, acts as the foundation of type-II diabetes treatment for decades due to its physicochemical and pharmacokinetic features, as well as its potential to lower haemoglobin A1C levels dramatically following oral administration.Metformin lowers hepatic gluconeogenesis, improves glucose sensitivity, promotes fatty acid oxidation (FAO) as well as lowers glucose consumption in the gastrointestinal tract by phosphorylating GLUT-enhancer factor.Metformin is a synthetic compound derived from the natural product combining guanidine with galegine obtained by Galega officinalis.In the 1920s, galegine, a monoguanidine product that consists of isoamylene as a side chain, was used as an anti-diabetic [16].However, metformin is presently recognized as one of the anti-diabetic medication, new research suggests that it is being studied for its pleiotropic benefits in a variety of disorders, including cardiovascular disease, neurodegeneration, and anti-aging.Metformin improves endothelial dysfunction as well as smooth muscle relaxation, which protects the vasculature.A comparison was made between the diabetic people who are not on metformin medication, longterm usage of metformin was shown to provide secondary benefits such as a decreased rate of cancer.Metformin must be taken carefully in old diabetics patients with renal disease due to the risk of developing lactic acidosis.When compared to sulfonylureas, it has a reduced rate of hypoglycemia.Metformin is marketed as instantaneous (Glucophage) and extended-release (Glucophage XR) pills and is used orally.Metformin hydrochloride is extremely water-soluble and dissolves quickly in the gastrointestinal tract.The instant dosage should be taken two to three times per day along meals, while the extended-free dosage should be taken once a day with dinner [17].

Synthesis of metformin
Metformin is a very basic chemical with a biguanide ring.Metformin was initially produced in a one-step process around 1922.Metformin is synthesized in a single step and is very simple to make.Metformin is made in a solventfree environment.It is made by combining Dimethylammonium chloride as well as dicyandiamide and heating them together [18] .

Insulin use
Insulin perhaps given single or in combination with oral low blood sugar medications to control blood glucose amount.Basal insulin augmentation can help if there is still some beta cell activity.If beta-cell fatigue occurs, basal-bolus insulin replenishment is required.People with severe low blood sugar amounts, determined as fasting plasma glucose (FPG) amount greater than 250 mg/dL, HbA1c levels greater than 10%, and symptoms of hyperglycemia who have not accomplished their glycemic targets with two or more OHAs, require insulin treatment [19].Injectable insulin comes in 4 main types: quick-acting, short-acting, intermediate-acting, and longacting.Long-acting forms are less likely to produce low blood sugar compared to short-acting forms.In 2006, both the European Medicines Evaluation Agency and the FDA authorized an inhaled form of fast reacting insulin for the cure of type 1 as well as type 2 diabetes in people.Both type-I and type-II diabetic people can consume this insulin due to its quick reaction in the body, as it can work directly inside the lungs [20].In contrast, recent studies represent that nasal insulin is extremely beneficial, if not better than, short-acting insulin.The business took off the market in October 2007 due to low sales.The pharmacological features of novel insulin analogues are preferred more than the regular insulins, due to their less mechanism time.Insulin lispro and insulin aspart are two fast-reacting insulin analogues that have been approved, as well as insulin glargine, a long-acting insulin analogy [21].

Phenoformin
Phenformin is a 1-(2-ethyl-phenyl)-biguanide compound which was once widely given as an anti-diabetic medication before being banned in several countries as it is expected to raise the risk of lactic acidosis.Following oral treatment, phenformin is readily absorbed.Phenformin does not bind with plasma proteins in a substantial manner.In the liver, it is hydroxylated to 4-hydroxy-phenformin. Due to its impaired metabolism, phenformin plasma concentrations are greater in individuals having weak CYP2D6 metabolizers, resulting in increased toxicity [22].P-glycoprotein is a substrate of phenformin (P-gp).As a result, inhibiting P-gp may raise phenformin plasma concentration, thereby raising the risk of lactic acidosis.Phenformin has an elimination half-life of roughly 11 hours.The majority of phenformin as well as its hydroxylated metabolite is excreted in the urine.

Synthesis of phenformin
Phenformin has been revived in recent years because of new antidiabetic pharmacological research and a trend to investigate alternate biological applications of older pharmaceuticals.The di-protonated version of phenformin was identified to construct a zinc (II)-phenformin molecule as a potential antidiabetic drug.A one-step, simple synthetic process is used to make phenformin, metformin, and Imeglimin.Both phenformin & metformin are made without the use of any solvents.Heating phenethylamine with cyanoguanidine yields phenformin with 37 percent yield [23].

Imeglimin
Imeglimin is the 1 st of a new class of medications known as "glimins" that was designed to cure type-II diabetes (T2DM).Imeglimin, also known as (6R) -(+)-4-dimethylamino-2-imino-6-methyl-1,2,5,6-tetrahydro-1,3,5triazine hydrochloride is a potential novel antihyperglycemic medicine that has shown antihyperglycemic benefits in several tests.Imeglimin is a new type-II diabetes medication still in development [24].It has been shown in lab tests to cure the 3 important pathophysiologic aspects about type-II diabetes: reduced glucose absorption by muscle fibre, excessive pulmonary gluconeogenesis, as well as enhanced beta-cell death.Because of its structure and hypothesized mode of action, Imeglimin is unlike any other T2DM medicine presently available [25].It operates in aerobic cells' mitochondria as an inhibitor of the oxidative phosphorylation pathway, allowing it to have strong metabolism effects in eukaryotic cells.Imeglimin was the foremost of the glimins, which are a group of anti-diabetic oral tetrahydro triazine-containing chemical compounds.Recenly, Imeglimin cleared phase 2b testing and is presently being tested in Japan for phase 3. It's primarily being investigated as an additional treatment for people with type-II diabetes which are previously taking drugs to boost insulin secretion and sensitivity.Further research has indicated that it may improve glucose metabolism balance in diabetics, which may have metabolic benefits.Positive phase 2b data revealed that it will decrease glycosylated haemoglobin (HbA1c) in people with T2DM as monotherapy in a dose-dependent way while also having a favourable tolerance and safety profile [26].There are currently just a few pharmacokinetic studies on imeglimin.According to Poxel Pharma's phase 2 randomised, double-blind tests Imeglimin, when given two times a day for 24 weeks, had no hazardous side effects and was accepted.The half-life of imeglimin is 12-20 hours.Imeglimin's effectiveness and safety profile in patients with kidney disease were identical to that of people with normal renal function [27].

Synthesis of Imeglimin
A solution of metformin HCl and NaOH was made in water and then it is added to a solution of acetaldehyde in water for 10 minutes.Then the solution was set for stirring for 1 hr at room temperature.A white solid resulted from the concentration of the solution.After that, the solution was dissolved in 10 mL ethanol and then the solution was filtered by using filter paper.A white solid was recovered after concentration, which yielded 93 % [28].Scheme 4: Synthesis of drug

Green Synthesis of Imeglimin in our Lab
We did reactions of various aliphatic and aromatic aldehydes in presence of banana ash which acts like safe, nontoxic, green base to form product Imeglimin drug and its other structural analog in good to moderate yield as per Scheme 5.
, 01 a Reaction conditions: 1 (1 mmol).b Isolated yields.c WEB used in the reaction instead of banana ash.g Grinding the reaction mixture.s Stirring the reaction mixture.mw Micro wave stirring of the reaction mixture.w Water used as a solvent in the reaction.m Methanol used as a solvent in the reaction.We can see lot of potential of our work and we are still exploring this to greater extent.

Conclusions
Many oral and injectable treatments are now available to treat T2DM, including the risk of hypoglycaemia, effectiveness in lowering diabetes-related health problems, influence on body mass, side effects, and contraindications.Imeglimin after metformin Insulin compounds has also been developed to better mimic natural insulin production.Metformin is still the primary line of treatment for the majority of individuals.When considering other alternate solutions or second-line treatment options, patient medical background like degree of low blood sugar, occurrence of co-morbidities, patient partiality and capacity to access treatments, as well as treatment properties such as blood-glucose-lowering efficiency and toughness, must be taken into account.Medication was discovered that efficiently treats type-II diabetes.More data is required to support Imeglimin long-term care and, eventually, FDA approval, given all of the preliminary data already available.There is currently only one completed Imeglimin trial, however the data have yet to be released.There are ways for the Imeglimin production using various chemical methods, it would be more prudent if the production of Imeglimin can be done using various environment friendly methods.Using of waste biomasses such as lemon peels ash, banana peels ash, orange peels ash, potato peels or any other vegetable or fruits peels can be used for the production of Imeglimin, for future research.We have done some exploration in this direction by using banana ash and got excellent results which still can be explored further.Finally, it's not apparent how Imeglimin will integrate into the current T2DM treatment strategy.Imeglimin's effect on morbidity and/or mortality in T2DM patients is still unknown.Imeglimin's long-term safety needs to be supported by more research.Based on current animal research and human trials, Imeglimin looks to be a viable adjuvant, if not a first-line treatment for T2DM.

Fig. 2 .
Fig. 2. Growth of the number of deaths with type-II diabetes

Fig 3 .
Fig 3. Types of drugs used for the treatment of type-II diabetes

Table 1 .
Treatment for type-II diabetes mellitus *For

Table 2 .
I Prescribing information for sulfonylureas