Advancements in Diabetes Treatment: Morpholine and Piperazine Derivatives


Diabetes mellitus is an endocrine chronic disease characterized by high sugar levels in the blood. It occurs when the pancreas does not produce enough insulin or when the organism has insulin resistance. Common symptoms of diabetes include thirst, polyuria, weight loss, blurred vision, hunger, numb or tingling hands or feet, fatigue, dry skin, sores that heal slowly, nausea, vomiting, and stomach pains. Type 1 diabetes symptoms can develop rapidly over a few weeks or months, typically occurring at an early age, while Type 2 diabetes develops slowly over several years and usually affects adults.

In 2014, 8.5% of individuals aged 18 and older had diabetes. In 2019, 1.5 million deaths were directly attributed to diabetes, with 48% of these deaths occurring in individuals under the age of 70. Additionally, diabetes contributed to an additional 460,000 renal disease fatalities, and elevated blood glucose levels were responsible for nearly 20% of cardiovascular mortality. Age-standardized diabetes mortality rates increased by 3% between 2000 and 2019, with a 13% rise in lower-middle-income nations. Conversely, there was a 22% global decline in the likelihood of dying from the four major noncommunicable diseases (cancer, chronic respiratory diseases, diabetes, and cardiovascular diseases) between the ages of 30 and 70 from 2000 to 2021.

The major long-term complications of diabetes include retinopathy, nephropathy, neuropathy, atherosclerosis, angina pectoris, myocardial infarction, transient ischemic attack, strokes, peripheral arterial disease, and immune dysfunction. Insulin, except for smooth muscle, is the primary hormone controlling glucose uptake from the blood into most body cells, including the liver, adipose tissue, and muscles. Thus, all types of diabetes mellitus are fundamentally caused by an inadequate supply of insulin or the insensitivity of its receptors. The body’s three main sources of glucose are glycogenolysis (breakdown of glycogen), intestinal absorption of meals, and gluconeogenesis. Insulin is essential in controlling glucose levels, increasing glucose transfer into fat and muscle cells, stimulating glycogen storage, and promoting gluconeogenesis.

Detailed Scheme Table of Diabetes Mellitus Information

Prevalence537 million adults globally (2021), projected to reach 783 million by 2045
Mortality1.5 million deaths (2019), significant deaths in individuals under 70
ComplicationsRetinopathy, nephropathy, neuropathy, atherosclerosis, myocardial infarction, stroke, immune dysfunction
Type 1 Diabetes TreatmentInsulin (short, rapid, intermediate, long-acting), Pramlintide
Type 2 Diabetes TreatmentInsulin, metformin, DPP-4 inhibitors, SGLT-2 inhibitors, GLP-1 receptor agonists
Prevention (Type 2)Balanced diet, regular exercise, maintaining healthy weight
Natural CompoundsAloe, cinnamon, turmeric, piperine, berberine
Economic ImpactUSD 966 billion in health expenditure (2021)
U.S. Specific Data29.7 million diagnosed cases (2021), highest prevalence in American Indian/Alaska Native and non-Hispanic Black adults

Type 1 diabetes has no proven preventive interventions. However, Type 2 diabetes, which accounts for 85-90% of cases worldwide, can often be avoided or delayed through a balanced diet, physical activity, and maintaining a normal body weight. More physical exercise (90 minutes or more per day) can lower the risk of diabetes by 28%. A diet rich in whole grains and fiber, as well as healthy fats like polyunsaturated fats found in fish, nuts, and vegetable oils, is beneficial in preventing diabetes. Limiting sugary drinks, consuming less red meat, and reducing other sources of saturated fat are also effective preventive measures.

Natural compounds with antidiabetic properties are found in various plants, including aloe, mint, banaba, bitter melon, caper bush, cinnamon, cocoa, coffee, fenugreek, garlic, guava, turmeric, tea, walnuts, shaggy bindweed, Yerba maté, Bambusa tulda, Ficus bengalensis, Ferula orientalis, Gymnema sylvestre, Dioscorea japonica, Artemisia abyssinica, Phaseolus vulgaris, Datura quercifolia, Cassia fistula, Citrus aurantium, Ficus benghalensis, Polygonum aviculare, Allium tuncelianum, Astragalus brachycalyx, Ferulago stelleta, and Rhizophora mucronata.

For instance, the thiazolidinedione-morpholine hybrid of vanillin, isolated from the medicinal plant Polygonum aviculare, showed good to moderate inhibition potential against α-glucosidase, α-amylase, and protein tyrosine phosphatase in vivo, with excellent in vitro inhibition of dipeptidyl peptidase-4 (DPP-4). Piperine, an alkaloid responsible for the pungent taste of black pepper (Piper nigrum), has also shown antidiabetic effects. When combined with a therapeutic dose of metformin, piperine significantly lowered blood glucose levels in diabetic mice compared to metformin alone. Additionally, aqueous extracts of black pepper, turmeric, ajwa pulp, and ajwa seeds have demonstrated significant reductions in serum glucose, glycosylated hemoglobin, and insulin levels in diabetic rats.

Berberine, an isoquinoline alkaloid from the Chinese herb Coptis chinensis, has marked antidiabetic effects. Piperidine-, piperazine-, and morpholine-substituted berberine compounds exhibit concentration-dependent insulin-resistant reversal actions superior to rosiglitazone. Despite the numerous natural substances, synthetic compounds for diabetes treatment are also extensively researched, including metformin, gliquidone, nateglinide, phenformin, rosiglitazone, glimepiride, pioglitazone, glibenclamide, exenatide, mitiglinide, gliclazide, chlorpropamide, glipizide, acetohexamide, tolbutamide, dapagliflozin, dulaglutide, liraglutide, glyburide, canagliflozin, repaglinide, thiazolidinediones, biguanides, sulfonylureas, gliptins, deazaxanthine, pyrazole, pyrrolidine, oxindole, isatin, imidazole, benzimidazole, triazole, oxadiazole, thiazole, pyridine, piperazine, thiazolidinone, thiadiazole, benzofuran, benzoxazole, coumarin, flavone, piperidine, xanthone, and pyrimidine.

Medications for Type 1 diabetes include short-acting insulin (Humulin R U-100 and Novolin R FlexPen), rapid-acting insulin (inhaled insulin Afrezza, insulin aspart, insulin glulisine, insulin lispro, and insulin lispro-aabc), intermediate-acting insulin (insulin isophane Humulin N U-100), long-acting insulin (insulin degludec Tresiba, insulin detemir Levemir, insulin glargine Basaglar KwikPen, Lantus, and insulin glargine-yfgn Semglee-yfgn), concentrated regular insulin (Humulin R U-500), and Pramlintide (SymlinPen).

Medications for Type 2 diabetes include the same insulin drugs and additional medications like α-glucosidase inhibitors (acarbose and miglitol), biguanides (metformin), dopamine-2 agonists (bromocriptine), dipeptidyl peptidase-4 (DPP-4) inhibitors (alogliptin and alogliptin-metformin), glucagon-like peptide-1 receptor agonists (GLP-1 receptor agonists) (dulaglutide and exenatide), sodium-glucose transporter (SGLT) 2 inhibitors (canagliflozin), thiazolidinediones (rosiglitazone), and other medications like aspirin and drugs for high cholesterol and blood pressure.

The U.S. Diabetes Surveillance System provides detailed data on diabetes at national, state, and county levels, covering aspects such as age, sex, race/ethnicity, and education. According to the CDC’s National Diabetes Statistics Report, approximately 29.7 million people in the U.S. had diagnosed diabetes in 2021. This includes 352,000 children and adolescents younger than 20 years, with 304,000 having Type 1 diabetes. Among adults aged 20 and older, 1.7 million reported having both Type 1 diabetes and using insulin, while 3.6 million started using insulin within a year of their diagnosis. Diabetes prevalence is highest among American Indian and Alaska Native adults (13.6%), followed by non-Hispanic Black adults (12.1%), Hispanic adults (11.7%), non-Hispanic Asian adults (9.1%), and non-Hispanic White adults (6.9%). Additionally, the prevalence of diagnosed diabetes varies significantly by education level and family income, with lower prevalence among individuals with higher education and income levels.

Globally, diabetes cases are expected to rise significantly. The Institute for Health Metrics and Evaluation projects that the number of people with diabetes will increase from 529 million in 2021 to 1.3 billion by 2050. This rapid growth presents significant challenges for health systems worldwide, especially considering the disease’s increased risk for ischemic heart disease and stroke. The prevalence rate is highest in North Africa and the Middle East, with a projected increase from 9.3% to 16.8% by 2050. Almost all global diabetes cases (96%) are Type 2 diabetes, with high body mass index (BMI) being the primary risk factor, accounting for 52.2% of Type 2 diabetes disability and mortality. Other significant risk factors include dietary risks, environmental and occupational risks, tobacco use, low physical activity, and alcohol use.

Effective management of diabetes requires a multifaceted approach, including lifestyle modifications, regular monitoring, and medication. Lifestyle changes such as a balanced diet, regular exercise, and maintaining a healthy weight are crucial. Monitoring blood glucose levels, using tools like continuous glucose monitoring (CGM) devices, and regular HbA1c testing provide valuable insights into blood sugar control. Medications, including insulin therapy and oral hypoglycemic agents, are essential in managing diabetes. New advancements, such as artificial pancreas systems and stem cell therapy, offer promising future directions for diabetes treatment.

Morpholine Derivatives as Antidiabetic Drugs

Recent studies have shown promising developments in the use of morpholine derivatives as antidiabetic drugs, with significant attention given to their potential to inhibit key enzymes associated with diabetes management. This article aims to provide a comprehensive overview of these findings, highlighting the synthesis, mechanism of action, and potential therapeutic benefits of morpholine-based compounds.

Overview of α-Glucosidase Inhibitors

One of the primary focuses of recent research is the development of α-glucosidase inhibitors. α-Glucosidase is an enzyme responsible for the breakdown of carbohydrates into glucose, and its inhibition can help in controlling blood glucose levels. Novel benzimidazole derivatives containing morpholine and piperazine structures have shown substantial inhibitory effects on α-glucosidase, with inhibition rates ranging from 63% to 99%. These compounds also exhibit antioxidant activity, which is beneficial in reducing oxidative stress associated with diabetes.

Synthesis and Evaluation of Benzimidazole Derivatives

Khan et al. synthesized a series of 1-benzyl-3-((2-substitutedphenyl)amino)-2-oxoethyl)-2-(morpholinomethyl)-1H-benzimidazol-3-ium chlorides and evaluated their α-glucosidase inhibitory activity. Among these, the compound with a 4-bromophenyl group demonstrated potent inhibitory potential. Other derivatives also showed moderate to good α-glucosidase inhibitory activity, suggesting the potential of these compounds as antidiabetic agents.

Role of Electron-Donating Groups

Research indicates that the presence of electron-donating groups, such as methyl and methoxy, on the phenyl ring of benzimidazole derivatives enhances their inhibitory activity. Docking simulations have shown that these groups facilitate hydrogen bond interactions with the enzyme’s active site, improving the efficacy of the inhibitors.

Optically Active Morpholine Derivatives

Optically active derivatives of 1,4-morpholin-2,5-dione have also been investigated for their α-glucosidase inhibitory activities. Compounds with extended side chains, particularly those containing a CH2OBn group, showed increased biological activity, indicating that modifications to the morpholine structure can significantly impact their therapeutic potential.

Piperazinyl and Morpholinyl Quinoline Derivatives

In vitro studies have revealed that piperazinyl and morpholinyl quinoline derivatives exhibit high inhibitory activity against various metabolic enzymes, including hCA I and II, AChE, BChE, and α-glycosidase. These compounds have potential applications in treating conditions such as gastric and duodenal ulcers, glaucoma, mountain sickness, epilepsy, osteoporosis, neurological disorders, and type-2 diabetes mellitus.

Morpholine-Substituted Thiadiazoles

Morpholine-substituted thiadiazoles have shown promising results as histamine H3 receptor antagonists, which can be used to treat obesity and type 2 diabetes. These compounds help reduce non-fasting glucose levels and dose-dependently block the increase in HbA1c, a key marker of long-term blood glucose levels.

Morpholino Thiazolyl-2,4-Thiazolidinediones

Morpholino thiazolyl-2,4-thiazolidinediones have been tested for their insulinotropic activities, showing positive effects on insulin release and glucose uptake. These compounds possess both pancreatic and extrapancreatic effects, making them valuable candidates for diabetes treatment.

Recent Developments in Morpholine Derivatives

In 2022, researchers discovered the antidiabetic potential of a novel morpholine derivative, which acts as a positive allosteric modulator (PAM) of the GLP-1 receptor. This compound showed significant improvements in glucose handling in diabetic patients without off-target activities, highlighting its therapeutic promise.

Hybrid Structures with Morpholine Moieties

Hybrid structures combining sulfonamide, 1,3,5-triazine, and thiazole with morpholine have demonstrated selective inhibition of dipeptidyl peptidase 4 (DPP-4), leading to improved blood glucose levels and antioxidant enzyme systems. These compounds have shown potential for dose-dependent improvement of insulin levels and glucose control.

Piperazine and Piperidine Derivatives

Piperazine and piperidine derivatives continue to be explored for their antidiabetic properties. Piperazine-derived compounds have shown promising DPP-4 inhibitory activity and moderate antihyperglycemic effects in vivo. Piperidine derivatives, including chalcones and sulfonamides, have demonstrated significant enzyme inhibition and antioxidant activities, further validating their potential as antidiabetic agents.

In conclusion, the ongoing research into morpholine, piperazine, and piperidine derivatives highlights their potential as effective antidiabetic drugs. These compounds offer various mechanisms of action, including enzyme inhibition and modulation of metabolic pathways, providing multiple therapeutic avenues for managing diabetes. Continued exploration and clinical development of these derivatives may lead to new and improved treatments for diabetes, addressing the growing global health challenge posed by this disease.

APPENDIX 1 – Morpholine Derivatives as Antidiabetic Drugs: Technical Data and Capabilities

Morpholine derivatives have shown substantial promise as antidiabetic agents, particularly in inhibiting enzymes like α-glucosidase, which play a crucial role in carbohydrate metabolism. This article provides a detailed examination of these compounds, their technical data, and their therapeutic potentials.

Chemical and Physical Properties of Morpholine

  • Chemical Formula: O(CH₂CH₂)₂NH
  • Molecular Weight: 87.12 g/mol
  • Appearance: Colorless liquid
  • Odor: Ammonia or fish-like
  • Boiling Point: 129°C (264°F)
  • Melting Point: -4.9°C (23.2°F)
  • Density: 0.999 g/cm³ at 20°C
  • Solubility: Miscible with water and most organic solvents
  • Vapor Pressure: 5.37 mm Hg at 25°C
  • Flash Point: 38°C (100°F) closed cup

Toxicity and Safety Information

  • LD₅₀ (oral, rat): 1050 mg/kg
  • LD₅₀ (oral, mouse): 525 mg/kg
  • LD₅₀ (oral, mammal): 1220 mg/kg
  • LC₅₀ (inhalation, mouse, 2 hours): 365 ppm
  • Permissible Exposure Limit (PEL): 20 ppm (70 mg/m³)
  • Recommended Exposure Limit (REL): 20 ppm (70 mg/m³) TWA; 30 ppm (105 mg/m³) STEL
  • Immediate Danger to Life or Health (IDLH): 1400 ppm

Synthesis and Applications

  • Production Methods:
    • Dehydration of diethanolamine with concentrated sulfuric acid.
    • Reaction of bis(2-chloroethyl) ether with ammonia.
    • High-temperature reaction of diethylene glycol and ammonia in the presence of hydrogen and a catalyst.
  • Uses:
    • pH adjustment in steam systems due to similar volatility to water.
    • Organic synthesis for creating enamines and as a building block for various pharmaceuticals.
    • Solvent for chemical reactions due to its low cost and polarity.
    • Emulsifier and solubility aid in fruit coatings (though banned in the EU).
    • Component in agricultural fungicides targeting ergosterol biosynthesis.

Antidiabetic Properties and Mechanisms

  • α-Glucosidase Inhibitors:
    • Benzimidazole derivatives with morpholine structures show inhibition rates from 63% to 99%.
    • Presence of electron-donating groups enhances inhibitory activity through hydrogen bond interactions.
  • Piperazinyl and Morpholinyl Quinoline Derivatives:
    • High inhibitory activity against hCA I and II, AChE, BChE, and α-glycosidase.
    • Potential applications include treatment of ulcers, glaucoma, epilepsy, osteoporosis, and type-2 diabetes mellitus.
  • Morpholine-Substituted Thiadiazoles:
    • Effective as histamine H3 receptor antagonists, useful in obesity and type 2 diabetes treatment.
  • Morpholino Thiazolyl-2,4-Thiazolidinediones:
    • Positive effects on insulin release and glucose uptake, offering both pancreatic and extrapancreatic effects.

Recent Developments

  • Novel Morpholine Derivatives:
    • 2022 research identified a new derivative acting as a positive allosteric modulator of GLP-1 receptor, improving glucose handling in diabetic patients without off-target activities.

Summary Table

Compound TypeInhibitory ActivityMechanism of ActionPotential Applications
Benzimidazole Derivatives63%-99% α-glucosidase inhibitionInhibits carbohydrate breakdownAntidiabetic, antioxidant
Piperazinyl/Morpholinyl QuinolineHigh activity against multiple enzymesEnzyme inhibitionType-2 diabetes, neurological disorders
ThiadiazolesHistamine H3 receptor antagonistsReduces non-fasting glucoseObesity, type 2 diabetes
ThiazolidinedionesPositive insulinotropic activityIncreases insulin release, glucose uptakePancreatic and extrapancreatic effects

The exploration of morpholine derivatives presents a significant advancement in the development of antidiabetic therapies. Their diverse mechanisms of action and potential applications across various medical conditions highlight their therapeutic promise. Ongoing research and clinical trials continue to uncover new insights, paving the way for innovative treatments in diabetes management.

APPENDIX – 2 : Diabetes Mellitus: Technical Data and Statistics

Overview and Types

Diabetes mellitus is a chronic disease characterized by high blood glucose levels due to the pancreas not producing enough insulin or the body’s cells not responding properly to insulin. There are two main types:

  • Type 1 Diabetes: Usually diagnosed in children and young adults, it’s an autoimmune condition where the body attacks insulin-producing cells in the pancreas.
  • Type 2 Diabetes: More common, typically develops in adults, and is often linked to obesity and lifestyle factors.

Prevalence and Mortality

  • Global Prevalence: As of 2021, approximately 537 million adults (20-79 years) are living with diabetes. This number is projected to rise to 783 million by 2045.
  • Mortality: In 2019, diabetes caused 1.5 million deaths globally, with a significant proportion occurring in individuals under 70 years old. Additionally, it contributed to 460,000 deaths due to renal disease and was responsible for nearly 20% of cardiovascular deaths​ ​.


Long-term complications of diabetes include:

  • Microvascular: Retinopathy, nephropathy, neuropathy
  • Macrovascular: Atherosclerosis, myocardial infarction, stroke
  • Others: Peripheral arterial disease, immune dysfunction​​.

Prevention and Management

  • Type 1 Diabetes: No proven preventive measures.
  • Type 2 Diabetes: Can often be prevented or delayed through a balanced diet, regular physical activity, and maintaining a healthy body weight. Physical exercise (90 minutes/day) can reduce the risk by 28%. A diet high in whole grains, fiber, and healthy fats, and low in sugary drinks and red meat, is recommended​ ​.

Natural and Synthetic Treatments

Natural antidiabetic compounds are found in plants such as aloe, cinnamon, and turmeric. Synthetic treatments include:

  • Type 1 Diabetes: Insulin (short-acting, rapid-acting, intermediate-acting, long-acting) and Pramlintide.
  • Type 2 Diabetes: In addition to insulin, medications like metformin, DPP-4 inhibitors (e.g., alogliptin), SGLT-2 inhibitors (e.g., canagliflozin), and GLP-1 receptor agonists (e.g., exenatide) are used​.

Current Statistics and Trends

  • U.S. Data: In 2021, 29.7 million Americans had diagnosed diabetes, including 352,000 children and adolescents. The prevalence was highest among American Indian/Alaska Native adults (13.6%) and non-Hispanic Black adults (12.1%)​ .
  • Global Data: Diabetes cases are expected to rise significantly, with the highest prevalence increase projected in North Africa and the Middle East (from 9.3% to 16.8% by 2050). The majority of cases are Type 2 diabetes, driven by high BMI and lifestyle factors.

Economic Impact

Diabetes causes significant healthcare expenditure. In 2021, global diabetes-related health expenditure was at least USD 966 billion, a 316% increase over the past 15 years​​.

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