Tetrahedron report 1240An overview of the synthetic routes to essential oral anti-diabetes drugs
Introduction
Diabetes mellitus (DM) is a chronic metabolic disorder characterized by hyperglycaemia resulting from lack of insulin secretion, impaired insulin sensitivity or both [1]. This disorder emerges as a growing threat to human health worldwide. In 2019, approximately 463 million adults were living with diabetes globally and the number is projected to rise to 700 million by 2045 if not given attention [2,3]. According to the World Health Organisation (WHO), diabetes was ranked the 9th leading cause of deaths in 2019, accounting for 4.2 million global deaths [4]. In 2019 alone, diabetes mellitus direct global expenditure was estimated to amount to USD 760 billion and is projected to reach USD 825 billion by 2045 [5].
Diabetes falls into two main categories, type-1 and type-2 with type-2 being the most prevalent accounting for 90% of all diabetes cases [6]. Type-2 DM is characterised by relative insulin deficiency, insulin resistance and increased hepatic glucose output and is influenced by factors such as aging, excess body weight, physical inactivity and increasing urbanization [7]. A number of life-threatening health complications such as nephropathy, retinopathy, cardiovascular diseases (CVDs), peripheral vascular disease and stroke are associated with type-2 diabetes. The cornerstone for management of type-2 DM includes lifestyle modifications such as diet and physical activity. Despite these lifestyle modifications being imperative, they are hardly entirely effective in managing type-2 DM. As a result, oral medications designed to correct one or more of these metabolic abnormalities are frequently prescribed [8]. There are several oral anti-diabetic drugs in the market and are classified as sulfonylureas, thiazolidinediones, meglitinides, sodium glucose co-transporter (SGLT2), α-glucosidase inhibitors, dipeptidyl peptidase-(IV) inhibitors, biguanide and incretin mimetics [9]. Prescription of antidiabetic drugs differ from patient to patient as is influenced by factors such as blood glucose level and other pre-existing underlying health conditions. These drugs can be prescribed as combination therapy when monotherapy is ineffective.
Synthetic chemistry has played a vital role in improving the public health of the modern society. This has been enabled by the curiosity of generations of scientists who have been constantly developing better synthetic strategies by adopting new methodologies and enabling technologies to warrant timely production of medications. Herein, we review synthetic strategies of type-2 DM oral medications (Table 1).
Section snippets
Sulfonylureas
Sulfonylureas, discovered by Janbon and co-workers in 1942 have been extensively used for treatment of type-2 DM for nearly 50 years [10]. Despite several anti-diabetic agents in the market, sulfonylureas remain one of the most prescribed due to affordability and possibility of mono-dosing [10,11]. Sulfonylureas work as an insulin secretagogue and are administered as either monotherapy or in combination with other diabetes medications. These drugs include gliclazide (Fig. 1), glipizide (Fig. 5)
Thiazolidinediones
Thiazolidinediones (TZDs), also known as glitazones are a class of oral antidiabetic drugs discovered in late 1990s for the management of type-2 diabetes. They are used in combination with other types of oral antidiabetic drugs such as sulfonylureas, metformin and acarbose thereby reducing the insulin dosage needed in insulin dependent patients. Drugs in this class include citiglitazone, englitazone, darglitazone, troglitazone, rosiglitazone and pioglitazone [34,35]. Rosiglitazone (Fig. 27) and
Meglitinides
Meglitinides, also known as glitinides, are oral medication used for management of type 2 diabetes mellitus. Like sulfonylureas, they are insulin secretagogues with short half-lives [49]. Main analogues of this class include nateglinide (Fig. 38) and repaglinide (Fig. 47). Repaglinide, the first member of the class was approved by FDA in 1997, followed by nateglinide in 2000 [49]. Synthetic routes towards repaglinide and nateglinide are herein reviewed.
Dipeptidyl peptidase (IV) inhibitors
Dipeptidyl peptidase IV (DPP-4) inhibitors also known as gliptins are a class of oral antidiabetic drugs first discovered in 1998 for the management of type-2 diabetes [59]. These drugs offer several benefits over other antidiabetic drugs such as lack of body weight gain and decreased occurrence of hypoglycaemic episodes [60]. A total of 17 gliptins has been discovered with 8 having been approved for use by the US FDA [59]. Sitagliptin, vildagliptin, saxagliptin, linagliptin and alogliptin are
Sodium glucose transporter inhibitors
Sodium glucose transporter-2 inhibitors are anti-diabetic drugs that inhibit the kidneys from reabsorbing glucose back into the blood stream by blocking sodium glucose transport proteins [81]. Five of the gliflozins which are approved for prescription includes dapagliflozin (Fig. 74), canagliflozin (Fig. 80), ipragliflozin, ertugliflozin (Fig. 87) and empagliflozin (Fig. 93) are herein reviewed. Chemical synthesis of gliflozins generally consists of three steps, which are aryl substituent
Biguanides
Biguanides are considered as antihyperglycemic rather than hypoglycaemic agents since they do not stimulate pancreatic β-cells and rarely cause hypoglycaemia [107]. This class acts by suppressing glucose production by the liver and increasing peripheral glucose uptake [107,108]. Discovered in the 1950s, there three drugs in this class namely metformin, buformin and phenformin. However, both phenformin and buformin were later discontinued from the international market due to high risk of lactic
Alpha glucosidase inhibitors
Alpha glucosidase inhibitors are used for management of type 2 diabetes through competitive and reversible inhibition of activity of intestinal alpha-glucosidase enzymes [112,113]. Alpha glucosidase enzymes such as glucoamylase, sucrase, maltase and isomaltose are responsible for converting complex non-absorbable carbohydrates into absorbable monosaccharides [112]. Therefore inhibition of these enzymes results in retarded carbohydrate digestion thus reducing postprandial hyperglycaemia and
Conclusion and outlook
The increasing high prevalence of type-2 DM worldwide is very concerning thus demanding for apt management of this disease. In response to this, many oral medications have been developed and are available in the market for type-2 DM management. However, the quest to discover more potent drugs and improve the existing synthetic routes remains a priority. In this work we reviewed synthetic routes towards various anti-diabetic drugs respective of their classification highlighting successes,
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Cloudius R. Sagandira graduated with a BSc in Biochemistry and Chemistry from the Nelson Mandela University in 2014 where he went on to receive his Honours degree in Formulation Science (Cum Laude) in 2015. In the same year, he joined Professor Paul Watts' group as a Master of Science candidate at the same University where he worked on potentially explosive azide chemistry in continuous flow systems and graduated in 2017 with distinction. Working in the same research group, he received his
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Cloudius R. Sagandira graduated with a BSc in Biochemistry and Chemistry from the Nelson Mandela University in 2014 where he went on to receive his Honours degree in Formulation Science (Cum Laude) in 2015. In the same year, he joined Professor Paul Watts' group as a Master of Science candidate at the same University where he worked on potentially explosive azide chemistry in continuous flow systems and graduated in 2017 with distinction. Working in the same research group, he received his chemistry PhD degree in 2019 where he developed a continuous flow synthetic procedure for oseltamivir phosphate an anti-influenza drug. Currently, he is a postdoctoral fellow in the same research group working on the synthesis of numerous drugs in flow
Agnes Z. Khasipo graduated with a BSc in Biochemistry and Chemistry from Nelson Mandela University in 2018. She received her BSc Honours degree in Chemistry (Cum Laude) from the same institution in 2019. In the same year, she joined Professor Paul Watts' research group as a Master of Science candidate which was later upgraded to PhD in 2021. Currently, she is working on continuous flow synthesis of sulfonylurea compounds as a PhD candidate in the same research group
Mellisa B. Sagandira graduated with a B Eng. (Hons) Production Engineering from Chinhoyi University of Technology in 2017. In 2019, she joined Professor Paul Watts research group as a MSc candidate where she worked on synthesis of xylidines in continuous flow systems and graduated in 2020 with a distinction. Currently, she is a PhD candidate in the same research group working on the continuous flow synthesis of an anti-coagulant drug
Paul Watts started his career as a lecturer at the University of Hull (UK) in 2002, being promoted to full professor in 2011. At the University of Hull he led the micro reactor and flow technology group. In February 2013, he moved to Nelson Mandela University to hold the distinguished position of ‘SARChI Research Chair in Microfluidic Bio/Chemical Processing’. He has published over 120 highly cited papers. He strongly believes that scientists should conduct research that impacts society; the biggest project underway involves the local production of key drugs as the morbidity and mortality from major diseases are much more devastating in Africa than in other regions of the world. The vision is that new technology will be used within South Africa to manufacture generic drugs; this could create jobs and a new manufacturing industry within the country