Diabetes is on the rise, largely attributed to factors like the increasing rates of obesity, sedentary lifestyles, and the consumption of sugary and high-calorie foods. Hyperglycemia, delayed wound healing, excessive drinking, weight loss, blurred vision, polyuria, and increased blood sugar in the urine are the main symptoms of diabetes [1]. In both types of diabetes, hyperglycemia causes disorders such as high osmotic pressure in the extracellular fluid, electrolyte depletion in the body, and vascular damage. This increases the risk of kidney failure, heart attack blindness, and stroke [2]. Type 2 diabetes mellitus, representing about 90% of all cases of diabetes has become a global health problem and affects about 180 million people worldwide [3,4]. An efficient approach to managing diabetes involves lowering elevated blood sugar levels following meals. This goal can be accomplished by diminishing the intake of dietary carbohydrates and/or by inhibiting the activity of two carbohydrate digestive enzymes (α-glucosidase and α-amylase) [[5], [6], [7], [8], [9], [10]].

Reactive oxygen species (ROS) are involved in cell injury and death in various conditions including cancer, aging, neurodegenerative disorders, and diabetes. Free radicals, which include ROS and reactive nitrogen species (RNS), are generated through various mechanisms such as radiation exposure, metal-catalyzed reactions, inflammatory processes, and mitochondrial electron transport [[11], [12], [13]]. Low concentrations of ROS can induce cell division while high concentrations can result in the breakdown of cellular structures and biomolecules, resulting in apoptosis and necrosis [[14], [15], [16], [17]]. Postprandial hyperglycemia increases the production of free radicals [18]. This can decrease the number of glucose transfer channels [19] and reduce insulin secretion from beta cells [20]. Consequently, oxidative stress caused by hyperglycemia may increase the risk of diabetes symptoms. Managing postprandial hyperglycemia and addressing obesity-related factors can reduce oxidative stress levels in individuals with diabetes. Antioxidants act as metabolic mediators that protect biological tissues from damage caused by free radicals [21].

One approach to reducing postprandial hyperglycemia is by limiting the activity of intestinal carbohydrate digestive enzymes. α-amylase is an important enzyme that hydrolyzes α-1-4-glucan bonds in polymeric substrates like starch and maltodextrin into shorter oligomers [22]. α-glucosidase is found in human intestinal mucous cells and hydrolyzes α-1-4-glycosidic bonds to release glucose from polysaccharides at their nonreducing ends. Dietary carbohydrates like starch are digested by α-amylase into large amounts of maltose which are then digested by α-glucosidase into glucose for absorption in the human intestine [23].

Hence, precise control of postprandial blood glucose levels is crucial for managing, preventing, and treating diabetes in patients by inhibiting α-glucosidase and α-amylase [[24], [25], [26], [27]]. α-amylase and α-glucosidase inhibitors limit the degradation and uptake of dietary carbohydrates in the gastrointestinal tract [[28], [29], [30], [31]].

Commonly used commercial medications like miglitol, acarbose, and voglibose are frequently employed in the management of type 2 diabetes due to their ability to inhibit both carbohydrate-degrading enzymes (α-glucosidase and α-amylase). These medications work by preventing the breakdown of complex carbohydrates and lowering blood sugar levels. However, they can lead to gastrointestinal side effects like gas, bloating, and diarrhea. Hence, there is a necessity to create new, safer, and more efficient therapeutic agents for managing blood sugar levels and addressing diabetes mellitus [32,33].

Natural products containing inhibitors of carbohydrate breakdown enzymes have been explored as an alternative method for preventing and treating type 2 diabetes [34]. Curcumin derived from turmeric rhizomes is well-known for its anti-inflammatory, antioxidant and antimicrobial properties. It has also been studied extensively for its potential in cancer prevention in various cancer models [[35], [36], [37], [38]]. Curcumin's chemical structure consists of two o-methoxy phenolic groups (aromatic ring structure) connected by seven aliphatic carbons. The carbon chain contains an α, β-aliphatic half-unsaturated β-diketone [39,40] (Fig. 1).

However, curcumin's low solubility in water along with its low stability and rapid metabolism limits its bioavailability [41]. Curcumin exhibits inhibitory effects on many enzymes due to its unique properties such as a flexible backbone and hydrophobic nature [42,43]. Considering the potential side effects of drugs, researchers have focused on developing new curcumin derivatives that can effectively control the development of diabetes by inhibiting α-glucosidase and α-amylase [31,[44], [45], [46], [47], [48]]. Importantly, several clinical trials have evaluated the efficacy of curcumin-based interventions in human subjects with diabetes. These studies have demonstrated that curcumin can modulate key signaling pathways involved in glucose and lipid metabolism, such as the activation of AMPK and the regulation of insulin sensitivity [49]. These investigations have reported that the administration of curcumin or its analogues can improve glycemic control, reduce oxidative stress, and mitigate diabetes-related complications, such as diabetic neuropathy and nephropathy [50,51]. Furthermore, the anti-inflammatory and antioxidant properties of curcumin have been exploited in the development of combination therapies. By co-administering curcumin with established antidiabetic drugs, researchers have observed synergistic effects in improving glycemic parameters and reducing the risk of diabetic complications [49,52]. Overall, the growing body of evidence suggests that curcumin and its derivatives hold promise as potential therapeutic agents for the management of diabetes and its associated comorbidities. Ongoing research continues to explore the optimization and clinical translation of these curcumin-based interventions.

Several structural modifications of dietary polyphenols have been shown to influence their inhibitory effects on the carbohydrate-metabolizing enzymes α-amylase and α-glucosidase. The research indicates that increasing the hydroxylation of flavonoids, the galloylation of catechins, and the presence of caffeoyl moieties all enhance the inhibitory activity against both α-amylase and α-glucosidase. In contrast, glycosylation of flavonoids tends to decrease their inhibitory effects on these enzymes. Additionally, the polymerization of proanthocyanidins was found to increase the inhibitory activity against α-amylase, while it caused a decrease in the inhibitory effects against α-glucosidase [[53], [54], [55], [56], [57]].

Numerous studies have investigated how the hydroxylation of curcumin, can influence its inhibitory activity against the carbohydrate-metabolizing enzymes α-amylase and α-glucosidase. The research findings indicate that increasing the degree of hydroxylation in the curcumin molecule enhances its ability to inhibit both α-amylase and α-glucosidase enzymes. Specifically, the addition of hydroxyl groups to the phenyl rings of curcumin was found to improve the inhibitory effects. Therefore, curcumin derivatives with a higher degree of hydroxylation demonstrate greater potential for managing hyperglycemia and related metabolic disorders, such as type 2 diabetes [52,58]. The enhanced enzyme inhibitory activity of hydroxylated curcuminoids makes them an interesting target for further research and development of antidiabetic therapeutics.

Previously, in our laboratory, we synthesized 14 different derivatives with curcumin-based pyrano[2,3-d]pyrimidines, varying only in their aryl group. Due to the importance of phenol groups in antioxidant activity and α-glucosidase and α-amylase inhibitory of curcumin, we synthesized nine hydroxyl benzaldehydes different in position and number of hydroxyl groups. However, among the evaluated derivatives, compounds L9, L12, and L8 were identified as potent inhibitors of the α-glucosidase enzyme, and compounds L9, L8, L12, L7, and L6 were the strongest inhibitors of the α-amylase enzyme, in vitro. On the other hand, since 3′,5′- dihydroxybenzaldehyde (L8), 2′,3′,4′-trihydroxy benzaldehyde (L9) and3′,5′-dihydroxy,4′-methoxy benzaldehyde (L12) derivatives inhibited α-glucosidase stronger than α-amylase and also showed suitable anti-oxidant/stability properties, it can be concluded that these derivatives are the most appropriate compounds for further animal/in vivo studies in the treatment of diabetes [58]. Resently, we produced curcumin-fused aldohexose. Since glucose binds to the active site of these enzymes via hydroxyl groups, prompting us to modify curcumin by attaching various aldohexose units. This modification occurs through the carbonyl group of the pentose attacking the CH2 group of curcumin. We tried to enhance binding and inhibitory capacity of curcumin against α-amylase and α-glucosidase enzymes by synthesizing new poly-hydroxy derivatives of curcumin according to the structural dynamics of the active site in the target enzymes and further used in a series of biological in vivo and in vitro assays. The results showed an increase in the inhibitory effect of curcumin after modification. In vivo studies confirmed the plasma glucose diminution after the administration of curcumin-hexose derivatives to Wistar rats. Results demonstrated the relevance of these curcumin-polyol derivatives as pro-drugs in the treatment of diabetes [45].

Following this discoveries, we decided to enhance this inhibitory effect and solubility in water along with its stability by creating novel aldopentose-fused derivatives of curcumin by attaching various monosaccharide units (ribose, arabinose, and xylose) based on the structure of the target enzymes' active sites. All three compounds are structurally and chemically identical, but due to the fact that arabinose and xylose are ribose epimers, the hydroxyl groups attached to carbon No. 2 and 3 have different spatial positions than ribose. The findings suggest a potential strategy for using curcumin derivatives to slow starch digestion by inhibiting digestive enzymes.