A Review of the In Vitro Inhibition of α-Amylase and α-Glucosidase by Chalcone Derivatives

Diabetes mellitus is a chronic metabolic disease relating to steady hyperglycemia resulting from the impairment of the endocrine and non-endocrine systems. Many new drugs having varied targets were discovered to treat this disease, especially type 2 diabetes. Among those, α-glucosidase inhibitors showed their effects by preventing the digestion of carbohydrates through their inhibition against α-amylase and α-glucosidase. Recently, chalcones have attracted considerable attention as they have a simple structure, are easily synthesized as well as have a variety of derivatives. Some reports suggested that chalcone and its derivates could inhibit α-amylase and α-glucosidase. This narrative review provides a comprehensive evaluation of the inhibition of chalcone and its derivatives against α-amylase and α-glucosidase that were reviewed and reported in published scientific articles. Twenty-eight articles were reviewed after screening 207 articles found in four databases, including PubMed, Google Scholar, VHL (Virtual Health Library), and GHL (Global Health Library). This review presented the inhibitory effects of varied chalcones, including chalcones with a basic structural framework, azachalcones, bis-chalcones, chalcone oximes, coumarin-chalcones, cyclohexane chalcones, dihydrochalcones, and flavanone-coupled chalcones. Many of these chalcones had significant inhibition against α-amylase as well as α-glucosidase that were comparable to or even stronger than standard inhibitors. This suggested that such compounds could be potential candidates for the discovery of new anti-diabetic remedies in the years to come.


TABLE 1: Details of search terms in each database
In total, 207 articles were found in the four databases, including PubMed, Google Scholar, VHL, and GHL. After the selection step, 28 articles were included to extract data. The selection of studies is illustrated in Figure 1. Many natural or synthetic chalcones have α-amylase and/or α-glucosidase inhibitory activities, including chalcones with a basic structural framework, azachalcones, bis-chalcones, chalcone analogs, chalcone oximes, coumarin-chalcone derivatives, cyclohexane chalcones, dihydrochalcones, and flavanone-coupled chalcones. Table 2 presents chalcones and their activities [3,. The structures of compounds are represented as SMILES notations (Simplified Molecular Input Line Entry System), which were obtained from PubChem (https://pubchem.ncbi.nlm.nih.gov/) by the name or chemical structure. Our set of compounds could be useful for future structure-activity relationship studies. 2023        (
Most synthesized oleanolic acid derivatives chalcones reported by Tang et al. (2014) exhibited moderate inhibitory activity against α-glucosidase [19]. The para-position of the secondary amine (compound 3c) and the presence of electron donating groups (compound 3e) were suggested to affect the inhibitory ability. Compound 3c was a strong inhibitor with an IC 50 value of 1.04 ± 0.19 μM. This proved that chalcone sulfonamide had a large potential as α-glucosidase inhibitor in the treatment of diabetes [20]. Chalcones 5'prenylated (1) and 5'-geranylated chalcone (14) were both a bit more effective than acarbose. It should be noted that 3'5'-diprenylated and digeranylated chalcones had a remarkeable inhibitory effect. Of which, the digeranylated chalcone (16) was the best inhibitor against α-glucosidase (IC 50 = 0.9 μM) [21].

Azachalcones
Of the twenty-seven synthesized azachalcone derivatives , compound 3, compound 5, compound 6, compound 16, and compound 28 were strong α-amylase and α-glucosidase inhibitor. Their IC 50 are presented in Table 2. Among these, compound 3, which had the 3-acetyl pyridine group and 2-methoxy-aryl group in its structure, was the most potent inhibitor against these enzymes [25].

Potential Toxicity of Chalcone Derivatives in Humans
Natural chalcones were considered relatively non-toxic compounds [32]. The prenylated chalcone from Humulus lupulus was known as xanthohumol to have anti-inflammatory effects in healthy humans if used in low doses achievable through the diet, it was safe and well tolerated by healthy adults at doses of 24 mg per day [33,34]. Licochalcone A was an ingredient in a moisturizer that has been shown to be effective and safe for people with mild to moderate acne [35]. Hydroxysafflor Yellow A for injection was safe and well-tolerated at all doses for treating acute ischemic stroke patients with blood stasis syndrome [36].
However, the toxicity of new synthetic chalcones were not well known. In addition, antidiabetic drugs that inhibit α-amylase and α-glucosidase enzymes known as acarbose have been reported to have side effects such as stomach discomfort, gas, bloating and diarrhea [37]. Some chalcone derivatives have been shown to be more active in vitro than acarbose. Therefore, concern about the toxicity and safety of these compounds was necessary.
Several studies on chalcones toxicity have been reported. 3-(4,5-dimethylthiazol-2-yl)-2,5diphenyltetrazolium bromide (MTT) assay on normal monkey kidney cells (Vero cells) and adenocarcinomic human epithelial cells (A549 cells) showed that 5-styryl-2-sulfonamidochalcones (2f and 2h) had no cytotoxic effect on the Vero cells and narrowed the toxicity on A549 cells [13]. Predictive toxicity studies have shown that chalcone triazoles are not mutagenic and are not irritating to the skin and eyes. In addition, their toxicity dose range is also predicted in silico with rat oral LD50 from 0.64 g/kg to 7.94 g/kg [22]. Meanwhile, chalcones and chalcone analogues in the study by Lee et al. (2014) showed embryotoxicity of zebrafish resulting in muscle defects [38].
Computational methods for chemical toxicity prediction can also be used to select potential candidates for further study or to design a series of new structures with reduced toxicity.

Conclusions
This narrative review presented chalcones and their derivatives as potential scaffolds with chemical characteristics that strongly affect α-amylase and α-glucosidase. Some compounds showed better efficacy in vitro than standard controls, suggesting approaches for developing new drugs to manage diabetes. Although the effects of chalcone derivatives were mentioned in several studies, the toxicity of new synthetic chalcones are not well known. Considerably more work will need to be done to determine the potential effects of Chalcones derivatives in humans. The results demonstrated positive findings that support the potential use of these candidates for discovering new anti-diabetic remedies in the years to come.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: Funding: This work was supported by the University of Medicine and Pharmacy at Ho Chi Minh City for Thanh-Dao Tran under grant number 162/2019/HD-DHYD. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.