Xanthenone based hydrazone derivatives (5a-n) have been synthesized as potential α-glucosidase inhibitors. All synthesized compounds (5a-n) are characterized by their FTIR, 1H NMR, 13C NMR and HRMS, and in case of 5g also by X-ray crystallographic technique. The compounds unveiled a varying degree of α-glucosidase inhibitory activity when compared with standard acarbose (IC50 = 375.38 ± 0.12 µM). Amongst the series, compound 5l (IC50 = 62.25 ± 0.11 µM) bearing a trifluoromethyl phenyl group is found to be the most active compound. Molecular modelling is performed to establish the binding pattern of the more active compound 5l, which revealed the significance of substitution pattern. The pharmacological properties of molecules are also calculated by MedChem Designer which determines the ADME (absorption, distribution, metabolism, excretion) properties of molecules. The solid state self-assembly of compound 5g is discussed to show the conformation and role of iminoamide moiety in the molecular packing.

In this study, a series of salicylic acid derivatives were designed and synthesized as novel non-saccharide α-glucosidase inhibitors. Biological evaluation indicated that when compared to acarbose, compounds T9, T10, and T32 exhibited a higher potency of α-glucosidase inhibitory activity with IC50 values of 0.15 ± 0.01 mM, 0.086 ± 0.01 mM and 0.32 ± 0.02 mM, respectively. Evaluation of the inhibition kinetics indicated that T9, T10, T32, and acarbose interacted with α-glucosidase in a mixed non-competitive inhibitory manner. Moreover, T9, T10, and T32 statically quenched the fluorescence of α-glucosidase by formation of an inhibitor-α-glucosidase complex. The docking results showed that hydrogen bonds were generated between the test compounds and α-glucosidase. The antioxidant study revealed that compound T10 exhibited a higher antioxidant activity via scavenging 1,1-diphenyl-2-picrylhydrazyl free radical (DPPH), thereby inhibiting lipid peroxidation and the total reduction capacity. In brief, the salicylic acid derivatives identified in this study were promising candidates for development as novel non-saccharide α-glucosidase inhibitors.

Regulation of α-glucosidase (EC 3.2.1.20) and its inhibitors is of great interest to researchers due to its clinical relevance as a target enzyme for the treatment of α-glucosidase-mediated diseases, such as type 2 diabetes mellitus and Pompe disease. In this study, we conducted a phloroglucinol-induced inhibition kinetics assay and performed computational molecular dynamics (MD) simulations to assess binding manner in α-glucosidase. The results showed that phloroglucinol reversibly inhibited α-glucosidase in a dose-dependent but non-competitive manner (Ki = 2.07 ± 0.16 mM). Interestingly, the maximum peak wavelength and the hydrophobic surface remained unchanged during the inhibition reaction, with computational MD simulations further revealing that phloroglucinol bound in front of the active site pocket rather than in the α-glucosidase active site. Therefore, we speculate that phloroglucinol-specific inhibition is mild and the inhibitor likely binds to a single binding site near but not in the active site. Our study provided insight into the effects and mechanisms associated with a mild inhibitor of α-glucosidase activity and promotes fundamental research and potential applications of inhibitors for treatment of α-glucosidase-mediated clinical disease.

Meroterpenoids isolated from guava (Psidium guajava) and Rhodomyrtus tomentosa possess special skeletons which incorporate terpenoids with phloroglucinol derivatives. Most of these meroterpenoids showed high cytotoxicity against cancer cell lines. However, their chemical diversity is very limited. Herein, we employed a biomimetic hetero-cycloaddition starting from ortho-quinone methides and an abundant natural product, β-caryophyllene, to generate meroterpene-like compounds. Considering that the source plant has hyperglycemic functions, α-glucosidase was selected as a target for bioassay. Nine compounds were screened out for promising activities (IC50 < 15 μM), which were better than the positive controls genistein and acarbose. The best inhibitor 12 (IC50 2.73 μM) possesses two caryophyllene moieties. They represented a new type of skeleton possessing activities against α-glucosidase. The kinetic study exhibited that these inhibitors belong to a non-competitive type. All these inhibitors may provide an opportunity to develop a new class of antidiabetic agents.

Mushrooms have been accepted as nutraceutical foods because of their high nutritional and functional values. They have also gained interest due to their medicinal properties, economic importance, and organoleptic merit. In this study, wild Ganoderma lucidum and four commercial mushrooms, that is, Pleurotus ostreatus, Volvariella volvacea, Hericium erinaceus, and Lentinus edodes from Pakistan were screened for their biological activities such as anticancer, antityrosinase, anti-α-glucosidase, and antithrombotic activities from their methanol, ethanol, and water extracts. Enzyme inhibition assay showed that selected mushrooms are potent inhibitors with %age inhibition ranging from 19.00% to 80.91%, and 32.85% to 83.38% for tyrosinase and α-glucosidase, respectively. The best tyrosinase inhibition was shown by P. ostreatus whereas L. edodes was found best as α-glucosidase inhibitor. These mushrooms were tested against cancer cell lines including HT-29 colon and H-1299 lungs carcinoma cell lines. G. lucidum showed 29% and 24% viability of cells against HT-29 and H-1299 cell lines, respectively. This antiproliferative effect was in dose-dependent manner, and the maximum inhibition was observed at 200 μg/ml. Mushrooms extracts were also found effective against clot lysis. The percentage of clot lysis was in the range of 27%-29%. The research would provide knowledge to the people of Pakistan about the importance of locally available commercial mushrooms and wild mushrooms for health improvement and prevention against different kinds of diseases.

In the present investigation we report the first target specific, highly diastereoselective synthesis of new class of pyranoquinolinyl/furoquinolinyl-acrylic acid diastereomers and evaluation of their invitro α-glucosidase inhibitory activity. All the products were thoroughly characterized by 1H NMR, 13C NMR, FT-IR, Mass spectral and CHN analysis. A highly diastereoselective target specific route of synthesis for the biologically active diastereomers were developed by usingchiral catalyst Europium tris[3-heptafluoropropylhydroxyl methylene]-(-)-camphorate (A) or Europiumtris[3-(trifluoromethyl)hydroxylmethylene]-(+)-camphorate (B). It was found that among a set of 4 diastereomeric products obtained, exodiasteromers of pyranoquinolinyl acrylic acid adducts exhibited relatively high α-glucosidase inhibitory activity. The newly synthesized compounds exhibited IC50 values in the range of (0.40 ± 0.02-30.3 ± 0.84 μM) as compared to standard acarbose (IC50 = 0.65 ± 0.02 μM). It was found that compounds 11a, 11c, 11d and 12d were found to be more active than standard acarbose. It was also found that unsubstituted compound (11a) or compounds with chlorine or methoxy substituent (11c, 11d, 12d) showed potential α-glucosidase inhibitory activity. However a reversal in activity was observed with Nitro substituent (11b, 13b) wherein the endodiastereomers were found to be more active than exodiastereomers. Molecular docking studies were used for design of the compound and understand the mode of binding between the compound and target enzyme. A plausible mechanism for the diastereoselective synthesis was also proposed.

Diabetes mellitus type 2 (DMT2) is a metabolic disease characterized by a chronic increase in glycemia that promotes several long-term complications and high mortality. Some enzymes involved in glycaemic control, such as α-(1,4)-glucosidase, have now been established as novel pharmacological targets. Coumarins have shown benefits in attenuating signs and complications of DMT2, including inhibition of this enzyme. In this work, new synthetic coumarins (bearing different amide and aryl substituents) were studied in vitro as inhibitors of α-(1,4)-glucosidase. Among them, five molecules proved to be excellent α-(1,4)-glucosidase inhibitors, being compound 7 (IC50 = 2.19 μM) about 200 times more potent than acarbose, a drug currently used for the treatment of DMT2. In addition, most of the coumarins presented uncompetitive inhibition for the α-(1,4)-glucosidase. Molecular docking studies revealed that coumarins bind to the active site of the enzyme in a more external area comparing to the substrate, without interfering with it, and displaying aromatic and hydrophobic interactions, as well as some hydrogen bonds. According to the results, aromatic interactions with two phenylalanine residues, 157 and 177, were the most common among the studied coumarins. This study is a step forward for the understanding of coumarins as potential anti-diabetic compounds displaying α-(1,4)-glucosidase inhibition.

The α-glucosidase (EC 3.2.1.20), a calcium-containing intestinal enzyme which is positioned in the cells which cover the intestinal microvilli brush border. The carbohydrates require metabolism by α-glucosidase before being absorbed into the small intestine, and as a result this enzyme represents a significant drug target for the effective management of diabetes. There are few α-glucosidase inhibitors in the clinical practice that are challenged by several limitations. Thus, new effective and safe therapeutic agents in this class are required. In this regard, plant secondary metabolites are a very promising source to be investigated. Herein in this review, we have focused on the preclinical studies on various glycosides with in vitro α-glucosidase inhibitory activity. The surveyed literature revealed marked inhibitory profile of various glycosides, and some of them were extremely potent relatively to the standard, acarbose. Therefore, these glycosides are strong candidates for further more detailed studies to ascertain their clinical potential and for effective contribution in effective management of diabetes, where multiple targets are required to address.

Paeonia species have been valued for their ethnomedicinal uses in various countries and received much interest among the scientific community for their therapeutic properties, including anti-microbial, anti-inflammatory, anti-cancer, nephroprotective and hepatoprotective effects. The multiple phytotherapeutical applications of Paeonia species inspired us to establish the phytochemical fingerprint and to evaluate the biological properties of ethyl acetate, methanol, and aqueous extracts from the roots and aerial parts of two Paeonia species (P. arietina G. Anderson and P. kesrounansis Thiébaut). Phytoconstituents of P. arietina and P. kesrounansis extracts were analyzed using 1D and 2D NMR and LC-DAD-ESI-MS. The total content of phenolics (TPC) and flavonoids (TFC) in the extracts was also evaluated. The antioxidant activity was profiled using DPPH, ABTS, CUPRAC, FRAP, phosphomolybdenum, and metal chelation assays. Enzyme inhibitory properties were evaluated against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), tyrosinase, α-amylase, and α-glucosidase. Phytochemical analysis of P. arietina and P. kesrounansis extracts showed the presence of galloyl esters of sugars, galloyl monoterpenes, and glycosylated flavonoids. The three solvent extracts presented different behavior in the bioassays. The highest antioxidant activity, tyrosinase and AChE inhibition were observed for the methanolic extract of the aerial parts of P. kesrounansis. In addition, the ethyl acetate extracts of the aerial parts of both plants were the most effective inhibitors of α-amylase. The highest BChE inhibition was observed for root methanolic extract of P. kesrounansis while the root ethyl acetate extract of P. arietina exerted the strongest inhibition of α-glucosidase. Methanol extract of P. kesrounansis aerial parts presented the highest TPC, while TFC was greatest in the corresponding extract of P. arietina. Our findings can be considered as a starting point for future studies to further validate the effectiveness and safety profiles of these plants in folk medicine.

Aldose reductase converts glucose to sorbitol in the polyol pathway. It is an important enzyme to prevent diabetic complications. In this study, we studied the inhibitory effects of bromophenol derivatives on aldose reductase (AR), α-glucosidase, and α-amylase enzymes. In the bromophenols series, compound 1f showed the maximum inhibition effect against AR with a Ki value of 0.05 ± 0.01 μM, while compound 1d showed the lowest inhibition effect against AR with a Ki value of 1.13 ± 0.99 μM. In addition, α-amylase from porcine pancreas and α-glucosidase from Saccharomyces cerevisiae were used as enzymes. In this study, all compounds were tested for the inhibition of the α-glucosidase enzyme and demonstrated efficient inhibition profiles with Ki values in the range of 43.62 ± 5.28 to 144.37 ± 16.37 nM against α-glucosidase. Additionally, these compounds were tested against the α-amylase enzyme, which determined an effective inhibition profile with IC50 values in the range of 9.63-91.47 nM. These compounds can be selective inhibitors of AR, α-glucosidase, and α-amylase enzymes as antidiabetic agents.