Design,synthesis and α-glucosidase inhibition study of novel embelin derivatives

Abstract

Embelin is a naturally occurring para-benzoquinone isolated from Embelia ribes (Burm. f.) of the Myrsinaceae family. It was first discovered to have potent inhibitory activity (IC₅₀ = 4.2?μM) against α-glucosidase in this study. Then, four series of novel embelin derivatives were designed, prepared and evaluated in α-glucosidase inhibition assays. The results show that most of the embelin derivatives synthesised are effective α-glucosidase inhibitors, with IC₅₀ values at the micromolar level, especially 10d, 12d, and 15d, the IC₅₀ values of which are 1.8, 3.3, and 3.6?μM, respectively. Structure–activity relationship (SAR) studies suggest that hydroxyl groups in the 2/5-position of para-benzoquinone are very important, and long-chain substituents in the 3-position are highly preferred. Moreover, the inhibition mechanism and kinetics studies reveal that all of 10d, 12d, 15d, and embelin are reversible and mixed-type inhibitors. Furthermore, docking experiments were carried out to study the interactions between 10d and 15d with α-glucosidase.     

Discovery of potent α-glucosidase inhibitor flavonols: Insights into mechanism of action through inhibition kinetics and docking simulations

Beside other pharmaceutical benefits, flavonoids are known for their potent α-glucosidase inhibition. In the present study, we investigated α-glucosidase inhibitory effects of structurally related 11 flavonols, among which quercetin-3-O-(3″-O-galloyl)-β-galactopyranoside (8) and quercetin 3-O-(6″-O-galloyl)-β-glucopyranoside (9) showed significant inhibition compared to the positive control, acarbose, with IC₅₀ values of 0.97 ± 0.02 and 1.35 ± 0.06 µM, respectively. It was found that while sugar substitution to C3-OH of C ring reduced the α-glucosidase inhibitory effect, galloyl substitution to these sugar units increased it. An enzyme kinetics analysis revealed that 7 was competitive, whereas 1, 2, 8, and 9 were uncompetitive inhibitors. In the light of these findings, we performed molecular docking studies to predict their inhibition mechanisms at atomic level.     

Inhibitory effect of α-ketoglutaric acid on α-glucosidase: integrating molecular dynamics simulation and inhibition kinetics

Abstract

The inhibition of α-glucosidase is used as a key clinical approach to treat type 2 diabetes mellitus and thus, we assessed the inhibitory effect of α-ketoglutaric acid (AKG) on α-glucosidase with both an enzyme kinetic assay and computational simulations. AKG bound to the active site and interacted with several key residues, including ASP68, PHE157, PHE177, PHE311, ARG312, TYR313, ASN412, ILE434 and ARG439, as detected by protein–ligand docking and molecular dynamics simulations. Subsequently, we confirmed the action of AKG on α-glucosidase as mixed-type inhibition with reversible and rapid binding. The relevant kinetic parameter IC₅₀ was measured (IC₅₀ = 1.738?±?0.041?mM), and the dissociation constant was determined (K_{i Slope} = 0.46?±?0.04?mM). Regarding the relationship between structure and activity, a high AKG concentration induced the slight modulation of the shape of the active site, as monitored by hydrophobic exposure. This tertiary conformational change was linked to AKG inhibition and mostly involved regional changes in the active site. Our study provides insight into the functional role of AKG due to its structural property of a hydroxyphenyl ring that interacts with the active site. We suggest that similar hydroxyphenyl ring-containing compounds targeting key residues in the active site might be potential α-glucosidase inhibitors. Abbreviations AKG alpha-ketoglutaric acid

pNPG 4-nitrophenyl-α-d-glucopyranoside

ANS 1-anilinonaphthalene-8-sulfonate

MD molecular dynamics.

Communicated by Ramaswamy H. Sarma     

Synthesis and α-glucosidase inhibition activity of dihydroxy pyrrolidines

A new series of Deacetylsarmentamide A and B derivatives, amides and sulfonamides of 3,4-dihydroxypyrrolidines as α-glucosidase inhibitors were designed and synthesized. The biological screening test against α-glucosidase showed that some of these compounds have the positive inhibitory activity against α-glucosidase. Saturated aliphatic amides were more potent than the olefinic amides. Among all the compounds, 5o/6o having polar –NH₂ group, 10f/11f having polar –OH group on phenyl ring displayed 3–4-fold more potent than the standard drugs. Acarbose, Voglibose and Miglitol were used as standard references. The promising compounds 6i, 5o, 6o, 10a, 11a, 10f and 11f have been identified. Molecular docking simulations were done for compounds to identify important binding modes responsible for inhibition activity of α-glucosidase.     

Molecular dynamics simulation integrating the inhibition kinetics of hydroxysafflor yellow A on α-glucosidase

Inhibition of α-glucosidase has attracted the attention of researchers due to its connection to type-2 diabetes. Hydroxysafflor yellow A (HSYA) extracted from Carthamus tinctorius L. is a natural antioxidant used in traditional Chinese medicine. In this study, the effect of HSYA on α-glucosidase was evaluated using inhibitory kinetics based on the antioxidant properties of HSYA and by performing computational simulation integration methods. HSYA reversibly inhibited α-glucosidase in a competitive inhibition manner and the evaluated kinetic parameters were IC₅₀ = 1.1 ± 0.22 mM and K_i = 1.04 ± 0.23 mM, respectively. The results of spectrofluorimetry showed that the inner hydrophobic regions of α-glucosidase, which are mostly in the active site, were exposed to the surface with increasing HSYA concentrations, indicating that the inactivation of α-glucosidase by HSYA was accompanied by regional unfolding. The molecular dynamics simulations indicated that the four rings of HSYA interact with four residues such as G217, A278, H279, and G280 at the entrance of the active site. Our study provides insight into the inhibition of α-glucosidase and the accompanying structural changes by HSYA. Based on its α-glucosidase-inhibiting effect and its potential as a natural antioxidant, HSYA is a potential agent for treating α-glucosidase-associated type-2 diabetes.     

Synthesis, α-glucosidase inhibition and molecular docking study of coumarin based derivatives

We have synthesized seventeen Coumarin based derivatives (1–17), characterized by ¹HNMR, ¹³CNMR and EI-MS and evaluated for α-glucosidase inhibitory potential. Among the series, all derivatives exhibited outstanding α-glucosidase inhibition with IC₅₀ values ranging between 1.10 ± 0.01 and 36.46 ± 0.70 μM when compared with the standard inhibitor acarbose having IC₅₀ value 39.45 ± 0.10 μM. The most potent derivative among the series is derivative 3 having IC₅₀ value 1.10 ± 0.01 μM, which are many folds better than the standard acarbose. The structure activity relationship (SAR) was mainly based upon by bring about difference of substituent’s on phenyl part. Molecular docking studies were carried out to understand the binding interaction of the most active compounds.     

Design and synthesis of novel quinazolinone-1,2,3-triazole hybrids as new anti-diabetic agents: In vitro α-glucosidase inhibition,kinetic, and docking study

A novel series of quinazolinone-1,2,3-triazole hybrids 10a-p were designed, synthesized, and evaluated for their in vitro α-glucosidase inhibitory activity leading to efficient anti-diabetic agents. All synthesized compounds exhibited good inhibitory activity against yeast α-glucosidase (IC₅₀ values in the range of 181.0–474.5 µM) even much more potent than standard drug acarbose (IC₅₀ = 750.0). Among them, quinazolinone-1,2,3-triazoles possessing 4-bromobenzyl moiety connected to 1,2,3-triazole ring (10g and 10p) demonstrated the most potent inhibitory activity towards α-glucosidase. Compound 10g inhibited α-glucosidase in a competitive manner with K_i value of 117 µM. Furthermore, the binding modes of the most potent compounds 10g and 10p in the α-glucosidase active site was studied through in silico docking studies. Also, lack of cytotoxicity of compounds 10g and 10p was confirmed via MTT assay.     

Green synthesis,inhibition studies of yeast α-glucosidase and molecular docking of pyrazolylpyridazine amines

An efficient and environmentally benign simple fusion reaction of 3-chloro-6-(3,5-dimethyl-1H-pyrazol-1-yl)pyridazine (1a) or 3-chloro-6-(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)pyridazine (2a) with different aliphatic/aromatic amines have produced a series of novel pyrazolylpyridazine amines (4a–4c & 5a–5m). All compounds exhibited moderate in vitro yeast α-glucosidase inhibition except m-chloro derivative 5g, which was found potent inhibitor of this enzyme with IC₅₀ value of 19.27 ± 0.005 µM. The molecular docking further helped in understanding the structure activity relationship of these compounds including 5g.     

Biscoumarin-1,2,3-triazole hybrids as novel anti-diabetic agents: Design,synthesis, in vitro α-glucosidase inhibition,kinetic, and docking studies

A novel series of biscoumarin-1,2,3-triazole hybrids 6a-n was prepared and evaluated for α-glucosidase inhibitory potential. All fourteen derivatives exhibited excellent α-glucosidase inhibitory activity with IC₅₀ values ranging between 13.0 ± 1.5 and 75.5 ± 7.0 µM when compared with the acarbose as standard inhibitor (IC₅₀ = 750.0 ± 12.0 µM). Among the synthesized compounds, compounds 6c (IC₅₀ = 13.0 ± 1.5 µM) and 6g (IC₅₀ = 16.4 ± 1.7 µM) exhibited the highest inhibitory activity against α-glucosidase and were non-cytotoxic towards normal fibroblast cells. Kinetic study revealed that compound 6c inhibits the α-glucosidase in a competitive mode. Furthermore, molecular docking investigation was performed to find interaction modes of the biscoumarin-1,2,3-triazole derivatives.     

Synthesis,nitric oxide release,and α-glucosidase inhibition of nitric oxide donating apigenin and chrysin derivatives

α-Glucosidase (AG) play crucial roles in the digestion of carbohydrates. Inhibitors of α-glucosidase (AGIs) are promising candidates for the development of anti-diabetic drugs. Here, five series of apigenin and chrysin nitric oxide (NO)-donating derivatives were synthesised and evaluated for their AG inhibitory activity and NO releasing capacity in vitro. Except for 9a–c, twelve compounds showed remarkable inhibitory activity against α-glucosidase, with potency being better than that of acarbose and 1-deoxynojirimycin. All organic nitrate derivatives released low concentrations of NO in the presence of l-cysteine. Structure activity relationship studies indicated that 5-OH, hydrophobic coupling chain, and carbonyl groups of the coupling chain could enhance the inhibitory activity. Apigenin and chrysin derivatives therefore represents a new class of promising compounds that can inhibit α-glucosidase activity and supply moderate NO for preventing the development of diabetic complications.     

Structural modifications of 2,3-indolobetulinic acid: Design and synthesis of highly potent α-glucosidase inhibitors

A series of nineteen nitrogen-containing lupane triterpenoids was obtained by modification of C2, C3, C20 and C28 positions of betulonic acid and their α-glucosidase inhibiting activity was investigated. Being a leader compound from our previous study, 2,3-indolo-betulinic acid was used as the main template for different modifications at C-(28)-carboxyl group to obtain cyano-, methylcyanoethoxy-, propargyloxy- and carboxamide derivatives. 20-Oxo- and 29-hydroxy-20-oxo-30-nor-analogues of 2,3-indolo-betulinic acid were synthesized by ozonolysis of betulonic acid followed by Fischer indolization reaction. To compare the influence of the fused indole or the seven-membered A-ring on the inhibitory activity, lupane A-azepanones with different substituents at C28 were synthesized. The structure-activity relationships revealed that the enzyme inhibition activity dramatically increased (up to 4730 times) when the carboxylic group of 2,3-indolo-betulinic acid was converted to the corresponding amide. Thus, the IC₅₀ values for glycine amide and L-phenylalanine amides were 0.04 and 0.05 μM, respectively. This study also revealed that 2,3-indolo-platanic acid is 4.5 times more active than the parent triterpenoid with IC₅₀ of 0.4 μM. Molecular modeling suggested that improved potency is due to additional polar interactions formed between C28 side chain and a sub-pocket of the α-glucosidase allosteric site.     

Synthesis of thiobarbituric acid derivatives: In vitro α-glucosidase inhibition and molecular docking studies

Synthesis, structure, and evaluation of in vitro α-glucosidase enzyme inhibition of a new class of diethylammonium salts of aryl substituted thiobarbituric acid is described. This protocol is straight, environmentally benign and efficient, involving Aldol-Michael addition reaction in one pot fashion. The 3D chemical structures of the synthesized compounds were assigned based on spectroscopic methods and X-ray single crystal diffraction analyses. All synthesized compounds 3a-3n were evaluated for their in vitro α-glucosidase enzyme inhibitory activity, whereas acarbose was used as the standard drug (IC₅₀ = 840 ± 1.73 µM). All tested compounds were found to possess varying degree of α-glucosidase enzyme inhibition activity with (IC₅₀ = 19.46 ± 1.84–415.8 ± 4.0 µM). Compound 3i (IC₅₀ = 19.4 ± 1.84 µM) exhibited the highest activity. To the best of knowledge this is the first report of the in vitro α-glucosidase enzyme inhibition by the diethylamonium salts of aryl substituted thiobarbituric acid. Furthermore, molecular docking studies of selected compounds were also performed to see interactions between active compounds and binding sites.     

Design,synthesis and biological evaluation of novel coumarin thiazole derivatives as α-glucosidase inhibitors

A new series of coumarin thiazole derivatives 7a-7t were synthesized, characterized by ¹H NMR, ¹³C NMR and element analysis, evaluated for their α-glucosidase inhibitory activity. The majority of the screened compounds displayed potent inhibitory activities with IC₅₀ values in the range of 6.24 ± 0.07–81.69 ± 0.39 μM, when compared to the standard acarbose (IC₅₀ = 43.26 ± 0.19 μM). Structure–activity relationship (SAR) studies suggest that the pattern of substitution in the phenyl ring is closely related to the biological activity of this class of compounds. Among all the tested molecules, compound 7e (IC₅₀ = 6.24 ± 0.07 μM) was found to be the most active compound in the library of coumarin thiazole derivatives. Enzyme kinetic studies showed that compound 7e is a non-competitive inhibitor with a K_i of 6.86 μM. Furthermore, the binding interactions of compound 7e with the active site of α-glucosidase were confirmed through molecular docking. This study has identified a new class of potent α-glucosidase inhibitors for further investigation.     

Design and synthesis of new fused carbazole-imidazole derivatives as anti-diabetic agents: In vitro α-glucosidase inhibition,kinetic, and in silico studies

Twenty three fused carbazole–imidazoles 6a–w were designed, synthesized, and screened as new α-glucosidase inhibitors. All the synthesized fused carbazole-imidazoles 6a-w were found to be more active than acarbose (IC₅₀?=?750.0?±?1.5?µM) against yeast α-glucosidase with IC₅₀ values in the range of 74.0?±?0.7–298.3?±?0.9?µM. Kinetic study of the most potent compound 6v demonstrated that this compound is a competitive inhibitor for α-glucosidase (K_i value?=?75?µM). Furthermore, the in silico studies of the most potent compounds 6v and 6o confirmed that these compounds interacted with the key residues in the active site of α-glucosidase.     

Design,synthesis, docking study, α-glucosidase inhibition,and cytotoxic activities of acridine linked to thioacetamides as novel agents in treatment of type 2 diabetes

A novel series of acridine linked to thioacetamides 9a–o were synthesized and evaluated for their α-glucosidase inhibitory and cytotoxic activities. All the synthesized compounds exhibited excellent α-glucosidase inhibitory activity in the range of IC₅₀ = 80.0 ± 2.0–383.1 ± 2.0 µM against yeast α-glucosidase, when compared to the standard drug acarbose (IC₅₀ = 750.0 ± 1.5 µM). Among the synthesized compounds, 2-((6-chloro-2-methoxyacridin-9-yl)thio)-N-(p-tolyl) acetamide 9b displayed the highest α-glucosidase inhibitory activity (IC₅₀ = 80.0 ± 2.0 μM). The in vitro cytotoxic assay of compounds 9a–o against MCF-7 cell line revealed that only the compounds 9d, 9c, and 9n exhibited cytotoxic activity. Cytotoxic compounds 9d, 9c, and 9n did not show cytotoxic activity against the normal human cell lines HDF. Kinetic study revealed that the most potent compound 9b is a competitive inhibitor with a K_i of 85 μM. Furthermore, the interaction modes of the most potent compounds 9b and 9f with α-glucosidase were evaluated through the molecular docking studies.     

Structure-activity relationships of bergenin derivatives effect on α-glucosidase inhibition

The α-glucosidase inhibitory activities of bergenin derivatives were evaluated. Bergenin derivatives were synthesized from bergenin which is a characteristic compound of B. ligulata. A new bergenin derivative, 11-O-(3′,4′-dimethoxybenzoyl)-bergenin showed the highest potent inhibitory activity among those of bergenin derivatives. The presence of substituents at 3′,4′-position in bergenin derivatives altered the α-glucosidase inhibitory activity. 11-O-(3′,4′-dimethoxybenzoyl)-bergenin was noncompetitive inhibitor for α-glucosidase. The present study reveals that bergenin derivatives could be classified as a new group of α-glucosidase inhibitors.     

Inhibitors of α-glucosidase, α-amylase and lipase from Chrysanthemum morifolium

A new endoperoxysesquiterpene lactone, 10α-hydroxy-1α,4α-endoperoxy-guaia-2-en-12,6α-olide (1), together with a flavanone, eriodictyol (2), and two flavone glycosides, acacetin-7-O-β-d-glucopyranoside (3) and acacetin-7-O-α-l-rhamopyranoside (4), were isolated from the methanol extract of Chrysanthemum morifolium flowers by a bioassay-guided fractionation. Compound 1 showed strong inhibitory effects against α-glucosidase and lipase activities, with IC₅₀ values of 229.3 and 161.0 μM, respectively. The flavone glycosides 3 and 4 inhibited both α-glucosidase and α-amylase, while flavanone 2 was only effective against α-amylase.     

Synthesis of pyrimidine-2,4,6-trione derivatives: Anti-oxidant,anti-cancer, α-glucosidase, β-glucuronidase inhibition and their molecular docking studies

This paper describes a facile protocol, efficient, and environmentally benign for the synthesis a series of barbiturate acid substituted at C5 position 3a–o. The desired compounds subjected in vitro for different set of bioassays including against anti-oxidant (DPPH and super oxide scavenger assays), anti-cancer, α-glucosidase and β-glucuronidase inhibitions. Compound 3m (IC₅₀ = 22.9 ± 0.5 μM) found to be potent α-glucosidase enzyme inhibitors and showed more activity than standard acarbose (IC₅₀ = 841 ± 1.73 μM). Compound 3f (IC₅₀ = 86.9 ± 4.33 μM) found to be moderate β-Glucuronidase enzyme inhibitors and showed activity comparatively less than the standard d-saccharic acid 1,4-lactone (IC₅₀ = 45.75 ± 2.16 μM). Furthermore, in sillico investigation was carried out to investigate bonding mode of barbiturate acid derivatives.     

Reaction mechanism of isomaltooligosaccharides synthesis by α-glucosidase fromAspergillus carbonarious

Summary An -glucosidase fromAspergillus carbonarious CCRC 30414 was employed for investigating the enzymatic synthesis of isomaltooligosaccharides from maltose. The enzyme transferred a glucose unit from the nonreducing end of maltose and other -linked glucosyl oligosaccharides to glucose and other glucosyl oligosaccharides which function as accepting co-substrates. The transfer of a glucose unit occurs most frequently to the 6-OH position of the nonreducing end of acceptor, but transfer to 4-OH position also occurs. Treatment of 30 % (w/v) maltose with the enzyme under optimum conditions afforded more than 50% isomaltooligosaccharides.