Synthesis of novel indenoquinoxaline derivatives as potent α-glucosidase inhibitors

A series of new N-(11H-Indeno[1,2-b]quinoxalin-11-ylidene)benzohydrazide derivatives (3a–3p) were synthesized and evaluated for their α-glucosidase inhibitory activity. The synthesized compounds 3d, 3f, 3g, 3k, 3n, 3p and 4 showed significant α-glucosidase inhibitory activity as compared to acrabose, a standard drug used to treat type II diabetes. Structures of the synthesized compounds were determined by using FT-IR, ¹H NMR, ¹³C NMR, mass spectrometry and elemental analysis techniques.     

Discovery of novel oxindole derivatives as potent α-glucosidase inhibitors

A series of 6-chloro-3-oxindole derivatives 1–25 were synthesized in high yields by the reaction of 6-chlorooxindole with different aromatic aldehydes in the presence of piperidine. All the synthesized compounds were isolated with E configuration. The structures were confirmed using spectroscopic techniques, including ¹H NMR and EIMS. These compounds showed varying degree of yeast α-glucosidase inhibition and seven were found as potent inhibitors of the enzyme. Compounds 2, 3, 4, 5, 6, 23, and 25 exhibited IC₅₀ values 2.71 ± 0.007, 11.41 ± 0.005, 37.93 ± 0.002, 15.19 ± 0.004, 24.71 ± 0.007, 17.33 ± 0.001, and 14.2 ± 0.002 μM, respectively, as compared to standard acarbose (IC₅₀, 38.25 ± 0.12 μM). Docking studies helped to find interactions between the enzyme and the active compounds. As a result of this study, oxindoles have been discovered as a new class of α-glucosidase inhibitors which have not been reported earlier.     

A concise synthesis and evaluation of new malonamide derivatives as potential α-glucosidase inhibitors

A series of new malonamide derivatives were synthesized by Michael addition reaction of N¹,N³-di(pyridin-2-yl)malonamide into α,β-unsaturated ketones mediated by DBU in DCM at ambient temperature. The inhibitory potential of these compounds in vitro, against α-glucosidase enzyme was evaluated. Result showed that most of malonamide derivatives were identified as a potent inhibitors of α-glucosidase enzyme. Among all the compounds, 4K (IC₅₀ = 11.7 ± 0.5 μM) was found out as the most active one compared to standard drug acarbose (IC₅₀ = 840 ± 1.73 μM). Further cytotoxicity of 4a–4m were also evaluated against a number of cancer and normal cell lines and interesting results were obtained.     

Catalytic asymmetric synthesis of indole derivatives as novel α-glucosidase inhibitors in vitro

Indole containing compounds have acquired conspicuous significance due to their wide spectrum of biological activities. Synthesis of a series of enantiomerically pure indole derivatives 3a-r via Friedel–Crafts alkylation of indole 1 with enones 2a-r were described here. The products were isolated in a moderate to excellent yields (upto 89%) with excellent enantioselectivities (upto 99.9% ee). These compounds 3a-r were evaluated for their in vitro α-glucosidase inhibitory activity and some of them were identified as potent inhibitors (IC₅₀ = 4.3 ± 0.13–43.9 ± 0.51 μM) with several fold higher activity than the clinically used α-glucosidase inhibitor, acarbose (IC₅₀ = 840 ± 1.73 μM). To the best of knowledge, this is the first report of the propanone substituted indole ring containing compounds by in vitro α-glucosidase enzyme inhibition.     

Hetarylcoumarins: Synthesis and biological evaluation as potent α-glucosidase inhibitors

In search of better α-glucosidase inhibitors, a series of novel hetarylcoumarins (3a-3j) were designed and synthesized through a facile multicomponent route where p-toluenesulfonic acid (PTSA) was explored as an efficient catalyst. These new scaffolds were further evaluated for their α-glucosidase inhibition potentials. All the derivatives exhibited good to excellent results which were comparable or even better than of standard drug acarbose. Of these compounds, a dihalogenated compound 3f was found to be the most effective one with IC₅₀: 2.53 ± 0.002 µM. Molecular docking has predicted the plausible binding interactions of compounds 3f, 3g and 3j with α-glucosidase.     

Mechanistic investigation of anthocyanidin derivatives as α-glucosidase inhibitors

Eight anthocyanidin derivatives (1–8) were evaluated as potential inhibitors of the catalysis of α-glucosidase. Among them, compounds 4 and 8 had the highest levels of inhibitory activity at 100 μM (IC₅₀ values of 14.4 ± 0.1 and 29.7 ± 1.2 μM) and acted in a dose-dependent manner. Enzyme kinetic analysis further revealed that these inhibitors interacted with α-glucosidase in a mixed noncompetitive mode. Moreover, fluorescence quenching studies provided parameters for calculating the binding mechanism between receptor and ligand. On the basis of these studies, and in silico simulations, we determined that the ligand was likely docked in the receptor. Thus, compounds 4 and 8 are excellent potential targets for in vitro cell-based and in vivo assays related to treatment of diabetes.     

Synthesis of benzothiazole derivatives as a potent α-glucosidase inhibitor

Diabetes is one of the pre-dominant metabolic disorders all over the world. It is the prime reason of mortality and morbidity due to hyperglycemia which is link with numerus obstacles. Delaying absorption and digestion of carbohydrate has great therapeutic impact for governing postprandial hyperglycemia. Consequently, alpha glucosidase is one of the potential therapeutic approaches that reduce absorption of glucose and delay carbohydrate digestion hence maintaining blood glucose level. In this regard we have synthesized benzothiazole based oxadiazole in search of potent anti-diabetic agent as α-glucosidase Inhibitors. Benzothiazole based oxadiazole derivatives 1–23 have been synthesized, characterized by ¹HNMR, ¹³CNMR, and MS and evaluated for α-glucosidase Inhibition. All analogs exhibited a varying degree of α-glucosidase inhibitory activity with IC₅₀ values ranging in between 0.5 ± 0.01–30.90 ± 0.70 μM when compared with the standard acarbose (IC₅₀ = 866.30 ± 3.20 μM). Structure activity relationship has been established for all compounds. Molecular docking studies were performed to predict the binding interaction of the compounds with the active site of enzyme.     

Synthesis,in vitro evaluation and molecular docking studies of thiazole derivatives as new inhibitors of α-glucosidase

A series of thiazole derivatives 1–21 were prepared, characterized by EI-MS and ¹H NMR and evaluated for α-glucosidase inhibitory potential. All twenty one derivatives showed good α-glucosidase inhibitory activity with IC₅₀ value ranging between 18.23 ± 0.03 and 424.41 ± 0.94 μM when compared with the standard acarbose (IC₅₀, 38.25 ± 0.12 μM). Compound (8) (IC₅₀, 18.23 ± 0.03 μM) and compound (7) (IC₅₀ = 36.75 ± 0.05 μM) exhibited outstanding inhibitory potential much better than the standard acarbose (IC₅₀, 38.25 ± 0.12 μM). All other analogs also showed good to moderate enzyme inhibition. Molecular docking studies were carried out in order to find the binding affinity of thiazole derivatives with enzyme. Studies showed these thiazole analogs as a new class of α-glucosidase inhibitors.     

Benzimidazole derivatives as new α-glucosidase inhibitors and in silico studies

Newly synthesized benzimidazole hydrazone derivatives 1–26 were evaluated for their α-glucosidase inhibitory activity. Compounds 1–26 exhibited varying degrees of yeast α-glucosidase inhibitory activity with IC₅₀ values between 8.40 ± 0.76 and 179.71 ± 1.11 μM when compared with standard acarbose. In this assay, seven compounds that showed highest inhibitory effects than the rest of benzimidazole series were identified. All the synthesized compounds were characterized by different spectroscopic methods adequately. We further evaluated the interaction of the active compounds with enzyme with the help of docking studies.     

Synthesis and biological evaluation of caffeic acid derivatives as potent inhibitors of α-MSH-stimulated melanogenesis

We have disclosed our effort to develop caffeic acid derivatives as potent and non-toxic inhibitors of α-MSH-stimulated melanogenesis to treat pigmentation disorders and skin medication including a cosmetic skin-whitening agent. The SAR studies revealed that cyclohexyl ester and secondary amide derivatives of caffeic acid showed significant inhibitory activities.     

Amine-linked diquercitols as new α-glucosidase inhibitors

Two new diastereomeric amine-linked diquercitols 7 and 8 were synthesized by reductive amination of ketoquercitol 4 and epimeric aminoquercitols 3 and 6. The ketone and amines were successfully prepared, without the formation of byproducts, from naturally available (+)-proto-quercitol (1). The amine-linked diquercitols showed inhibitory effect against α-glucosidases with more pronounced potency than their original aminoquercitol monomers.     

Synthesis of Bis-indolylmethane sulfonohydrazides derivatives as potent α-Glucosidase inhibitors

In search of better α-glucosidase inhibitors, a series of bis-indolylmethane sulfonohydrazides derivatives (1-14) were synthesized and evaluated for their α-glucosidase inhibitory potential. All derivatives exhibited outstanding α-glucosidase inhibition with IC₅₀ values ranging between 0.10 ± 0.05 to 5.1 ± 0.05 μM when compared with standard drug acarbose having IC₅₀ value 856.28 ± 3.15 μM. Among the series, analog 7 (0.10 ± 0.05 μM) with tri-chloro substitution on phenyl ring was identified as the most potent inhibitor of α-glucosidase (∼ 8500 times). The structure activity relationship has been also established. Molecular docking studies were also performed to help understand the binding interaction of the most active analogs with receptors. From the docking studies, it was observed that all the active bis-indolylmethane sulfonohydrazides derivatives showed considerable binding interactions within the active site (acarbose inhibition site) of α-glucosidase. We also evaluated toxicity of all derivatives and found none of them are toxic.     

In search of new α-glucosidase inhibitors: Imidazolylpyrazole derivatives

Under three different reaction conditions (conventional heating, microwave irradiations and amino acid catalysis), a series of imidazolylpyrazoles (2a-2k) were synthesized in good to excellent yields from a mixture of three precursors: aryl(hetaryl)pyrazole-4-carbaldehydes (1a-1k), benzil and ammonium acetate. α-Glucosidase inhibition assay revealed a new class of highly potent agents wherein each compound displayed significant inhibitory potentials (in terms of percentage inhibition and relative IC₅₀ values) as compared to that of the reference drug (Acarbose). Moreover, molecular modelling of most potent compounds 2h, 2j and 2k also helped in understanding the structure and activity relationship.     

Synthesis and biological evaluation of indole derivatives as α-amylase inhibitor

A series of twenty indole hydrazone analogs (1–21) were synthesized, characterized by different spectroscopic techniques such as ¹H NMR and EI-MS, and screened for α-amylase inhibitory activity. All analogs showed a variable degree of α-amylase inhibition with IC₅₀ values ranging between 1.66 and 2.65 μM. Nine compounds that are 1 (2.23 ± 0.01 μM), 8 (2.44 ± 0.12 μM), 10 (1.92 ± 0.12 μM), 12 (2.49 ± 0.17 μM), 13 (1.66 ± 0.09 μM), 17 (2.25 ± 0.1 μM), 18 (1.87 ± 0.25 μM), 20 (1.83 ± 0.63 μM), and 19 (1.97 ± 0.02 μM) showed potent α-amylase inhibition when compared with the standard acarbose (1.05 ± 0.29 μM). Other analogs showed good to moderate α-amylase inhibition. The structure activity relationship is mainly focusing on difference of substituents on phenyl part. Molecular docking studies were carried out to understand the binding interaction of the most active compounds.     

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.     

Docking and SAR studies of salacinol derivatives as α-glucosidase inhibitors

Salacinol is a potent α-glucosidase inhibitor isolated from Salacia reticulata, and a good lead compound for an antidiabetic drug. It is essential to clarify the binding state of salacinol to α-glucosidase for efficient optimization study using structure-based drug design. Redocking simulations of two inhibitors, acarbose and casuarine whose complex structures are known, were performed to assure the appropriate docking pose prediction. The simulation reproduced both experimental binding states with accuracy. Then, using the same simulation protocol, the binding mode of salacinol and its derivatives has been predicted. Salacinol bound to the protein with a similar binding mode as casuarine, and the predicted structures could explain most of the structure–activity relationships of salacinol derivatives.     

Synthesis of indole analogs as potent β-glucuronidase inhibitors

Natural products are the main source of motivation to design and synthesize new molecules for drug development. Designing new molecules against β-glucuronidase inhibitory is utmost essential. In this study indole analogs (1–35) were synthesized, characterized using various spectroscopic techniques including ¹H NMR and EI-MS and evaluated for their β-glucuronidase inhibitory activity. Most compounds were identified as potent inhibitors for the enzyme with IC₅₀ values ranging between 0.50 and 53.40 μM, with reference to standard d-saccharic acid 1,4-lactone (IC₅₀ = 48.4 ± 1.25 μM). Structure-activity relationship had been also established. The results obtained from docking studies for the most active compound 10 showed that hydrogen bond donor features as well as hydrogen bonding with (Oε1) of nucleophilic residue Glu540 is believed to be the most importance interaction in the inhibition activity. It was also observed that hydroxyl at fourth position of benzylidene ring acts as a hydrogen bond donor and interacts with hydroxyl (OH) on the side chain of catalysis residue Tyr508. The enzyme-ligand complexed were being stabilized through electrostatic π-anion interaction with acid-base catalyst Glu451 (3.96 Å) and thus preventing Glu451 from functioning as proton donor residue.     

Synthesis,biological evaluation and molecular docking studies of chromone hydrazone derivatives as α-glucosidase inhibitors

A series of chromone hydrazone derivatives 4a–4p have been synthesized, characterized by ¹H NMR and ¹³C NMR and evaluated for their in vitro α-glucosidase inhibitory activity. Out of these tested compounds, six (4a, 4b, 4d, 4j, 4o and 4p) displayed potent α-glucosidase inhibitory activity with IC₅₀ values in the range of 20.1 ± 0.19 μM to 45.7 ± 0.23 μM, as compared to the standard drug acarbose (IC₅₀ = 817.38 ± 6.27 μM). Among this series, compound 4d (IC₅₀ = 20.1 ± 0.19 μM) with 4-sulfonamide substitution at phenyl part of hydrazide was found to be the most active compound. Lineweaver-Burk plot analysis indicated that compound 4d is a non-competitive inhibitor of α-glucosidase. The binding interactions of the most active analogs were confirmed through molecular docking studies. Docking studies showed 4d are interacting with the residues Glu-276, Asp-214, Asp-349 and Arg-439 through hydrogen bonds, arene-anion and arene-cation interactions. In summary, our studies shown that these chromone hydrazone derivatives are a new class of α-glucosidase inhibitors.     

Triazinoindole analogs as potent inhibitors of α-glucosidase: Synthesis,biological evaluation and molecular docking studies

A new series of triazinoindole analogs 1–11 were synthesized, characterized by EI-MS and ¹H NMR, evaluated for α-glucosidase inhibitory potential. All eleven (11) analogs showed different range of α-glucosidase inhibitory potential with IC₅₀ value ranging between 2.46 ± 0.008 and 312.79 ± 0.06 μM when compared with the standard acarbose (IC₅₀, 38.25 ± 0.12 μM). Among the series, compounds 1, 3, 4, 5, 7, 8, and 11 showed excellent inhibitory potential with IC₅₀ values 2.46 ± 0.008, 37.78 ± 0.05, 28.91 ± 0.0, 38.12 ± 0.04, 37.43 ± 0.03, 36.89 ± 0.06 and 37.11 ± 0.05 μM respectively. All other compounds also showed good enzyme inhibition. The binding modes of these analogs were confirmed through molecular docking.     

Pyrimidine-fused heterocycle derivatives as a novel class of inhibitors for α-glucosidase

The needs for diverse inhibitors of α-glucosidase (α-Gls) encouraged us to synthesize five different poly-hydroxy functionalized pyrimidine-fused heterocyclic (PHPFH) molecules, having either aliphatic or aromatic side chains (C₁–C₅) and their inhibitory activities were examined spectroscopically against yeast and mouse intestinal α-Gls. The results revealed that aromatic substitution of the synthetic compounds has significant impact on their inhibitory properties. Moreover C₃ with the substituted moiety as 4-(4-aminophenylsulfonyl) phenyl (4-APSP) revealed strong inhibitory activity with non-competitive and competitive inhibition modes against yeast and mouse α-Gls, respectively. Furthermore, in the presence of increasing concentration of C₃, both Trp and 1-anilinonaphthalene-8-sulfonic acid (ANS) fluorescence intensities of yeast α-Gls were gradually decreased, suggesting that C₃ binding induced significant structural alteration which was accompanied with the reduction of hydrophobic surfaces. Also, the interaction between yeast α-Gls and C₃ was proved to be spontaneous and driven mainly by hydrophobic forces. Overall, this study suggests that aromatic substitution on pyrimidine-fused heterocyclic (PFH) scaffold may represent a novel class of promising inhibitors of α-Gls.