The aim of the study was to isolate digestive enzymes inhibitors from Mimosa pudica through a bioassay-guided fractionation approach. Repeated silica gel and sephadex LH 20 column chromatographies of bioactive fractions afforded stigmasterol, quercetin and avicularin as digestive enzymes inhibitors whose IC50 values as compared to acarbose (351.02 ± 1.46 μg mL-1) were found to be as 91.08 ± 1.54, 75.16 ± 0.92 and 481.7 ± 0.703 μg mL-1, respectively. In conclusion, M. pudica could be a good and safe source of digestive enzymes inhibitors for the management of diabetes in future.
A series of 1, 2, 4-triazole derivatives bearing piperidine moiety has been introduced as new anti-diabetic drug candidates with least cytotoxicity. p-Chlorophenylsulfonyl chloride (1) and ethyl nipecotate (2) were the starting reagents that resulted into corresponding 3,4,5-trisubstituted-1,2,4-triazole (6) through a series of steps. A series of electrophiles, 9a-e, were synthesized by reacting 4-bromobutyryl chloride (7) with differently substituted aromatic amines (8a-e) under basic aqueous medium. Target derivatives, 10a-e, were synthesized by the reaction of compound 6 with N-aryl-4-bromobutanamides (9a-e) in an aprotic solvent. Structures of all the derivatives were verified by spectroscopic analysis using IR, 1H-NMR, 13C-NMR and EIMS. Most of the derivatives revealed moderate to good α-glucosidase inhibitory activity with reference to acarbose. The moderate hemolytic potential demonstrated least toxicity.
A natural pentacyclic triterpenoid oleanolic acid 1 and its biotransformed metabolites 2-3 are potential α-glucosidase inhibitors. To elucidate the inhibitory mechanism of compounds 1, 2 and 3 against α-glucosidase, we calculated (i) their electronic and optical properties using DFT and TD-DFT at the B3LYP/6-31G(d) level in gas and IEF-PCM solvent; and (ii) their binding energies to α-glucosidase via docking study. DFT results showed that the α-glucosidase inhibtion is mainly depend on the polarity parameters of the studied compounds. Docking results revealed that the activity increased with binding energies (i.e. the stability of ligand-receptor complex). The specroscopic data of oleanolic acid 1 and its metabolites 2 and 3 are well predicetd for 13C NMR chemical shifts (R2=99%) and 1H NMR chemical shifts (R2=90%); and for (ii) UV/vis spectra. The assignments and interpretation of NMR chemical shifts and bathochromic shift of λMAX absorption bands are discussed.
A new series of triazinoindole analogs 1-11 were synthesized, characterized by EI-MS and (1)H 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.
A series of twenty-six analogs of benzimidazole based oxadiazole have been synthesized and evaluated against alpha-glycosidase enzyme. Most the analogs showed excellent to good inhibitory potential. Among the screened analogs, analog 1, 2, 3 and 14 with IC50 values 4.6 ± 0.1, 9.50 ± 0.3, 2.6 ± 0.1 and 9.30 ± 0.4 µM respectively showedexcellent inhibitory potential than reference drug acarbose (IC50 = 38.45 ± 0.80 µM). Some of the analogs like 19, 21, 22 and 23 with methyl and methoxy substituent on phenyl ring show hydrophobic interaction and were found with no inhibitory potential. The binding interactions between synthesized analogs and ligands protein were confirmed through molecular docking study. Various spectroscopic techniques like 1H NMR, 13C NMR, and EI-MS were used for characterization of all synthesized analogs. These derivatives were synthesized by simple mode of synthesis like heterocyclic ring formation.
Discovery of α-glucosidase inhibitors has been actively pursued with the aim to develop therapeutics for the treatment of type-II diabetes mellitus and the other carbohydrate mediated disease. In continuation of our drug discovery research on potential antidiabetic agents, we synthesized novel tris-indole-oxadiazole hybrid analogs (1-21), structurally characterized by various spectroscopic techniques such as 1H NMR, EI-MS, and 13C NMR. Elemental analysis was found in agreement with the calculated values. All compounds were evaluated for α-glucosidase inhibiting potential and showed potent inhibitory activity in the range of IC50=2.00±0.01-292.40±3.16μM as compared to standard acarbose (IC50=895.09±2.04µM). The pharmacokinetic predictions of tris-indole series using descriptor properties showed that almost all compounds in this series indicate the drug aptness. Detailed binding mode analyses with docking simulation was also carried out which showed that the inhibitors can be stabilized by the formation of hydrogen bonds with catalytic residues and the establishment of hydrophobic contacts at the opposite side of the active site.
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.
Herein, we report the synthesis and inhibitory potential of indazole (Methyl 1H-indazole-4-carboxylate) derivatives (1-13) against α-amylase and α-glucosidase enzymes. The described derivatives demonstrated good inhibitory potential with IC50 values, ranging between 15.04 ± 0.05 to 76.70 ± 0.06 µM ± SEM for α-amylase and 16.99 ± 0.19 to 77.97 ± 0.19 µM ± SEM for α-glucosidase, respectively. In particular, compounds (8-10 and 12) displayed significant inhibitory activities against both the screened enzymes, with their inhibitory potential comparable to the standard acarbose (12.98 ± 0.03 and 12.79 ± 0.17 µM ± SEM, respectively). Additionally, the influence of different substituents on enzyme inhibition activities was assessed to study the structure activity relationships. Molecular docking simulations were performed to rationalize the binding of derivatives/compounds with enzymes. All the synthesized derivatives (1-13) were characterized with the aid of spectroscopic instruments such as 1H-NMR, 13C-NMR, HR-MS, elemental analysis and FTIR.Communicated by Ramaswamy H. Sarma.
Thiourea derivatives having benzimidazole 1-17 have been synthesized, characterized by 1H NMR, 13C NMR and EI-MS and evaluated for α-glucosidase inhibition. Identification of potential α-glucosidase inhibitors were done by in vitro screening of 17 thiourea bearing benzimidazole derivatives using Baker's yeast α-glucosidase enzyme. Compounds 1-17 exhibited a varying degree of α-glucosidase inhibitory activity with IC50 values between 35.83±0.66 and 297.99±1.20μM which are more better than the standard acarbose (IC50=774.5±1.94μM). Compound 10 and 14 showed significant inhibitory effects with IC50 value 50.57±0.81 and 35.83±0.66μM, respectively better than the rest of the series. Structure activity relationships were established. Molecular docking studies were performed to understand the binding interaction of the compounds.
Twenty derivatives of 5-aryl-2-(6'-nitrobenzofuran-2'-yl)-1,3,4-oxadiazoles (1-20) were synthesized and evaluated for their α-glucosidase inhibitory activities. Compounds containing hydroxyl and halogens (1-6, and 8-18) were found to be five to seventy folds more active with IC50 values in the range of 12.75±0.10-162.05±1.65μM, in comparison with the standard drug, acarbose (IC50=856.45±5.60μM). Current study explores the α-glucosidase inhibition of a hybrid class of compounds of oxadiazole and benzofurans. These findings may invite researchers to work in the area of treatment of hyperglycemia. Docking studies showed that most compounds are interacting with important amino acids Glu 276, Asp 214 and Phe 177 through hydrogen bonds and arene-arene interaction.
α-Glucosidase is a catabolic enzyme that regulates the body's plasma glucose levels by providing energy sources to maintain healthy functioning. 2-Amino-thiadiazole (1-13) and 2-amino-thiadiazole based Schiff bases (14-22) were synthesized, characterized by 1H NMR and HREI-MS and screened for α-glucosidase inhibitory activity. All twenty-two (22) analogs exhibit varied degree of α-glucosidase inhibitory potential with IC50 values ranging between 2.30 ± 0.1 to 38.30 ± 0.7 μM, when compare with standard drug acarbose having IC50 value of 39.60 ± 0.70 μM. Among the series eight derivatives 1, 2, 6, 7, 14, 17, 19 and 20 showed outstanding α-glucosidase inhibitory potential with IC50 values of 3.30 ± 0.1, 5.80 ± 0.2, 2.30 ± 0.1, 2.70 ± 0.1, 2.30 ± 0.1, 5.50 ± 0.1, 4.70 ± 0.2, and 5.50 ± 0.2 μM respectively, which is many fold better than the standard drug acarbose. The remaining analogs showed good to excellent α-glucosidase inhibition. Structure activity relationship has been established for all compounds. The binding interactions of these compounds were confirmed through molecular docking.
Current study based on the synthesis of new thiazole derivatives via "one pot" multicomponent reaction, evaluation of their in vitro α-glucosidase inhibitory activities, and in silico studies. All synthetic compounds were fully characterized by (1)H NMR, (13)C NMR and EIMS. CHN analysis was also performed. These newly synthesized compounds showed activities in the range of IC50=9.06±0.10-82.50±1.70μM as compared to standard acarbose (IC50=38.25±0.12μM). It is worth mentioning that most of the compounds such as 1 (IC50=23.60±0.39μM), 2 (IC50=22.70±0.60μM), 3 (IC50=22.40±0.32μM), 4 (IC50=26.5±0.40μM), 6 (IC50=34.60±0.60μM), 7 (IC50=26.20±0.43μM), 8 (IC50=14.06±0.18μM), 9 (IC50=17.60±0.28μM), 10 (IC50=27.16±0.41μM), 11 (IC50=19.16±0.19μM), 12 (IC50=9.06±0.10μM), 13 (IC50=12.80±0.21μM), 14 (IC50=11.94±0.18μM), 15 (IC50=16.90±0.20μM), 16 (IC50=12.60±0.14μM), 17 (IC50=16.30±0.29μM), and 18 (IC50=32.60±0.61μM) exhibited potent inhibitory potential. Molecular docking study was performed in order to understand the molecular interactions between the molecule and enzyme. Newly identified α-glucosidase inhibitors except few were found to be completely non-toxic.
A series of thiazole derivatives 1-21 were prepared, characterized by EI-MS and (1)H 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±0.94μM when compared with the standard acarbose (IC50, 38.25±0.12μM). Compound (8) (IC50, 18.23±0.03μM) and compound (7) (IC50=36.75±0.05μM) exhibited outstanding inhibitory potential much better than the standard acarbose (IC50, 38.25±0.12μM). 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.
We describe here the synthesis of dihydropyrimidines derivatives 3a-p, and evaluation of their α-glucosidase enzyme inhibition activities. Compounds 3b (IC50=62.4±1.5 μM), 3c (IC50=25.3±1.26 μM), 3d (IC50=12.4±0.15 μM), 3e (IC50=22.9±0.25 μM), 3g (IC50=23.8±0.17 μM), 3h (IC50=163.3±5.1 μM), 3i (IC50=30.6±0.6 μM), 3m (IC50=26.4±0.34 μM), and 3o (IC50=136.1±6.63 μM) were found to be potent α-glucosidase inhibitors in comparison to the standard drug acarbose (IC50=840±1.73 μM). The compounds were also evaluated for their in vitro cytotoxic activity against PC-3, HeLa, and MCF-3 cancer cell lines, and 3T3 mouse fibroblast cell line. All compounds were found to be non cytotoxic, except compounds 3f and 3m (IC50=17.79±0.66-20.44±0.30 μM), which showed a weak cytotoxic activity against the HeLa, and 3T3 cell lines. In molecular docking simulation study, all the compounds were docked into the active site of the predicted homology model of α-glucosidase enzyme. From the docking result, it was observed that most of the synthesized compounds showed interaction through carbonyl oxygen atom and polar phenyl ring with active site residues of the enzyme.
Heterocyclic molecules have been frequently investigated to possess various biological activities during the last few decades. The present work elaborates the synthesis and enzymatic inhibition potentials of a series of sulfonamides. A series of 1-arylsulfonyl-4-Phenylpiperazine (3a-n) geared up by the reaction of 1-phenylpiperazine (1) and different (un)substituted alkyl/arylsulfonyl chlorides (2a-n), under defined pH control using water as a reaction medium. The synthesized molecules were characterized by 1H-NMR, 13C-NMR, IR and EI-MS spectral data. The enzyme inhibition study was carried on α-glucosidase, lipoxygenase (LOX), acetyl cholinesterase (AChE) and butyryl cholinesterase (BChE) enzymes supported by docking simulation studies and the IC50 values rendered a few of the synthesized molecules as moderate inhibitors of these enzymes where, the compound 3e exhibited comparatively better potency against α-glucosidase enzyme. The synthesized compounds showed weak or no inhibition against LOX, AChE and BChE enzymes.
In recent decade, the entrance of α-N-heterocyclic thiosemicarbazones derivates (Triapne, COTI-2 and DpC) in clinical trials for cancer and HIV-1 has vastly increased the interests of medicinal chemists towards this class of organic compounds. In the given study, a series of eighteen new (3a-r) 3-ethoxy salicylaldehyde-based thiosemicarbazones (TSC), bearing aryl and cycloalkyl substituents, were synthesized and assayed for their pharmacological potential against carbonic anhydrases (hCA I and hCA II), cholinesterases (AChE and BChE) and α-glycosidase. The hCA I isoform was inhibited by these novel 3-ethoxysalicylaldehyde thiosemicarbazone derivatives (3a-r) in low nanomolar levels, the Ki of which differed between 144.18 ± 26.74 and 454.92 ± 48.32 nM. Against the physiologically dominant isoform hCA II, the novel compounds demonstrated Kis varying from 110.54 ± 14.05 to 444.12 ± 36.08 nM. Also, these novel derivatives (3a-r) effectively inhibited AChE, with Ki values in the range of 385.38 ± 45.03 to 983.04 ± 104.64 nM. For BChE was obtained with Ki values in the range of 400.21 ± 35.68 to 1003.02 ± 154.27 nM. For α-glycosidase the most effective Ki values of 3l, 3n, and 3q were with Ki values of 12.85 ± 1.05, 16.03 ± 2.84, and 19.16 ± 2.66 nM, respectively. Moreover, the synthesized TCSs were simulated using force field methods whereas the binding energies of the selected compounds were estimated using MM-GBSA method. The findings indicate the present novel 3-ethoxy salicylaldehyde-based thiosemicarbazones to be excellent hits for pharmaceutical applications.
The 2-amino-5-(3/4-fluorostyryl)acetophenones were prepared and reacted with benzaldehyde derivatives to afford the corresponding 5-styryl-2-aminochalcone hybrids. The trans geometry of the styryl and α,β-unsaturated carbonyl arms, and the presence of NH…O intramolecular hydrogen bond were validated using 1H-NMR and X-ray data. The 2-amino-5-styrylacetophenones and their 5-styryl-2-aminochalcone derivatives were screened in vitro for their capability to inhibit α-glucosidase and/or α-amylase activities. Their antioxidant properties were evaluated in vitro through the 2,2-diphenyl-1-picrylhydrazyl (DPPH) and nitric oxide (NO) free radical scavenging assays. Kinetic studies of the most active derivatives from each series against α-glucosidase and/or α-amylase activities have been performed supported by molecular docking studies to determine plausible protein-ligand interactions on a molecular level. The key aspects of the pharmacokinetics of these compounds, i.e., absorption, distribution, metabolism, and excretion have also been simulated at theoretical level. The most active compounds from each series, namely, 2a and 3e, were evaluated for cytotoxicity against the normal monkey kidney cells (Vero cells) and the adenocarcinomic human epithelial (A549) cell line to establish their safety profile at least in vitro.
In the current research work, a series of new N-(alkyl/aralkyl)-N-(2,3-dihydro-1,4-benzodioxan-6-yl)-4-chlorobenzenesulfonamides has been synthesized by reacting 1,4-benzozzdioxan-6-amine (1) with 4-chlorobenzenesulfonyl chloride (2) to yield N-(2,3-dihydro-1,4-benzodioxan-6-yl)-4-chlorobenzenesulfonamide (3) which was further reacted with different alkyl/aralkyl halides (4a-n) to afford the target compounds (5a-n). Structures of the synthesized compounds were confirmed by IR, 1H-NMR, EI-MS spectral techniques and CHN analysis data. The results of enzyme inhibition showed that the molecules, N-2-phenethyl-N-(2,3-dihydro-1,4-benzodioxin-6-yl)-4-chlorobenzenesulfonamide (5j) and N-(1-butyl)-N-(2,3-dihydro-1,4-benzodioxin-6-yl)-4-chlorobenzenesulfonamide (5d), exhibited moderate inhibitory potential against acetylcholinesterase with IC50 values 26.25±0.11 μM and 58.13±0.15 μM respectively, whereas, compounds N-benzyl-N-(2,3-dihydro-1,4-benzodioxin-6-yl)-4-chlorobenzenesulfonamide (5i) and N-(pentane-2-yl)-N-(2,3-dihydro-1,4-benzodioxin-6-yl)-4-chlorobenzenesulfonamide (5f) showed moderate inhibition against α-glucosidase enzyme as evident from IC50 values 74.52±0.07 and 83.52±0.08 μM respectively, relative to standards Eserine having IC50 value of 0.04±0.0001 μM for cholinesterases and Acarbose having IC50 value 38.25±0.12 μM for α-glucosidase, respectively.
In an effort to design and synthesize a new class of α-glucosidase inhibitor, we synthesized benzothiazole hybrid having benzohydrazide moiety (5). Compound 5 was reacted with various substituted aryl aldehyde to generate a small library of compounds 6-35. Synthesis of compounds was confirmed by the spectral information. These compounds were screened for their α-glucosidase activity. They showed a varying degree of α-glucosidase inhibition with IC50 values ranging between 5.31 and 53.34 μM. Compounds 6, 7, 9-16, 19, 21-30, 32-35 showed superior activity as compared to standard acarbose (IC50 = 906 ± 6.3 μM). This has identified a new class of α-glucosidase inhibitors. The predicted physico-chemical properties indicated the drug appropriateness for most of these compounds, as they obey Lipinski's rule of five (RO5). A hybrid B3LYP density functional theory (DFT) was employed for energy, minimization of 3D structures for all synthetic compounds using 6-311 + G(d,p) basis sets followed by molecular docking to explore their interactions with human intestinal C- and N-terminal domains of α-glucosidase. All compounds bind to the prospective allosteric site of the C- terminal domain, and consequently, may be considered as mixed inhibitors. It was hypothesized that both the dipole moment and H-bond interactions govern the biological activation of these compounds.
Oxadiazole derivatives (6-28) having hydrazone linkage, were synthesized through condensation reaction between benzohydrazide 5 with various benzaldehydes. The oxadiazoles derivatives (6-28) were evaluated for their α-glucosidase inhibitory activity. The IC50 values for inhibition activity vary in the range between 2.64 ± 0.05 and 460.14 ± 3.25 μM. The IC50 values were being compared to the standard acarbose (IC50=856.45 ± 5.60 μM) and it was found that compounds 6-9, 12, 13, 16, 18, 20, 22-28 were found to be more active than acarbose, while other compounds showed no activity. Structure-activity relationship (SAR) studies suggest that oxadiazole benzohydrazones (6-28) inhibitory potential is dependent on substitution of the N-benzylidene part. Compound 18 (IC50=2.64 ± 0.05 μM), which has trihydroxy substitution at C-2', C-4', and C-5' on N-benzylidene moiety, recorded the highest inhibition activity that is three-hundred times more active than the standard drug, acarbose (IC50=856.45 ± 5.60 μM). Compound 23 (IC50=34.64 ± 0.35 μM) was found to be the most active among compounds having single hydroxyl substitution. Shifting hydroxyl from C-2' to C-4' (6) and C-3' (7) reduces inhibitory activity significantly. Compounds with chlorine substituent (compounds 16, 28, and 27) showed potent activities but lower as compared to hydroxyl analogs. Substituent like nitro or methyl groups at any position suppresses enzyme inhibition activity. This reveals the important presence of hydroxyl and halo groups to have enzyme inhibitory potential.