A new library of 2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl aryl ether derivatives (1-23) were synthesized and characterized by EI-MS and 1H NMR, and screened for their α-amylase inhibitory activity. Out of twenty-three derivatives, two molecules 19 (IC50=0.38±0.82µM) and 23 (IC50=1.66±0.14µM), showed excellent activity whereas the remaining compounds, except 10 and 17, showed good to moderate inhibition in the range of IC50=1.77-2.98µM when compared with the standard acarbose (IC50=1.66±0.1µM). A plausible structure-activity relationship has also been presented. In addition, in silico studies was carried out in order to rationalize the binding interaction of compounds with the active site of enzyme.
In our previous report, we have identified 3,4-dihydropyrimidine scaffold as promising class of urease inhibitor in a structure based virtual screen (SBVS) experiment. In present study, we attempted to optimize the scaffold by varying C-5 substituent. The elongation of the C-5 chain was achieved by the reaction of C-5 ester with hydrazine leading to C-5 carbohydrazides which were further used as building blocks for the synthesis of fifteen new compounds having diverse moieties. A significantly higher in vitro urease inhibitory activity with IC50 values in submicromolar range was observed for semithiocarbazide derivatives (4a-c, 0.58-0.79µM) and isatin Schiff base derivative 5a (0.23µM). Docking analysis suggests that the synthesized compounds were anchored well in the catalytic site and extending to the entrance of binding pocket and thus restrict the mobility of the flap by interacting with its key amino acid residues. The overall results of urease inhibition have shown that these compounds can be further optimized and developed as lead urease inhibitors.
Salak fruit (Salacca zalacca), commonly known as snake fruit, is used indigenously as food and for medicinal applications in Southeast Asia. This study was conducted to evaluate the α-glucosidase inhibitory activity of salak fruit extracts in correlation to its Fourier transform infrared spectroscopy (FT-IR) fingerprint, utilizing orthogonal partial least square. This calibration model was applied to develop a rapid analytical method tool for quality control of this fruit. A total of 36 extracts prepared with different solvent ratios of ethanol⁻water (100, 80, 60, 40.20, 0% v/v) and their α-glucosidase inhibitory activities determined. The FT-IR spectra of ethanol⁻water extracts measured in the region of 400 and 4000 cm−1 at a resolution of 4 cm−1. Multivariate analysis with a combination of orthogonal partial least-squares (OPLS) algorithm was used to correlate the bioactivity of the samples with the FT-IR spectral data. The OPLS biplot model identified several functional groups (C⁻H, C=O, C⁻N, N⁻H, C⁻O, and C=C) which actively induced α-glucosidase inhibitory activity.
On the basis of previous report on promising α-glucosidase inhibitory activity of 5-bromo-2-aryl benzimidazole derivatives, these derivatives were further screened for urease inhibitory and cytotoxicity activity in order to get more potent and non-cytotoxic potential dual inhibitor for the patients suffering from diabetes as well as peptic ulcer. In this study, all compounds showed varying degree of potency in the range of (IC50=8.15±0.03-354.67±0.19μM) as compared to standard thiourea (IC50=21.25±0.15μM). It is worth mentioning that derivatives 7 (IC50=12.07±0.05μM), 8 (IC50=10.57±0.12μM), 11 (IC50=13.76±0.02μM), 14 (IC50=15.70±0.12μM) and 22 (IC50=8.15±0.03μM) were found to be more potent inhibitors than standard. All compounds were also evaluated for cytotoxicity towards 3T3 mouse fibroblast cell line and found to be completely non-toxic. Previously benzimidazole 1-25 were also showed α-glucosidase inhibitory potential. In silico studies were performed on the lead molecules i.e.2, 7, 8, 11, 14, and 22, in order to rationalize the binding interaction of compounds with the active site of urease enzyme.
A series of dimeric naphthoquinones containing natural 2-hydroxy-1-4-naphthoquinone moiety was designed, synthesized, and evaluated against neuraminidase of H5N1 virus. p-hydroxy derivatives showed higher inhibition when compared to p-halogenated compounds. Molecular docking studies conducted with H5N1 neuraminidase clearly demonstrated different binding modes of the most active compound onto the open and closed conformations of loop 150. The results thus provide not only evidences of a novel scaffold evaluated as inhibitor, but also a rational explanation involving molecular modeling and the role of loop 150 in the binding.
Keeping in mind the pharmacological importance of 2-aminothiazole and 1,2,4-triazole heterocyclic moieties, a series of novel ethylated bi-heterocyclic acetamide hybrids, 9a-p, was synthesized in a multi-step protocol. The structures of newly synthesized compounds were characterized by 1H NMR, 13C NMR, IR and EI-MS spectral studies. The inhibitory effects of these bi-heterocyclic acetamides (9a-n) were evaluated against elastase and all these molecules were identified as potent inhibitors relative to the standard used. The Kinetics mechanism was analyzed by Lineweaver-Burk plots which revealed that, 9h, inhibited elastase competitively by forming an enzyme-inhibitor complex. The inhibition constants Ki calculated from Dixon plots for this compound was 0.9 µM. The computational study was articulate with the experimental results and these ligands unveiled good binding energy values (kcal/mol). So, these molecules can be considered as promising medicinal scaffolds for the treatment of skin melanoma, wrinkle formation, uneven pigmentation, and solar elastosis.
This study was carried out on 30 patients to: i) determine the efficacy of low dose captopril as monotherapy (with or without a diuretic) in the treatment of various grades of hypertension. ii) assess the quality of life of these patients 12 weeks after commencement of therapy. Our results showed that there was a sustained and significant fall in both mean systolic and diastolic blood pressure from 171.9 ± 24 to 150.5 ± 25 mm Hg and 109.0 ± 14 to 93.6 ± 15mmHg respectively (p<0.001). Improvement in quality of life was however not statistically significant (p<0.05). We concluded that low dose captopril used alone or in combination with a diuretic can be considered for the initial therapy of mild to moderate hypertension. The optimal dosage and the longterm benefits on quality of life need further evaluation in a larger series.
Heterocyclic chemistry is an important field of organic chemistry due to therapeutic potential. The minor modification in the structure of poly-functional compounds has great effect on therapeutic ability. In the presented research work, substituted 1,3,4-oxadiazole derivatives, 8a-p, have been synthesized by the reaction of 1-(4-bromomethylbenzenesulfonyl)-3-methylpiperidine (7) and 5-substituted-1,3,4-oxadiazole-2-thiol (4a-p). The 5-substituted-1,3,4-oxadiazole-2-thiol were synthesized by converting carboxylic acids correspondingly into esters, hydrazides and oxadiazoles. Secondly the electrophile, 1-(4-Bromomethylbenzenesulfonyl)-3-methylpiperidine (7), was prepared by the reaction of 3-methylpiperidine with 4-bromomethylbenzenesulfonyl chloride in the presence of water and Na2CO3 under pH of 9-10. The compounds were structurally corroborated through spectroscopic data analysis of IR, EI-MS and 1H-NMR. The screening for antibacterial activity revealed the compounds to be moderate to excellent inhibitors against bacteria under study. Anti-enzymatic activity was assessed against urease enzyme and 1-{[4-({[5-(3-nitrophenyl)-1,3,4-oxadiazol-2-yl]sulfanyl}methyl)phenyl]sulfonyl}-3-methylpiperidine (8d) was the most active one.
α-Amylase is a target for type-2 diabetes mellitus treatment. However, small molecule inhibitors of α-amylase are currently scarce. In the course of developing small molecule α-amylase inhibitors, we designed and synthesized thiadiazole quinoline analogs (1-30), characterized by different spectroscopic techniques such as 1HNMR and EI-MS and screened for α-amylase inhibitory potential. Thirteen analogs 1, 2, 3, 4, 5, 6, 22, 23, 25, 26, 27, 28 and 30 showed outstanding α-amylase inhibitory potential with IC50 values ranges between 0.002±0.60 and 42.31±0.17μM which is many folds better than standard acarbose having IC50 value 53.02±0.12μM. Eleven analogs 7, 9, 10, 11, 12, 14, 15, 17, 18, 19 and 24 showed good to moderate inhibitory potential while seven analogs 8, 13, 16, 20, 21 and 29 were found inactive. Our study identifies novel series of potent α-amylase inhibitors for further investigation. Structure activity relationship has been established.
The α-amylase acts as attractive target to treat type-2 diabetes mellitus. Therefore in discovering a small molecule as α-amylase inhibitor, we have synthesized benzofuran carbohydrazide analogs (1-25), characterized through different spectroscopic techniques such as 1HNMR and EI-MS. All screened analog shows good α-amylase inhibitory potentials with IC50 value ranging between 1.078±0.19 and 2.926±0.05µM when compared with acarbose having IC50=0.62±0.22µM. Only nine analogs among the series such as analogs 3, 5, 7, 8, 10, 12, 21, 23 and 24 exhibit good inhibitory potential with IC50 values 1.644±0.128, 1.078±0.19, 1.245±0.25, 1.843±0.19, 1.350±0.24, 1.629±0.015, 1.353±0.232, 1.359±0.119 and 1.488±0.07µM when compare with standard drug acarbose. All other analogs showed good to moderate α-amylase inhibitory potentials. The SAR study was conducted on the basis of substituent difference at the phenyl ring. The binding interaction between analogs and active site of enzyme was confirmed by docking studies.
Bisindolylmethane thiosemicarbazides 1-18 were synthesized, characterized by 1H NMR and ESI MS and evaluated for urease inhibitory potential. All analogs showed outstanding urease inhibitory potentials with IC50 values ranging between 0.14 ± 0.01 to 18.50 ± 0.90 μM when compared with the standard inhibitor thiourea having IC50 value 21.25 ± 0.90 μM. Among the series, analog 9 (0.14 ± 0.01 μM) with di-chloro substitution on phenyl ring was identified as the most potent inhibitor of urease. The structure activity relationship has been also established on the basis of binding interactions of the active analogs. These binding interactions were identified by molecular docking studies.
The potential of N. lappacheum and N. mutabile seed as a source of α-amylase inhibitor peptides was explored based on the local traditional practice of using the seed. Different gastro-digestive enzymes (i.e. pepsin or chymotrypsin) or a sequential digestion were used to extract the peptides. The effects of digestion time and enzyme to substrate (E:S) ratio on the α-amylase inhibitory activity were investigated. Results showed that chymotrypsin was effective in producing the inhibitor peptides from rambutan seed protein at E:S ratio 1:20 for 1 h, whereas pepsin was more effective for pulasan seed protein under the same condition. A total of 20 and 31 novel inhibitor peptides were identified, respectively. These peptides could bind with the subsites of α-amylase (i.e. Trp58, Trp59, Tyr62, Asp96, Arg195, Asp197, Glu233, His299, Asp300, and His305) and formed a sliding barrier that preventing the formation of enzyme/substrate intermediate leading to lower α-amylase activity.
We have synthesized oxadiazole derivatives (1-16), characterized by 1H NMR, 13C NMR and HREI-MS and screened for thymidine phosphorylase inhibitory potential. All derivatives display varied degree of thymidine phosphorylase inhibition in the range of 1.10 ± 0.05 to 49.60 ± 1.30 μM when compared with the standard inhibitor 7-Deazaxanthine having an IC50 value 38.68 ± 1.12 μM. Structure activity relationships (SAR) has been established for all compounds to explore the role of substitution and nature of functional group attached to the phenyl ring which applies imperious effect on thymidine phosphorylase activity. Molecular docking study was performed to understand the binding interaction of the most active derivatives with enzyme active site.
Elevated blood glucose and increased activities of secreted phospholipase A2 (sPLA2) are strongly linked to coronary heart disease. In this report, our goal was to develop small heterocyclic compound that inhibit sPLA2. The title compounds were also tested against α-glucosidase and α-amylase. This array of enzymes was selected due to their implication in blood glucose regulation and diabetic cardiovascular complications. Therefore, two distinct series of quinoxalinone derivatives were synthesised; 3-[N'-(substituted-benzylidene)-hydrazino]-1H-quinoxalin-2-ones 3a-f and 1-(substituted-phenyl)-5H-[1,2,4]triazolo[4,3-a]quinoxalin-4-ones 4a-f. Four compounds showed promising enzyme inhibitory effect, compounds 3f and 4b-d potently inhibited the catalytic activities of all of the studied proinflammatory sPLA2. Compound 3e inhibited α-glucosidase (IC50 = 9.99 ± 0.18 µM); which is comparable to quercetin (IC50 = 9.93 ± 0.66 µM), a known inhibitor of this enzyme. Unfortunately, all compounds showed weak activity against α-amylase (IC50 > 200 µM). Structure-based molecular modelling tools were utilised to rationalise the SAR compared to co-crystal structures with sPLA2-GX as well as α-glucosidase. This report introduces novel compounds with dual activities on biochemically unrelated enzymes mutually involved in diabetes and its complications.
Angiotensin I-converting enzyme (ACE) inhibitors derived from foods are valuable auxiliaries to agents such as captopril. Eight highly functional ACE inhibitory peptides from the mushroom, Agaricus bisporus, were identified by LC-MS/MS. Among these peptides, the most potent ACE inhibitory activity was exhibited by AHEPVK, RIGLF and PSSNK with IC₅₀ values of 63, 116 and 129 μM, respectively. These peptides exhibited high ACE inhibitory activity after gastrointestinal digestion. Lineweaver-Burk plots suggested that AHEPVK and RIGLF act as competitive inhibitors against ACE, whereas PSSNK acts as a non-competitive inhibitor. Mushrooms can be a good component of dietary supplement due to their readily available source and, in addition, they rarely cause food allergy. Compared to ACE inhibitory peptides isolated from other edible mushrooms, AHEPVK, RIGLF and PSSNK have lower IC₅₀ values. Therefore, these peptides may serve as an ideal ingredient in the production of antihypertensive supplements.
Preliminary investigations on 14 plant extracts (obtained by ethanolic and aqueous extraction) identified those having high antioxidant and a significant total phenolic content. Antihyperglycemic, α-amylase and α-glucosidase inhibition activities were also observed. A correlation between the antihyperglycemic activity, total phenolic content and antioxidant (DPPH scavenging) activity was established. To further substantiate these findings, the possibility of tannins binding non-specifically to enzymes and thus contributing to the antihyperglycemic activity was also investigated. Our study clearly indicated that the antihyperglycemic activity observed in the plant extracts was indeed not due to non-specific tannin absorption.
In this work the development of an inhibitive assay for copper using the molybdenum-reducing enzyme assay is presented. The enzyme is assayed using 12-molybdophosphoric acid at pH 5.0 as an electron acceptor substrate and NADH as the electron donor substrate. The enzyme converts the yellowish solution into a deep blue solution. The assay is based on the ability of copper to inhibit the molybdenum-reducing enzyme from the molybdate-reducing Serratia sp. Strain DRY5. Other heavy metals tested did not inhibit the enzyme at 10 mg l(-1). The best model with high regression coefficient to measure copper inhibition is one-phase binding. The calculated IC50 (concentration causing 50% inhibition) is 0.099 mg l(-1) and the regression coefficient is 0.98. The comparative LC50, EC50 and IC50 data for copper in different toxicity tests show that the IC50 value for copper in this study is lower than those for immobilized urease, bromelain, Rainbow trout, R. meliloti, Baker's Yeast dehydrogenase activity Spirillum volutans, P. fluorescens, Aeromonas hydrophilia and synthetic activated sludge assays. However the IC50 value is higher than those for Ulva pertusa and papain assays, but within the reported range for Daphnia magna and Microtox assays.
Increased prevalence of methicillin-resistant Staphylococcus aureus (MRSA) has become a major threat to the health sector worldwide due to their virulence, limited therapeutic options and their distribution in both hospital and community settings. Discovery and development of new anti-MRSA agents as alternatives to the very few antibiotics left in the armamentarium are, thus, urgently required. Recently, an efflux mechanism in MRSA has been identified as one of the main contributors of resistance towards various structurally unrelated antibiotics. The potential of reserpine (a phytoalkaloid) as efflux pump inhibitor (EPI) against various microbes remains limited as the concentration needed for inhibition is toxic to humans. This study therefore aimed to evaluate 13 alkaloid compounds as potential inhibitory agents and/or potential EPIs against a panel of three MRSA isolates which not only differ in their susceptibility to vancomycin (amongst the last drugs available to treat serious MRSA infection), but also exhibited active efflux activity. Results indicated berberine's moderate inhibitiory activity against two MRSA isolates scoring a minimum inhibitory concentration (MIC) value of 125 microg/ml. Notable efflux inhibitory activity (ranging from two- to eightfold Ethidium Bromide MIC reduction) meanwhile was detected from quinine, piperine and harmaline using reserpine as the positive control. Findings from this study support the opinion that a vast number of potential phytocompounds with pharmacological potential await discovery. Therapeutic application of these compounds, however, warrants further investigation to ascertain their pharmacodynamics and safety aspects.
A library of novel 2,5-disubtituted-1,3,4-oxadiazoles with benzimidazole backbone (3a-3r) was synthesized and evaluated for their potential as β-glucuronidase inhibitors. Several compounds such as 3a-3d, 3e-3j, 3l-3o, 3q and 3r showed excellent inhibitory potentials much better than the standard (IC50=48.4±1.25μM: d-saccharic acid 1,4-lactone). All the synthesized compounds were characterized satisfactorily by using different spectroscopic methods. We further evaluated the interaction of the active compounds and the enzyme active site with the help of docking studies.