Potent Α-glucosidase Inhibitors Research Articles

Novel sulfonamide-functionalized arylidene indolones as potent α-glucosidase inhibitors: Synthesis, characterization, and in vitro and in silico studies

3-Arylidene-1-(2,6-dichlorophenyl)indolones and in particular their 5-methylaminosulfonyl derivatives efficiently inhibit α-glucosidase enzyme. The results are corroborated by in silico docking studies which show the binding of aminosulfonyl derivatives to be more favorable due to additional hydrogen bonding. The most active compound of the series shows the IC50 of 6.19 μm.

Phytochemical, biological, and in-silico analysis of Colutea armata Hemsl. & Lace: A possible source of bioactive natural compounds

The Colutea genus of plants has been studied for its medicinal qualities, particularly antifungal. The current study is the first to examine and contrast the biological functions and chemical makeup of whole-plant extracts of Colutea armata Hemsl. & Lace. made with dichloromethane (DCM) solvent and methanol (MeOH) solvent. The ability of the extracts under study to block specific enzymes, such as α-glucosidase, tyrosinase, acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and phosphodiesterase. Likewise, spectrophotometric techniques were used to estimate the total bioactive components and potential for antioxidants (DPPH). Additionally, GC–MS metabolomics was done to establish the composition of potential secondary metabolites. Moreover, the in-silico docking studies confirmed the specific compound responsible for biological activities. The varying concentrations of alkaloidal, phenolic and flavonoid components were found in MeOH and DCM extracts, which might be responsible for the notable DPPH, α-glucosidase, and tyrosinase inhibitory potentials. In the contrast, moderate AChE, BChE, and phosphodiesterase inhibition were noted. Additionally, the extracts presented considerable antifungal (S. cerevisiae) and anti-bacterial (K. pneumoniae, S. typhi, E. coli, and S. aureus). In addition, GC–MS profiling of both the MeOH and the DCM extracts revealed the tentative presence of 19 and 33 secondary metabolites, respectively, mostly phenolic, flavonoid, glycoside, terpenes, steroids, and alkaloids, this may be the cause of the plant extract under study's reported biological potential. To conclude, our findings highlighted C. armata as a lead source for naturally bioactive compounds that may open the door to industrial uses.

Biological Importance of Flavonoid Bavachinin in the Medicine: Perspectives of Medicinal Importance, Pharmacological Activities and Analytical Techniques

Backgrounds: Phytochemicals are an important class of natural compounds present in vegetables, herbs, fruits, and seeds. Phytochemicals have been used in medicine for the treatment of human disorders in the form of drugs, medicine, and Nutraceuticals. Flavonoid class secondary metabolites were found to be present in medicinal plants and some food materials derived from plants. Flavonoid class phytochemicals have beneficial health aspects and numerous pharmacological activities in the medicine. Psoralea corylifolia has been widely used in medicine for the treatment of skin diseases, including vitiligo, alopecia areata, leukoderma, and psoriasis. More than 90 different types of phytocompounds have been separated and isolated from Psoralea corylifolia. Bavachinin is a flavonoid class phytochemical, found to be present in the seeds of Psoralea corylifolia. Bavachinin possesses anti-bacterial, anti-oxidative, anti-inflammatory, α-glucosidase and nitric oxide inhibitory potential. Method: Scientific data on bavachinin have been collected from different literature databases such as Google, Google Scholar, PubMed, Science Direct and Scopus in the present work and analyzed to know the biological importance of bavachinin. Scientific research data on bavachinin have been collected in the present work for their medicinal importance, pharmacological activities and analytical aspects. Further, all the collected scientific data have been separated into different sub-sections i.e., Medicinal importance, pharmacological activities and analytical aspects of bavachinin. Detailed pharmacological activity data of bavachinin have been analyzed in the present work to know the therapeutic potential of bavachinin in medicine. Analytical data of bavachinin have been collected and analyzed in the present work to know the biological importance of bavachinin in modern medicine for the standardization of Psoralea corylifolia. Results: Literature data analysis of different scientific research works revealed the biological importance of flavonoids in medicine. Flavonoid class phytochemicals have anti-inflammatory, antioxidant, anti-viral, anti-cancer and anti-ageing properties in medicine. Scientific data analysis revealed the effectiveness of bavachinin in cancer, blood glucose, Alzheimer's disease, Parkinson's disease, inflammation, immune system, T cell differentiation, oxidative damage and enzymes. However, therapeutic efficacy, metabolism, biotransformation, pharmaceutical product development and pharmacokinetic parameters of bavachinin have also been discussed in the present work. Analytical data signified the importance of modern analytical tools for the separation, isolation and identification of bavachinin. Conclusion: Scientific data analysis of different research work revealed the biological importance and therapeutic benefit of bavachinin in medicine.

In-vitro high-throughput library screening-Kinetics and molecular docking studies of potent inhibitors of α-glucosidase.

High throughput screening of synthetic compounds against vital enzymes is the way forward for the determination of potent enzyme inhibitors. In-vitro high throughput library screening of 258 synthetic compounds (comp. 1-258), was performed against α-glucosidase. The active compounds out of this library were investigated for their mode of inhibition and binding affinities towards α-glucosidase through kinetics as well as molecular docking studies. Out of all the compounds selected for this study, 63 compounds were found active within the IC50 range of 3.2 μM to 50.0 μM. The most potent inhibitor of α-glucosidase out of this library was the derivative of an oxadiazole (comp. 25). It showed the IC50 value of 3.23 ± 0.8 μM. Other highly active compounds were the derivatives of ethyl-thio benzimidazolyl acetohydrazide with IC50 values of 6.1 ± 0.5 μM (comp. 228), 6.84 ± 1.3 μM (comp. 212), 7.34 ± 0.3 μM (comp. 230) and 8.93 ± 1.0 μM (comp. 210). For comparison, the standard (acarbose) showed IC50 = 378.2 ± 0.12 μM. Kinetic studies of oxadiazole (comp. 25) and ethylthio benzimidazolyl acetohydrazide (comp. 228) derivatives indicated that Vmax and Km, both change with changing concentrations of inhibitors which suggests an un-competitive mode of inhibition. Molecular docking studies of these derivatives with the active site of α-glucosidase (PDB ID:1XSK), revealed that these compounds mostly interact with acidic or basic amino acid residues through conventional hydrogen bonds along with other hydrophobic interactions. The binding energy values of compounds 25, 228, and 212 were -5.6, -8.7 and -5.4 kcal.mol-1 whereas RMSD values were 0.6, 2.0, and 1.7 Å, respectively. For comparison, the co-crystallized ligand showed a binding energy value of -6.6 kcal.mol-1 along with an RMSD value of 1.1 Å. Our study predicted several series of compounds as active inhibitors of α-glucosidase including some highly potent inhibitors.

New Halogenated Flavonoids from Adenosma bracteosum and Vitex negundo and Their α-Glucosidase Inhibition.

Adenosma bracteosum and Vitex negundo are natural sources of methoxylated flavonoids. Little is known about the α-glucosidase inhibition of multi-methoxylated flavonoid derivatives. Eighteen natural flavonoids were isolated from A. bracteosum and V. negundo. Seven halogenated derivatives were synthesized. Their chemical structures were elucidated by extensive NMR analysis and high-resolution mass spectroscopy as well as comparisons in literature. All compounds were evaluated for their α-glucosidase inhibition. Most compounds showed good activity with IC50 values ranging from 16.7 to 421.8 μM. 6,8-Dibromocatechin was the most active compound with an IC50 value of 16.7 μM. A molecular docking study was conducted, indicating that those compounds are potent α-glucosidase inhibitors.

Identification of novel oxadiazole-based benzothiazole derivatives as potent inhibitors of α-glucosidase and urease: Synthesis, in vitro bio-evaluation and their in silico molecular docking study

This research work represents a synthetic approach for the development of hybrids derivatives of oxadiazole-based benzothiazole (1–17) and diversity in derivatives was achieved using variety of aryl ring of S-substituted benzothiazole to see the effect on the biological activities. All the synthesized derivatives were evaluated for their in vitro α-glucosidase and urease inhibitory potential. The α-glucosidase and urease inhibition profile of the new derivatives represents moderate to good inhibitory potential with IC50 values ranging from 4.60 ± 1.20 µM to 48.40 ± 7.70 µM (α-glucosidase) and 8.90 ± 2.80 to 57.30 ± 7.70 µM (urease) respectively. The results were compared to standard acarbose (38.60 ± 4.50 µM) and thiourea (58.70 ± 6.80 µM) drugs respectively. Among the synthesized series, the analogs 1 having IC50 values of and 4.60 ± 1.20 (α-glucosidase), 8.90 ± 2.80 (urease) and 2 with IC50 values of 5.60 ± 1.60 (α-glucosidase) and 10.90 ± 2.10(urease) were found to be significantly active against targeted α-glucosidase and urease enzymes. The structure of all the newly synthetics scaffolds were confirmed by using different types of spectroscopic techniques such as HREI-MS, 1H- and 13C- NMR spectroscopy. The molecular docking studies of the synthesized derivatives showed good correlations with the experimental findings. The binding modes of active compounds and their interactions with active site residues revealed them as possible anti-diabetics and anti-urease leads. The degree of activity and docking studies displayed by the novel innovative structural hybrids of oxadiazole-based benzothiazole moieties make these compounds new active leads and promising candidates for the development of anti-diabetics and anti-urease agents.

Design, synthesis, in vitro anti-α-glucosidase evaluations, and computational studies of new phthalimide-phenoxy-1,2,3-triazole-N-phenyl (or benzyl) acetamides as potential anti-diabetic agents

An important target in the treatment of type 2 diabetes is α-glucosidase. Inhibition of this enzyme led to delay in glucose absorption and decrease in postprandial hyperglycemia. A new series of phthalimide-phenoxy-1,2,3-triazole-N-phenyl (or benzyl) acetamides 11a–n were designed based on the reported potent α-glucosidase inhibitors. These compounds were synthesized and screened for their in vitro inhibitory activity against the latter enzyme. The majority of the evaluated compounds displayed high inhibition effects (IC50 values in the range of 45.26 ± 0.03–491.68 ± 0.11 µM) as compared to the positive control acarbose (IC50 value = 750.1 ± 0.23 µM). Among this series, compounds 11j and 11i represented the most potent α-glucosidase inhibitory activities with IC50 values of 45.26 ± 0.03 and 46.25 ± 0.89 µM. Kinetic analysis revealed that the compound 11j is a competitive inhibitor with a Ki of 50.4 µM. Furthermore, the binding interactions of the most potent compounds in α-glucosidase active site were studied through molecular docking and molecular dynamics. The latter studies confirmed the obtained results through in vitro experiments. Furthermore, in silico pharmacokinetic study of the most potent compounds was also performed.

Synthesis, biological evaluation and molecular docking studies of 8-(hetero)aryl caffeine derivatives

A series of 8-(hetero)aryl caffeine was synthesized by the CH bond activation reaction using Pd-NHCs complexes as a catalyst. 8-(hetero)aryl caffeine derivatives were screened for their antioxidant, antimicrobial, and enzyme inhibitory activities and in-silico studies. The 4a, 4b, 4e, 4f, 4 g, 4i, and 4n showed significant total antioxidant capacity (TAC) of 64.03, 50.87, 70.02, 98.14, 71.81, 45.48, and 44.28 µg AAE/mg, respectively. The 4a, 4b, 4d, 4e, 6 h, 4i, 4j, 4k, and 4l were found active against Staphylococcus aureus at a minimum inhibitory concentration of 25, 12.5, 12.5, 12.5, 12.5, 6.25, 6.25, 6.25, and 6.25 µg/ml, respectively. Some derivatives displayed activity against Escherichia coli, Bacillus subtilus, Klebsiella pneumonae, and Pseudomonas aeruginosa.A good activity was exhibited against Alternaria solani among five fungal strains. All the compounds (4a–4n) showed excellent protein kinase inhibitory activity except 4e, 4 g, and 4n. Additionally, 8-(hetero)aryl caffeine derivatives showed α-amylase inhibition potential (IC50 = 1.49 ± 0.317 to 7.44 ± 0.156 μg/ml) compared to standard acarbose (IC50 = 4.34 ± 0.333 μg/ml). The 4b, 4d, 4j, 4 m, and 4n compounds displayed good α-glucosidase inhibitory potential. Molecular modeling was done for protein kinase, α-amylase, and α-glucosidase. The results of these activities proved the caffeine derivatives to be bioactive.

In vitro evaluation of novel mefenamic acid derivatives as potential α-glucosidase and urease inhibitors: Design, synthesis, in silico and cytotoxic studies

This study aim to synthesize new 1,3,4-oxadiazole derivatives incorporating mefenamic acid as promising α-glucosidase and urease inhibitors, potentially leading to the treatment of postprandial hyperglycemia as well as H. pylori related disorders. In this regards, we have designed a series of Mefenamic acid derivatives. The synthetic compounds were structurally elucidated through 1H NMR, 13C NMR and HR-EIMS analysis. The biological evaluation of these derivatives against α-glucosidase and urease enzyme depicted some novel derivatives with potent inhibition against the said enzymes. All the derivatives exhibited potent inhibition against α-glucosidase enzymes with IC50 ranging from 25.81 ± 1.63–113.61 ± 1.31 µM against standard drug acarbose (IC50 = 375.82 ± 1.76 µM) while with respect to urease these derivatives possessed inhibitory potential varied between IC50 = 8.04 ± 1.01–58.18 ± 1.03 µM against the standard thiourea (IC50 = 21.0 ± 1.76 µM). The cell viability results revealed that all of the derivatives were found least cytotoxic. Furthermore, molecular docking studies of the most potent derivatives identify number of key features involved in binding interactions between potential inhibitors and the enzyme's active site.

Indole-carbohydrazide linked phenoxy-1,2,3-triazole-N-phenylacetamide derivatives as potent α-glucosidase inhibitors: design, synthesis, in vitro α-glucosidase inhibition, and computational studies

BackgroundA new series of indole-carbohydrazide-phenoxy-1,2,3-triazole-N-phenylacetamide hybrids 11a–o was designed based on molecular hybridization of the active pharmacophores of the potent α-glucosidase inhibitors. These compounds were synthesized and evaluated against α-glucosidase.MethodsThe 15 various derivatives of indole-carbohydrazide-phenoxy-1,2,3-triazole-N-phenylacetamide scaffold were synthesized, purified, and fully characterized. These derivatives were evaluated against yeast α-glucosidase in vitro and in silico. ADMET properties of the most potent compounds were also predicted.ResultsAll new derivatives 11a–o (IC50 values = 6.31 ± 0.03–49.89 ± 0.09 µM) are excellent α-glucosidase inhibitors in comparison to acarbose (IC50 value = 750.0 ± 10.0 µM) that was used as a positive control. Representatively, (E)-2-(4-((4-((2-(1H-indole-2-carbonyl)hydrazono)methyl) phenoxy)methyl)-1H-1,2,3-triazol-1-yl)-N-(4-methoxyphenyl)acetamide 11d with IC50 = 6.31 µM against MCF-7 cells, was 118.8-times more potent than acarbose. This compound is an uncompetitive inhibitor against α-glucosidase and showed the lowest binding energy at the active site of this enzyme in comparison to other potent compounds. Furthermore, computational calculations predicted that compound 11d can be an orally active compound.ConclusionAccording to obtained data, compound 11d can be a valuable lead compound for further structural development and assessments to obtain effective and potent new α-glucosidase inhibitors.

Identification and Isolation of α-Glucosidase Inhibitors from Siraitia grosvenorii Roots Using Bio-Affinity Ultrafiltration and Comprehensive Chromatography.

The discovery of bioactive compounds from medicinal plants has played a crucial role in drug discovery. In this study, a simple and efficient method utilizing affinity-based ultrafiltration (UF) coupled with high-performance liquid chromatography (HPLC) was developed for the rapid screening and targeted separation of α-glucosidase inhibitors from Siraitia grosvenorii roots. First, an active fraction of S. grosvenorii roots (SGR2) was prepared, and 17 potential α-glucosidase inhibitors were identified based on UF-HPLC analysis. Second, guided by UF-HPLC, a combination of MCI gel CHP-20P column chromatography, high-speed counter-current countercurrent chromatography, and preparative HPLC were conducted to isolate the compounds producing active peaks. Sixteen compounds were successfully isolated from SGR2, including two lignans and fourteen cucurbitane-type triterpenoids. The structures of the novel compounds (4, 6, 7, 8, 9, and 11) were elucidated using spectroscopic methods, including one- and two-dimensional nuclear magnetic resonance spectroscopy and high-resolution electrospray ionization mass spectrometry. Finally, the α-glucosidase inhibitory activities of the isolated compounds were verified via enzyme inhibition assays and molecular docking analysis, all of which were found to exhibit certain inhibitory activity. Compound 14 exhibited the strongest inhibitory activity, with an IC50 value of 430.13 ± 13.33 μM, which was superior to that of acarbose (1332.50 ± 58.53 μM). The relationships between the structures of the compounds and their inhibitory activities were also investigated. Molecular docking showed that the highly active inhibitors interacted with α-glucosidase through hydrogen bonds and hydrophobic interactions. Our results demonstrate the beneficial effects of S. grosvenorii roots and their constituents on α-glucosidase inhibition.

Novel N′-substituted benzylidene benzohydrazides linked to 1,2,3-triazoles: potent α-glucosidase inhibitors

Herein, various N′-substituted benzylidene benzohydrazide-1,2,3-triazoles were designed, synthesized, and screened for their inhibitory activity toward α-glucosidase. The structure of derivatives was confirmed using 1H- and 13C-NMR, FTIR, Mass spectrometry, and elemental analysis. All derivatives exhibited good inhibition with IC50 values in the range of 0.01 to 648.90 µM, compared with acarbose as the positive control (IC50 = 752.10 µM). Among them, compounds 7a and 7h showed significant potency with IC50 values of 0.02 and 0.01 µM, respectively. The kinetic study revealed that they are noncompetitive inhibitors toward α-glucosidase. Also, fluorescence quenching was used to investigate the interaction of three inhibitors 7a, 7d, and 7h, with α-glucosidase. Accordingly, the binding constants, the number of binding sites, and values of thermodynamic parameters were determined for the interaction of candidate compounds toward the enzyme. Finally, the in silico cavity detection plus molecular docking was performed to find the allosteric site and key interactions between synthesized compounds and the target enzyme.

The potential antidiabetic properties of green and purple tea [Camellia sinensis (L.) O Kuntze], purple tea ellagitannins, and urolithins.

Tea (Camellia sinensis) has been consumed for centuries as traditional medicine for various diseases, including diabetes. The mechanism of action of many traditional medicines, including tea, often requires elucidation. Purple tea is a natural mutant of Camellia sinensis, grown in China and Kenya, and is rich in anthocyanins and ellagitannins. Here we aimed to determine whether commercial green and purple teas are a source of ellagitannins and whether green and purple teas, purple tea ellagitannins and their metabolites urolithins have antidiabetic activity. Targeted UPLC-MS/MS was employed to quantify the ellagitannins corilagin, strictinin and tellimagrandin I, in commercial teas. The inhibitory effect of commercial green and purple teas and purple tea ellagitannins was evaluated on α-glucosidase and α-amylase. The bioavailable urolithins were then investigated for additional antidiabetic effects, by evaluating their effect on cellular glucose uptake and lipid accumulation. Corilagin, strictinin and tellimagrandin I (ellagitannins) were identified as potent inhibitors of α-amylase and α-glucosidase, with Ki values significantly lower (p < 0.05) than acarbose. Commercial green-purple teas were identified as ellagitannin sources, with especially high concentrations of corilagin. These commercial purple teas, containing ellagitannins, were identified as potent α-glucosidase inhibitors with IC50 values significantly lower (p < 0.05) than green teas and acarbose. Urolithin A and urolithin B were as effective (p > 0.05) as metformin in increasing glucose uptake in adipocytes, muscle cells and hepatocytes. In addition, similar (p > 0.05) to metformin, both urolithin A and urolithin B reduced lipid accumulation in adipocytes and hepatocytes. This study identified green-purple teas as an affordable widely available natural source with antidiabetic properties. Furthermore, additional antidiabetic effects of purple tea ellagitannins (corilagin, strictinin and tellimagrandin I) and urolithins were identified.

Enzyme activity- and chemometrics-assisted comprehensive two-dimensional liquid chromatography coupled with ion mobility quadrupole time-of-flight mass spectrometry for the analysis of honeysuckle

A unique and effective comprehensive two-dimensional liquid chromatography system was established and applied for the analysis of bioactive components in honeysuckle. Under the optimal conditions, Eclipse Plus C18 (2.1 × 100 mm, 3.5 μm, Agilent) and SB-C18 (4.6 × 50 mm, 1.8 μm, Agilent) columns were chosen for the first dimension (1D) and the second dimension (2D) separation. The optimal flow rates of 1D and 2D were 0.12 mL/min and 2.0 mL/min, respectively. Additionally, the proportion of organic solution was optimized to enhance orthogonality and integrated shift, and full gradient elution mode was adopted to improve chromatographic resolution. Furthermore, a total of 57 compounds were identified by molecular weight, retention time and collision cross-section value obtained from ion mobility mass spectrometry. Based on the data obtained from the principal component analysis, partial least squares discriminant analysis, and hierarchical cluster analysis, the categories of honeysuckle in different regions were significantly different. Moreover, the half maximal inhibitory concentration values of most samples were between 0.37 and 1.55 mg/mL, and most samples were potent α-glucosidase inhibitors, which is better for the evaluation of the quality of drugs from two aspects of substance content and activity.

Synthesis and biological evaluation of novel isatin-hydrazide conjugates as potential antidiabetic agents

Diabetes mellitus is a severe metabolic disorder, which has very high prevalence rate and resulting into other health devastating complications. Pancreatic insulin resistance and -cell dysfunction are its defining features resulting in high blood glucose level. This study's objective was to locate substances with possible anti-hyperglycemic effect that block α-glucosidase. For these studies several novel indole-hydrazide conjugates (3a–3r) were synthesized and examined using a variety of spectroscopic methods. Comparing the investigated compounds from the 3a–3r series to the reference medication acarbose 1C50 = 873.34 ± 1.67 µM, all the compounds demonstrated potent inhibition of α-glucosidase with IC50 values of in range of 0.51–42.91 µM. The highest inhibition was seen with the analogs 3p and 3o having IC50 values of 0.51 ± 0.06 and 1.57 ± 0.08 µM, respectively. Structure-activity relationships showed that the α-glucosidase potential of these compounds vary with various substituents pattern on the novel indole-hydrazide. Kinetics and docking examination revealed that the active compounds accommodate well in the active site of α-glucosidase and displayed mixed-type of inhibition.

Screening and Elucidation of Chemical Structures of Novel Mammalian α-Glucosidase Inhibitors Targeting Anti-Diabetes Drug from Herbals Used by E De Ethnic Tribe in Vietnam.

Among ten extracts of indigenous medicinal plants, the MeOH extract of Terminalia triptera Stapf. (TTS) showed the most efficient mammalian α-glucosidase inhibition for the first time. The data of screening bioactive parts used indicated that the TTS trunk bark and leaves extracts demonstrated comparable and higher effects compared to acarbose, a commercial anti-diabetic drug, with half-maximal inhibitory concentration (IC50) values of 181, 331, and 309 µg/mL, respectively. Further bioassay-guided purification led to the isolation of three active compounds from the TTS trunk bark extract and identified as (-)-epicatechin (1), eschweilenol C (2), and gallic acid (3). Of these, compounds 1 and 2 were determined as novel and potent mammalian α-glucosidase inhibitors. The virtual study indicated that these compounds bind to α-glucosidase (Q6P7A9) with acceptable RMSD values (1.16-1.56 Å) and good binding energy (DS values in the range of -11.4 to -12.8 kcal/mol) by interacting with various prominent amino acids to generate five and six linkages, respectively. The data of Lipinski's rule of five and absorption, distribution, metabolism, excretion and toxicity (ADMET)-based pharmacokinetics and pharmacology revealed that these purified compounds possess anti-diabetic drug properties, and the compounds are almost not toxic for human use. Thus, the findings of this work suggested that (-)-epicatechin and eschweilenol C are novel potential mammalian α-glucosidase inhibitor candidates for type 2 diabetes treatment.

Synthesis, in vitro inhibitor screening, structure–activity relationship, and molecular dynamic simulation studies of novel thioquinoline derivatives as potent α-glucosidase inhibitors

New series of thioquinoline structures bearing phenylacetamide 9a–p were designed, synthesized and the structure of all derivatives was confirmed using different spectroscopic techniques including FTIR, 1H-NMR, 13C-NMR, ESI–MS and elemental analysis. Next, the α-glucosidase inhibitory activities of derivatives were also determined and all the synthesized compounds (IC50 = 14.0 ± 0.6–373.85 ± 0.8 μM) were more potent than standard inhibitors acarbose (IC50 = 752.0 ± 2.0 μM) against α-glucosidase. Structure–activity relationships (SARs) were rationalized by analyzing the substituents effects and it was shown that mostly, electron-donating groups at the R position are more favorable compared to the electron-withdrawing group. Kinetic studies of the most potent derivative, 9m, carrying 2,6-dimethylphenyl exhibited a competitive mode of inhibition with Ki value of 18.0 µM. Furthermore, based on the molecular dynamic studies, compound 9m depicted noticeable interactions with the α-glucosidase active site via several H-bound, hydrophobic and hydrophilic interactions. These interactions cause interfering catalytic potential which significantly decreased the α-glucosidase activity.

Coumarin linked thiazole derivatives as potential α-glucosidase inhibitors to treat diabetes mellitus.

Diabetes is a leading cause of kidney failure, blindness, heart attacks and lower limb amputation. Prevalence of diabetes is rising globally. α-glucosidase is validated target for controlling hyperglycemia because of its role in catalysing hydrolysis of carbohydrates to glucose in GIT. In an attempt to find novel safe and effective α-glucosidase inhibitors, coumarin linked thiazole was identified as potential scaffold on the basis of its interactions with the active site of α-glucosidase studied in silico. A series of coumarin linked thiazole derivatives were synthesized and analyzed for α-glucosidase inhibitory potential in an in-vitro assay. The synthesized molecules showed potent inhibition of α-glucosidase with IC50 values ranging from 0.14 to 9.38μM. The most potent compound 2-[(4-bromophenyl) amino)-N-(4- (2-oxo-2H-chromen-3-yl) thiazol-2-yl] acetamide was further docked with α-glucosidase and molecular dynamics studies were carried out for 100ns which suggested the stability of protein and ligand in the protein active site over the simulation period and role of hydrophobic interactions slightly more than the electrostatic/polar interactions in ligand- receptor stability. In summary, our results demonstrate efficacy of coumarin-linked thiazole as potential leads for further optimization and development.

Exploring thiazole-based Schiff base analogs as potent α-glucosidase and α-amylase inhibitor: their synthesis and in-silico study

In search of potent antidiabetic agents here in this study a new series of thiazole-based Schiff base analogs (1–20) have been synthesized, characterized by 1HNMR, 13CNMR, HREI-MS and evaluated as dual inhibitor for α-glucosidase and α-amylase. All analogs of the series found active and exhibited variable degree of inhibitory potential ranging from 1.10 ± 0.10–17.20 ± 0.30 µM as compared to reference drug acarbose IC50 = for 9.80 ± 0.20 µM α-glucosidase and from 0.90 ± 0.01 to 16.20 ± 0.30 µM as compared to reference drug acarbose IC50 = 10 0.30 ± 0.20 µM for α-amylase. Compounds 3, 5, 6, 7, 14, 15, 16, 18 and 19 exhibited outstanding α-glucosidase as well as α-amylase inhibitory potential as compared to reference drug acarbose. Structure activity relationships SAR) have established for all the synthesized analogs. A molecular docking study has been conducted to develop an idea about binding interaction of compounds and enzymes. All synthesized compounds were tested for cytotoxicity and found nontoxic.

Regioselective syntheses of 2-oxopyridine carbonitrile derivatives and evaluation for antihyperglycemic and antioxidant potential

A library of 2-oxopyridine carbonitriles 1–34 was synthesized by regioselective nucleophilic substitution reactions. In the first step, a one-pot multicomponent reaction yield pyridone intermediates. The resulting pyridone intermediates were then reacted with phenacyl halides in DMF and stirred at 100 °C for an hour to afford the desired compounds in good yields. Structures of synthetic molecules were characterized by EI-MS, HREI-MS, 1H NMR, and 13C NMR, and all thirty-four (34) compounds were found to be new. All synthetic compounds were examined for antidiabetic and antioxidant potential. The compounds exhibited α-glucosidase inhibitory potential in the range of IC50 = 3.00 ± 0.11–43.35 ± 0.67 μM and α-amylase inhibition potential in the range of IC50 = 9.20 ± 0.14–65.56 ± 1.05 μM. Among the tested compounds, 1 showed the most significant α-glucosidase inhibitory activity, with an IC50 value of 3.00 ± 0.11 μM, while the most active compound against α-amylase was 6, with an IC50 value = 9.20 ± 0.14 μM. The kinetic studies and analysis indicated that the compounds followed the competitive mode of inhibition. In addition, the molecular docking studies showed the interaction profile of all molecules with the binding site residues of α-glucosidase and α-amylase enzymes.