Novel C-2 Symmetric Molecules as α-Glucosidase and α-Amylase Inhibitors: Design, Synthesis, Kinetic Evaluation, Molecular Docking and Pharmacokinetics (original) (raw)
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Journal of the Iranian Chemical Society, 2019
In a search for α-amylase and α-glucosidase inhibitors to treat type II diabetes, a new series of N-(3-acetyl-2-methyl-4-phenylquinolin-6-yl)arylamides were synthesized from 3-acetyl-2-methyl-4-phenylquinolines. Initially, nitro function of 1-(2-methyl-6-nitro-4-phenylquinolin-3-yl) ethanone was converted into the corresponding amine by grinding it with zinc dust and ammonium chloride (reducing agent) which in turn successfully converted into the N-(3-acetyl-2-methyl-4-phenylquinolin-6-yl) arylamides by treating it with coupling reagents such as EDC, HATU, and DCC. All the synthesized compounds were found to afford excellent yields with HATU, moderate in EDC, and very less in DCC and hence, HATU was considered as a suitable coupling reagent. These analogs are structurally characterized by NMR, NMR-DEPT, and HRMS. All the synthesized compounds were evaluated for in-silico and in-vitro α-glucosidase and α-amylase inhibitory activity using acarbose as standard and all the compounds showed positive results by in-silico and in-vitro α-amylase inhibition assay. Among the tested compounds, compound 5c and 5d in α-glucosidase as well as in α-amylase are found to have least binding energy value. These compounds found to form more stable ligand-receptor complex amongst other compounds. In addition, in experimental part, also the compounds 5c and 5d exhibited 56.90 ± 0.77% and 59.46 ± 0.61% of the higher potent α-glucosidase inhibitory activity with IC 50 values 171.75 ± 3.95 µmol/mL and 171.67 ± 1.57 µmol/mL significantly (p < 0.05) compared to the remaining seven test samples. And similarly, the compound 5c and 5d possessed α-amylase inhibitory activity at a concentration of 100 µg/mL (55.42 ± 0.42% and 55.42 ± 1.14%) with IC 50 values 138.92 ± 4.44 µmol/ mL and 158.78 ± 2.34 µmol/mL.
Bulletin of the National Research Centre
Background Diabetes mellitus (DM) is one of the most defying health risk in the twenty-first century promoting a high rate of morbidity and mortality that could possibly increase if no intervention is in place. However, drugs for curing DM are available but are associated with adverse side effect necessitating the pursuit for a safe antidiabetic drugs. The present study was conducted in order to develop a QSAR model that would be used to predict the activities of salicylic acid derivatives, as well as to determine the binding interactions of the compounds with α-glucosidase using molecular docking studies. Results Model one was selected and reported as the best model based on its fitness with the following validation keys: R2(trng set) = 0.968, R2(adj) = 0.957, Q2(cv) = 0.932, LOF = 0.085 and R2(test set) = 0.864. Five potent analogues were designed using the ligand-based method with their predicted activities been calculated and found to be higher compared to the lead compound. Fur...
PLOS ONE
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) sh...
BMC Chemistry, 2019
Diabetes is an emerging metabolic disorder. α-Glucosidase inhibitors, such as acarbose, delay the hydrolysis of carbohydrates by interfering with the digestive enzymes. This action decreases the glucose absorption and the postprandial glucose level. We have synthesized 25 tricyclic 2-phenoxypyrido[3,2-e][1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-ones hybrids and evaluated their α-glucosidase inhibitory activity. Compounds 6h and 6d have shown stronger activity than that of acarbose. Compound 6h exhibited the highest inhibition with an IC 50 of 104.07 µM. Molecular modelling studies revealed that compound 6h inhibits α-glucosidase due to the formation of a stable ligand-αglucosidase complex and extra hydrogen bond interactions, and directed in the binding site by Trp329.25 tricyclic 2-phenoxypyrido[3,2-e][1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-ones hybrids have been synthesized and evaluated their α-glucosidase inhibitory activity. Compounds 6h have shown stronger activity than that of acarbose
Molecules
Current antidiabetic drugs have severe side effects, which may be minimized by new selective molecules that strongly inhibit α-glucosidase and weakly inhibit α-amylase. We have synthesized novel alkoxy-substituted xanthones and imidazole-substituted xanthones and have evaluated them for their in silico and in vitro α-glucosidase and α-amylase inhibition activity. Compounds 6c, 6e, and 9b promoted higher α-glucosidase inhibition (IC50 = 16.0, 12.8, and 4.0 µM, respectively) and lower α-amylase inhibition (IC50 = 76.7, 68.1, and >200 µM, respectively) compared to acarbose (IC50 = 306.7 µM for α-glucosidase and 20.0 µM for α-amylase). Contrarily, derivatives 10c and 10f showed higher α-amylase inhibition (IC50 = 5.4 and 8.7 µM, respectively) and lower α-glucosidase inhibition (IC50 = 232.7 and 145.2 µM, respectively). According to the structure–activity relationship, attaching 4-bromobutoxy or 4′-chlorophenylacetophenone moieties to the 2-hydroxy group of xanthone provides higher α-...
α-amylase and α-glucosidase potent isatin derivatives, 2021
Managing diabetes that is a global life-threatening problem, remains a challenge for the scientific community. The inhibition of α-amylase and α-glucosidase enzymes which are responsible for the digestion of dietary carbohydrates is an effective strategy to control postprandial hyperglycemia. Herein, we report the novel and highly potent inhibitors of α-amylase and α-glucosidase, namely isatin-hydrazide conjugates 1a-1j that are easily accessed in two steps from simple and inexpensive commercially available isatin. The in vitro bio-evaluations of these compounds revealed that conjugates 1a, 1h and 1f are highly potent inhibitors of α-amylase with IC 50 values of 19.6, 12.1 and 18.3 µg/ml, respectively as compared to the standard, acarbose (IC 50 = 36.2 µg/ml). Similarly, the conjugates 1a, 1b, 1d, 1f and 1i showed significant activity against α-glucosidase with IC 50 values of 14.8, 25.6, 13.2, 14.5 and 16.5 µg/ml, respectively as compared to the acarbose (IC 50 = 34.5 µg/ml). Notably, the compounds 1a and 1f were found to be highly potent against both α-amylase and α-glucosidase enzymes, demonstrating about twofold better inhibitory activity than the reference inhibitor. Molecular docking studies were performed to recognize the possible binding modes of the compounds with the active pocket of the enzymes. The results of this study divulge the potential of these compounds as powerful and inexpensive lead molecules for future investigations.
Multifunctional isoxazolidine derivatives as α-amylase and α-glucosidase inhibitors
Bioorganic Chemistry, 2020
A series of novel isoxazolidines based on benzaldehyde derivatives have been synthesized from the cycloaddition of chiral menthone-based nitrone and allyl phenyl ethers. All synthetic compounds were assessed for their in vitro PPA, HPA and HLAG inhibitory activity. The results revealed that all targets exhibited better inhibitory effect against PPA (12.3 < IC50 < 38.2 μM), HPA (10.1±0.4< IC50 < 26.8±0.2 μM) and HLAG (65.4±1.2< IC50 < 274.8±1.1μM) when compared with the reference inhibitor, acarbose (IC50=284.6±0.3 μM for PPA, 296.6±0.8 μM for HPA, 780.4±0.3 μM for HLAG) with the highest PPA inhibitory activity was ascribed to compound 3g against both PPA and HPA, and 3b against HLAG enzymes, respectively. Structural activity relationships (SARs) were also established for all synthesized compounds and the interaction modes of the most potent inhibitor (3g) and the active site with residues of three enzymes were confirmed through molecular docking studies. Furthermore, a combination of molecular docking analysis with the in vitro activities can help to improve prediction success and encourages the uses of some of these molecules as potential alternatives toward the modulation of T2D.
Molecules
The ambident electrophilic character of the 5-bromo-2-hydroxychalcones and the binucleophilic nature of 2-aminothiophenol were exploited to construct the 2-aryl-4-(4-bromo-2-hydroxyphenyl)benzo[1,5]thiazepines. The structures and conformation of these 2-aryl-4-(4-bromo-2-hydroxyphenyl)benzo[1,5]thiazepines were established with the use of spectroscopic techniques complemented with a single crystal X-ray diffraction method. Both 1H-NMR and IR spectroscopic techniques confirmed participation of the hydroxyl group in the intramolecular hydrogen-bonding interaction with a nitrogen atom. SC-XRD confirmed the presence of a six-membered intramolecularly hydrogen-bonded pseudo-aromatic ring, which was corroborated by the DFT method on 2b as a representative example in the gas phase. Compounds 2a (Ar = -C6H5), 2c (Ar = -C6H4(4-Cl)) and 2f (Ar = -C6H4(4-CH(CH3)2) exhibited increased inhibitory activity against α-glucosidase compared to acarbose (IC50 = 7.56 ± 0.42 µM), with IC50 values of 6.7...
Iranian Journal of Basic Medical Sciences, 2021
Objective(s): Alpha-amylase and alpha-glucosidase enzyme inhibition is an effective and rational approach for controlling postprandial hyperglycemia in type II diabetes mellitus (DM). Several inhibitors of this therapeutic class are in clinical use but are facing challenges of safety, efficacy, and potency. Keeping in view the importance of these therapeutic inhibitors, in this study we are reporting 10 new oxadiazole analogs 5 (a-g) & 4a (a-c) as antidiabetic agents. Materials and Methods: The newly synthesized derivatives 5 (a-g) & 4a (a-c) were characterized using different spectroscopic techniques including FTIR,1HNMR, 13CNMR, and elemental analysis data. All compounds were screened for their in vitro α-amylase and α-glucosidase enzyme inhibitory potential, while two selected compounds (5a and 5g) were screened for cytotoxicity using MTT assay. Results: Two analogues 5a and 4a (a) exhibited strong inhibitory potential against α-glucosidase enzyme, i.e., IC50 value=12.27±0.41 µg/...
Chemical Papers, 2019
One of the therapeutic approaches in the management of type 2 diabetes is delaying the glucose absorption through α-glucosidase enzyme inhibition, which can reduce the occurrence of postprandial hyperglycemia. Based on this thought, a series of novel chloro-substituted 2-(2-methyl-1-phenyl-1H-pyrrol-3-yl)-2-oxo-N-(pyridin-3-yl) acetamide derivatives 5a-i were synthesized and their α-glucosidase inhibitory activities were evaluated. All the synthesized compounds have shown moderate to excellent in vitro α-glucosidase inhibitory activity with IC 50 values in the range of 111-673 µM) as compared to acarbose, the standard drug (750 ± 9 µM). Compound 5e (111 ± 12 µM), among the series, was the most potent inhibitor of α-glucosidase in a competitive mode of action based on the kinetic study. The molecular docking study of compounds 5e and 5a revealed that they have a lower free binding energy (− 4.27 kcal/mol and − 3.17 kcal/mol, respectively) than acarbose (− 2.47 kcal/mol), which indicates that the target compound binds more easily to the enzyme than acarbose does. The outcomes from the molecular docking studies supported the results obtained from the in vitro assay. In conclusion, the overall results of our study reveal that the synthesized compounds could be a potential candidate in the search for novel α-glucosidase inhibitors to manage postprandial hyperglycemia incidence.