Synthesis, biological activity and molecular docking of new tricyclic series as α-glucosidase inhibitors (original) (raw)
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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.
Bioorganic Chemistry, 2014
Pyridine-2,4,6-tricarbohydrazide Acarbose MMFF94X + Solvation a b s t r a c t A range of novel pyridine 2,4,6-tricarbohydrazide derivatives (4a-4h) were synthesized and its biological inhibition towards aand b-glucosidases was studied. Most of the compounds demonstrate to be active against a-glucosidase, and quite inactive/completely inactive against b-glucosidase. A number of compounds were found to be more active against a-glucosidase than the reference compound acarbose (IC 50 38.25 ± 0.12 lM); being compound 4d with the p-hydroxy phenyl motive the most active (IC 50 20.24 ± 0.72 lM). Molecular modeling studies show the interactions of compound 4d with the active site of target a-glucosidase kinase.
Bioorganic chemistry, 2018
Herein, condensation of aryl(hetaryl)pyrazole-4-carbaldehydes 1(a-c) with substituted pyrazolones 2(a-d) lead to the corresponding arylidene-pyrazolones 3(a-l) which were tested against α-glucosidase enzyme. The synthesized compounds displayed moderate to good activity. Among these, a coumarin derivative 3k exhibited excellent results (IC2.10 ± 0.004 µM) in comparison to clinical drug acarbose (IC37.38 ± 0.12 µM). The ligand-protein interactions were identified through docking and stabilizing energy calculations.
Journal of The Taiwan Institute of Chemical Engineers, 2017
α-Glucosidase inhibitors have extensively been exploited for the effective management of type 2 diabetes and associated complications by significantly reducing the postprandial increase in glucose and plasma insulin levels. In this endeavour, we designed and synthesized a new series of coumarinyl iminothiazolidinone hybrid compounds (6a-o) using a one-pot multi-component approach. The hybrid structures were accessed in good chemical yields. The synthesized compounds were tested for their glucosidase inhibitory efficacy using acarbose as a standard inhibitor (IC 50 = 38.2 ± 0.12 μM). In-vitro analysis of the hybrid molecules identified several potential leads for the development of potent glucosidase inhibitors with IC 50 values in the range of 0.09-0.92 μM with compound 6g being the most potent drug candidate (IC 50 = 0.09 ± 0.001 μM). Furthermore, compound 6f was identified as the lead inhibitor against maltaseglucoamylase with comparable inhibitory efficacy to acarbose with an IC 50 value of 0.07 ± 0.016 μM. Binding interactions of potent compounds with the key residues in the active site of the glucosidase enzyme were revealed by molecular docking analysis. In summary, these new structural leads based on the hybrid pharmacophores could be developed as potential inhibitors of α-glucosidase for treating postprandial hyperglycemia.
1,4-Disubstituted-1,2,3-triazoles were synthesized by Cu(I) catalyzed click reaction, where the azides, with electron donating and electron withdrawing groups acted as 1,3-dipoles and 1- ethynyl-1-cyclohexanol served as the terminal alkyne. These synthesized triazoles were subjected to enzymatic assay which showed promising activity against α–glucosidase; 1-(2- Cyano-4-nitrophenyl)-4-(1-hydroxycyclohexyl)-1H-1,2,3-triazole 3m being the most active members of the library. Molecular docking studies of these triazoles with the homologymodeled α–glucosidase protein were also performed to delineate ligand-protein interactions at molecular level which suggested that Phe157, Arg312 and His279 are the major interacting residues in the biding site of the protein and may have a significant role in the inhibition of enzyme’s function.
Pakistan journal of pharmaceutical sciences, 2019
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.
Bioorganic chemistry, 2014
A new series of triazinoindole analogs 1-11 were synthesized, characterized by EI-MS and 1 H NMR, evaluated for a-glucosidase inhibitory potential. All eleven (11) analogs showed different range of a-glucosidase inhibitory potential with IC 50 value ranging between 2.46 ± 0.008 and 312.79 ± 0.06 lM when compared with the standard acarbose (IC 50 , 38.25 ± 0.12 lM). Among the series, compounds 1, 3, 4, 5, 7, 8, and 11 showed excellent inhibitory potential with IC 50 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 lM respectively. All other compounds also showed good enzyme inhibition. The binding modes of these analogs were confirmed through molecular docking.
ACS Omega
In the present study, a series of 2,3-dihydro-1,5benzothiazepine derivatives 1B−14B has been synthesized sand characterized by various spectroscopic techniques. The enzyme inhibitory activities of the target analogues were assessed using in vitro and in vivo mechanism-based assays. The tested compounds 1B−14B exhibited in vitro inhibitory potential against αglucosidase with IC 50 = 2.62 ± 0.16 to 10.11 ± 0.32 μM as compared to the standard drug acarbose (IC 50 = 37.38 ± 1.37 μM). Kinetic studies of the most active derivatives 2B and 3B illustrated competitive inhibitions. Based on the α-glucosidase inhibitory effect, the compounds 2B, 3B, 6B, 7B, 12B, 13B, and 14B were chosen in vivo for further evaluation of antidiabetic activity in streptozotocin-induced diabetic Wistar rats. All these evaluated compounds demonstrated significant antidiabetic activity and were found to be nontoxic in nature. Moreover, the molecular docking study was performed to elucidate the binding interactions of most active analogues with the various sites of the αglucosidase enzyme (PDB ID 3AJ7). Additionally, quantitative structure−activity relationship (QSAR) studies were performed based on the α-glucosidase inhibitory assay. The value of correlation coefficient (r) 0.9553 shows that there was a good correlation between the 1B−14B structures and selected properties. There is a correlation between the experimental and theoretical results. Thus, these novel compounds could serve as potential candidates to become leads for the development of new drugs provoking an anti-hyperglycemic effect.
Carbohydrate Research, 2013
The synthesis of a set of pyrimidine-fused derivatives (L1-L8), resulting from the incorporation of different fragments on the pyrimidine-fused heterocycle (PFH) of the earlier reported a-glucosidase (a-Gls) inhibitor (C1-C5), allowed the discovery of new ligands with modest and selective inhibitory activity. The PFH core (substructure 2) was proved to play a significant role in their inhibitory properties. Additionally, the substituent on substructures 1 and 3 of the heterocyclic ring was demonstrated to be important in the enzyme inhibitory action of the pyrimidine-fused derivatives. Moreover, these ligands show selective inhibitory properties for a-Gls over porcine pancreatic a-amylase (a-Amy) which is important in terms of their reduced susceptibility for the possible development of intestinal disturbance side effects. Therefore, low to moderate a-Amy inhibition with effective a-Gls inhibitory action may offer a better therapeutic strategy. Overall, these compounds can potentially offer a new opportunity to develop novel antidiabetic drugs with selective inhibitory action against a-Gls.
Bioorganic Chemistry, 2019
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