Synthesis,in vitro evaluation and molecular docking studies of thiazole derivatives as new inhibitors of α-glucosidase

A series of thiazole derivatives 1–21 were prepared, characterized by EI-MS and ¹H 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 ± 0.94 μM when compared with the standard acarbose (IC₅₀, 38.25 ± 0.12 μM). Compound (8) (IC₅₀, 18.23 ± 0.03 μM) and compound (7) (IC₅₀ = 36.75 ± 0.05 μM) exhibited outstanding inhibitory potential much better than the standard acarbose (IC₅₀, 38.25 ± 0.12 μM). 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.     

Synthesis,biological evaluation and molecular docking studies of chromone hydrazone derivatives as α-glucosidase inhibitors

A series of chromone hydrazone derivatives 4a–4p have been synthesized, characterized by ¹H NMR and ¹³C NMR and evaluated for their in vitro α-glucosidase inhibitory activity. Out of these tested compounds, six (4a, 4b, 4d, 4j, 4o and 4p) displayed potent α-glucosidase inhibitory activity with IC₅₀ values in the range of 20.1 ± 0.19 μM to 45.7 ± 0.23 μM, as compared to the standard drug acarbose (IC₅₀ = 817.38 ± 6.27 μM). Among this series, compound 4d (IC₅₀ = 20.1 ± 0.19 μM) with 4-sulfonamide substitution at phenyl part of hydrazide was found to be the most active compound. Lineweaver-Burk plot analysis indicated that compound 4d is a non-competitive inhibitor of α-glucosidase. The binding interactions of the most active analogs were confirmed through molecular docking studies. Docking studies showed 4d are interacting with the residues Glu-276, Asp-214, Asp-349 and Arg-439 through hydrogen bonds, arene-anion and arene-cation interactions. In summary, our studies shown that these chromone hydrazone derivatives are a new class of α-glucosidase inhibitors.     

Design,synthesis and biological evaluation of novel coumarin thiazole derivatives as α-glucosidase inhibitors

A new series of coumarin thiazole derivatives 7a-7t were synthesized, characterized by ¹H NMR, ¹³C NMR and element analysis, evaluated for their α-glucosidase inhibitory activity. The majority of the screened compounds displayed potent inhibitory activities with IC₅₀ values in the range of 6.24 ± 0.07–81.69 ± 0.39 μM, when compared to the standard acarbose (IC₅₀ = 43.26 ± 0.19 μM). Structure–activity relationship (SAR) studies suggest that the pattern of substitution in the phenyl ring is closely related to the biological activity of this class of compounds. Among all the tested molecules, compound 7e (IC₅₀ = 6.24 ± 0.07 μM) was found to be the most active compound in the library of coumarin thiazole derivatives. Enzyme kinetic studies showed that compound 7e is a non-competitive inhibitor with a K_i of 6.86 μM. Furthermore, the binding interactions of compound 7e with the active site of α-glucosidase were confirmed through molecular docking. This study has identified a new class of potent α-glucosidase inhibitors for further investigation.     

Triazinoindole analogs as potent inhibitors of α-glucosidase: Synthesis,biological evaluation and molecular docking studies

A new series of triazinoindole analogs 1–11 were synthesized, characterized by EI-MS and ¹H 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.     

Synthesis,in vitro α-glucosidase inhibitory activity and molecular docking studies of new thiazole derivatives

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 ¹H NMR, ¹³C 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 ± 1.70 μM as compared to standard acarbose (IC₅₀ = 38.25 ± 0.12 μM). It is worth mentioning that most of the compounds such as 1 (IC₅₀ = 23.60 ± 0.39 μM), 2 (IC₅₀ = 22.70 ± 0.60 μM), 3 (IC₅₀ = 22.40 ± 0.32 μM), 4 (IC₅₀ = 26.5 ± 0.40 μM), 6 (IC₅₀ = 34.60 ± 0.60 μM), 7 (IC₅₀ = 26.20 ± 0.43 μM), 8 (IC₅₀ = 14.06 ± 0.18 μM), 9 (IC₅₀ = 17.60 ± 0.28 μM), 10 (IC₅₀ = 27.16 ± 0.41 μM), 11 (IC₅₀ = 19.16 ± 0.19 μM), 12 (IC₅₀ = 9.06 ± 0.10 μM), 13 (IC₅₀ = 12.80 ± 0.21 μM), 14 (IC₅₀ = 11.94 ± 0.18 μM), 15 (IC₅₀ = 16.90 ± 0.20 μM), 16 (IC₅₀ = 12.60 ± 0.14 μM), 17 (IC₅₀ = 16.30 ± 0.29 μM), and 18 (IC₅₀ = 32.60 ± 0.61 μM) 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.     

Molecular docking studies and synthesis of novel bisbenzimidazole derivatives as inhibitors of α-glucosidase

A series of bisbenzimidazole derivatives starting from o-phenylenediamine and 4-nitro-o-phenylenediamine were prepared with oxalic acid. Most of the reactions were conducted using both the microwave and conventional methods to compare yields and reaction times. The operational simplicity, environmental friendly conditions and high yield in a significantly short reaction time were the major benefits. All substances’ inhibitory activities against α-glucosidase were evaluated. The results may suggest a significant role for the nature of bisbenzimidazole compounds in their inhibitory action against α-glucosidase. They showed different range of α-glucosidase inhibitory potential with IC₅₀ value ranging between 0.44 ± 0.04 and 6.69 ± 0.01 μM when compared to the standard acarbose (IC₅₀, 13.34 ± 1.26 μM). This has described a new class of α-glucosidase inhibitors. Molecular docking studies were done for all compounds to identify important binding modes responsible for inhibition activity of α-glucosidase.     

Synthesis,in vitro evaluation and molecular docking studies of novel amide linked triazolyl glycoconjugates as new inhibitors of α-glucosidase

A series of N-substituted amide linked triazolyl β-d-glucopyranoside derivatives (4a-l) were synthesized and their in vitro inhibitory activity against yeast α-glucosidase enzyme [EC.3.2.1.20] was assessed. Compounds 4e (IC₅₀ = 156.06 μM), 4f (IC₅₀ = 147.94 μM), 4k (IC₅₀ = 127.71 μM) and 4l (IC₅₀ = 121.33 μM) were identified as the most potent inhibitors for α-glucosidase as compared to acarbose (IC₅₀ = 130.98 μM) under the same in vitro experimental conditions. Kinetic study showed that both 4e and 4f inhibit the enzyme in a competitive manner with p-nitrophenyl α-d-glucopyranoside as substrate. Molecular docking studies of 4e, 4f, 4k and 4l were also carried out using homology model of α-glucosidase to find out the binding modes responsible for the inhibitory activity. This study revealed that the binding affinity of compounds 4e, 4f, 4k and 4l for α-glucosidase were −8.2, −8.6, −8.3 and −8.5 kcal/mol respectively, compared to that of acarbose (−8.9 kcal/mol). The results suggest that the N-substituted amide linked triazole glycoconjugates can reasonably mimic the substrates for the yeast α-glucosidase.     

Synthesis of 1H-1,2,3-triazole derivatives as new α-glucosidase inhibitors and their molecular docking studies

Inhibition of α-glucosidase is an effective strategy for controlling the post-prandial hyperglycemia in diabetic patients. For the identification of new inhibitors of this enzyme, a series of new (R)-1-(2-(4-bromo-2-methoxyphenoxy) propyl)-4-(4-(trifluoromethyl) phenyl)-1H-1,2,3-triazole derivatives were synthesized (8a–d and 10a–e). The structures were confirmed by NMR, mass spectrometry and, in case of compound 8a, by single crystal X-ray crystallography. The α-glucosidase inhibitory activities were investigated in vitro. Most derivatives exhibited significant inhibitory activity against α-glucosidase enzyme. Their structure-activity relationship and molecular docking studies were performed to elucidate the active pharmacophore against this enzyme. Compound 10b was the most active analogue with IC₅₀ value of 14.2 µM, while compound 6 was found to be the least active having 218.1 µM. A preliminary structure-activity relationship suggested that the presence of 1H-1,2,3-triazole ring in 1H-1,2,3-triazole derivatives is responsible for this activity and can be used as anti-diabetic drugs. The molecular docking studies of all active compounds were performed, in order to understand the mode of binding interaction and the energy of this class of compounds.     

Synthesis of novel indenoquinoxaline derivatives as potent α-glucosidase inhibitors

A series of new N-(11H-Indeno[1,2-b]quinoxalin-11-ylidene)benzohydrazide derivatives (3a–3p) were synthesized and evaluated for their α-glucosidase inhibitory activity. The synthesized compounds 3d, 3f, 3g, 3k, 3n, 3p and 4 showed significant α-glucosidase inhibitory activity as compared to acrabose, a standard drug used to treat type II diabetes. Structures of the synthesized compounds were determined by using FT-IR, ¹H NMR, ¹³C NMR, mass spectrometry and elemental analysis techniques.     

Synthesis and biological evaluation of α-1-C-4′-arylbutyl-l-arabinoiminofuranoses,a new class of α-glucosidase inhibitors

A series of α-1-C-4′-arylbutyl-l-arabinoiminofuranoses 3 with functional groups attached to the phenyl ring, which are potential α-glycosidase inhibitors, was designed and synthesized by using a Negishi cross-coupling reaction as the key reaction. Arylbutyl derivatives 3a–e showed potent inhibitory activities against intestinal maltase. Among them, difluorophenylbutyl derivative 3e showed good inhibition activities against intestinal isomaltase and sucrase as compared to those of 1 and commercial drugs.     

The synthesis and biological evaluation of 1-C-alkyl-L-arabinoiminofuranoses, a novel class of α-glucosidase inhibitors

The asymmetric synthesis of 1-C-alkyl-l-arabinoiminofuranoses 1 was achieved by asymmetric allylic alkylation (AAA), ring closing metathesis (RCM), and Negishi cross coupling as key reactions. Some of the prepared compounds showed potent inhibitory activities towards intestinal maltase, with IC₅₀ values comparable to those of commercial drugs such as acarbose, voglibose, and miglitol, which are used in the treatment of type 2 diabetes. Among them, the inhibitory activity (IC₅₀ = 0.032 μM) towards intestinal sucrase of 1c was quite strong compared to the above commercial drugs.     

Hetarylcoumarins: Synthesis and biological evaluation as potent α-glucosidase inhibitors

In search of better α-glucosidase inhibitors, a series of novel hetarylcoumarins (3a-3j) were designed and synthesized through a facile multicomponent route where p-toluenesulfonic acid (PTSA) was explored as an efficient catalyst. These new scaffolds were further evaluated for their α-glucosidase inhibition potentials. All the derivatives exhibited good to excellent results which were comparable or even better than of standard drug acarbose. Of these compounds, a dihalogenated compound 3f was found to be the most effective one with IC₅₀: 2.53 ± 0.002 µM. Molecular docking has predicted the plausible binding interactions of compounds 3f, 3g and 3j with α-glucosidase.     

Pyrimidine-fused heterocycle derivatives as a novel class of inhibitors for α-glucosidase

The needs for diverse inhibitors of α-glucosidase (α-Gls) encouraged us to synthesize five different poly-hydroxy functionalized pyrimidine-fused heterocyclic (PHPFH) molecules, having either aliphatic or aromatic side chains (C₁–C₅) and their inhibitory activities were examined spectroscopically against yeast and mouse intestinal α-Gls. The results revealed that aromatic substitution of the synthetic compounds has significant impact on their inhibitory properties. Moreover C₃ with the substituted moiety as 4-(4-aminophenylsulfonyl) phenyl (4-APSP) revealed strong inhibitory activity with non-competitive and competitive inhibition modes against yeast and mouse α-Gls, respectively. Furthermore, in the presence of increasing concentration of C₃, both Trp and 1-anilinonaphthalene-8-sulfonic acid (ANS) fluorescence intensities of yeast α-Gls were gradually decreased, suggesting that C₃ binding induced significant structural alteration which was accompanied with the reduction of hydrophobic surfaces. Also, the interaction between yeast α-Gls and C₃ was proved to be spontaneous and driven mainly by hydrophobic forces. Overall, this study suggests that aromatic substitution on pyrimidine-fused heterocyclic (PFH) scaffold may represent a novel class of promising inhibitors of α-Gls.     

Benzimidazole derivatives as new α-glucosidase inhibitors and in silico studies

Newly synthesized benzimidazole hydrazone derivatives 1–26 were evaluated for their α-glucosidase inhibitory activity. Compounds 1–26 exhibited varying degrees of yeast α-glucosidase inhibitory activity with IC₅₀ values between 8.40 ± 0.76 and 179.71 ± 1.11 μM when compared with standard acarbose. In this assay, seven compounds that showed highest inhibitory effects than the rest of benzimidazole series were identified. All the synthesized compounds were characterized by different spectroscopic methods adequately. We further evaluated the interaction of the active compounds with enzyme with the help of docking studies.     

Synthesis,biological evaluation,and metabolic stability of chlorogenic acid derivatives possessing thiazole as potent inhibitors of α-MSH-stimulated melanogenesis

A series of catechol and dioxolane analogs containing thiazole CGA derivatives have been synthesized and evaluated for their inhibitory activity against α-MSH. The inhibitory activity was improved by replacing an α,β-unsaturated carbonyl of previously reported caffeamides with thiazole motif. Surprisingly, compound 7d, one of the derivatives of dioxolane analogs, displayed the most potent inhibitory activity with an IC₅₀ of 0.90 μM. Further studies on metabolic stability and bioactivation potential were also accomplished.     

Synthesis, α-glucosidase inhibition,and molecular docking studies of novel N-substituted hydrazide derivatives of atranorin as antidiabetic agents

A series of novel N-substituted hydrazide derivatives were synthesized by reacting atranorin, a compound with a natural depside structure (1), with a range of hydrazines. The natural product and 12 new analogues (2–13) were investigated for inhibition of α-glucosidase. The N-substituted hydrazide derivatives showed more potent inhibition than the original. The experimental results were confirmed by docking analysis. This study suggests that these compounds are promising molecules for diabetes therapy. Molecular dynamics simulations were carried out with compound 2 demonstrating the best docking model using Gromac during simulation up to 20 ns to explore the stability of the complex ligand-protein. Furthermore, the activity of all synthetic compounds 2–13 against a normal cell line HEK293, used for assessing their cytotoxicity, was evaluated.     

Synthesis,biological evaluation and SAR studies of ursolic acid 3β-ester derivatives as novel CETP inhibitors

Cholesteryl ester transfer protein (CETP) is an attractive therapeutic target for the prevention and treatment of cardiovascular diseases by lowering low-density lipoprotein cholesterol levels as well as raising high-density lipoprotein cholesterol levels in human plasma. Herein, a series of ursolic acid 3β-ester derivatives were designed, synthesized and evaluated for the CETP inhibiting activities. Among these compounds, the most active compound is U12 with an IC₅₀ value of 2.4 μM in enzymatic assay. The docking studies showed that the possible hydrogen bond interactions between the carboxyl groups at both ends of the molecule skeleton and several polar residues (such as Ser191, Cys13 and Ser230) in the active site region of CETP could significantly enhance the inhibition activity. This study provides structural insight of the interactions between these pentacyclic triterpenoid 3β-ester derivatives and CETP protein for the further modification and optimization.     

Design,synthesis and biological evaluation of metronidazole–thiazole derivatives as antibacterial inhibitors

A series of metronidazole–thiazole derivatives has been designed, synthesized and evaluated as potential antibacterial inhibitors. All the synthesized compounds were determined by elemental analysis, ¹H NMR and MS. They were also tested for antibacterial activity against Escherichia coli, Bacillus thuringiensis, Bacillus subtilis and Pseudomonas aeruginosa as well as for the inhibition to FabH. The results showed that compound 5e exhibited the most potent inhibitory activity against E. coli FabH with IC₅₀ of 4.9 μM. Molecular modeling simulation studies were performed in order to predict the biological activity of proposed compounds. Toxicity assay of compounds 5a, 5b, 5d, 5e, 5g and 5i showed that they were noncytotoxic against human macrophage. The results revealed that these compounds offered remarkable viability.     

A concise synthesis and evaluation of new malonamide derivatives as potential α-glucosidase inhibitors

A series of new malonamide derivatives were synthesized by Michael addition reaction of N¹,N³-di(pyridin-2-yl)malonamide into α,β-unsaturated ketones mediated by DBU in DCM at ambient temperature. The inhibitory potential of these compounds in vitro, against α-glucosidase enzyme was evaluated. Result showed that most of malonamide derivatives were identified as a potent inhibitors of α-glucosidase enzyme. Among all the compounds, 4K (IC₅₀ = 11.7 ± 0.5 μM) was found out as the most active one compared to standard drug acarbose (IC₅₀ = 840 ± 1.73 μM). Further cytotoxicity of 4a–4m were also evaluated against a number of cancer and normal cell lines and interesting results were obtained.     

Docking and SAR studies of salacinol derivatives as α-glucosidase inhibitors

Salacinol is a potent α-glucosidase inhibitor isolated from Salacia reticulata, and a good lead compound for an antidiabetic drug. It is essential to clarify the binding state of salacinol to α-glucosidase for efficient optimization study using structure-based drug design. Redocking simulations of two inhibitors, acarbose and casuarine whose complex structures are known, were performed to assure the appropriate docking pose prediction. The simulation reproduced both experimental binding states with accuracy. Then, using the same simulation protocol, the binding mode of salacinol and its derivatives has been predicted. Salacinol bound to the protein with a similar binding mode as casuarine, and the predicted structures could explain most of the structure–activity relationships of salacinol derivatives.