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.     

Dihydropyrimidones: As novel class of β-glucuronidase inhibitors

Dihydropyrimidones 1–37 were synthesized via a ‘one-pot’ three component reaction according to well-known Biginelli reaction by utilizing Cu(NO₃)₂·3H₂O as catalyst, and screened for their in vitro β-glucuronidase inhibitory activity. It is worth mentioning that amongst the active molecules, compounds 8 (IC₅₀ = 28.16 ± .056 μM), 9 (IC₅₀ = 18.16 ± 0.41 μM), 10 (IC₅₀ = 22.14 ± 0.43 μM), 13 (IC₅₀ = 34.16 ± 0.65 μM), 14 (IC₅₀ = 17.60 ± 0.35 μM), 15 (IC₅₀ = 15.19 ± 0.30 μM), 16 (IC₅₀ = 27.16 ± 0.48 μM), 17 (IC₅₀ = 48.16 ± 1.06 μM), 22 (IC₅₀ = 40.16 ± 0.85 μM), 23 (IC₅₀ = 44.16 ± 0.86 μM), 24 (IC₅₀ = 47.16 ± 0.92 μM), 25 (IC₅₀ = 18.19 ± 0.34 μM), 26 (IC₅₀ = 33.14 ± 0.68 μM), 27 (IC₅₀ = 44.16 ± 0.94 μM), 28 (IC₅₀ = 24.16 ± 0.50 μM), 29 (IC₅₀ = 34.24 ± 0.47 μM), 31 (IC₅₀ = 14.11 ± 0.21 μM) and 32 (IC₅₀ = 9.38 ± 0.15 μM) found to be more potent than the standard d-saccharic acid 1,4-lactone (IC₅₀ = 48.4 ± 1.25 μM). Molecular docking study was conducted to establish the structure–activity relationship (SAR) which demonstrated that a number of structural features of dihydropyrimidone derivatives were involved to exhibit the inhibitory potential. All compounds were characterized by spectroscopic techniques such as ¹H, ¹³C NMR, EIMS and HREI-MS.     

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.     

Unsymmetrically disubstituted urea derivatives: A potent class of antiglycating agents

A series of unsymmetrically disubstituted urea derivatives 1–28 has been synthesized and screened for their antiglycation activity in vitro. Compounds 26 (IC₅₀ = 4.26 ± 0.25 μM), 1 (IC₅₀ = 5.8 ± 0.08 μM), 22 (IC₅₀ = 4.26 ± 0.25 μM), 6 (IC₅₀ = 6.4 ± 0.02 μM), 5 (IC₅₀ = 6.6 ± 0.26 μM), 2 (IC₅₀ = 7.02 ± 0.31 μM), 3 (IC₅₀ = 7.14 ± 0.84 μM), 27 (IC₅₀ = 7.27 ± 0.36 μM), 4 (IC₅₀ = 8.16 ± 1.04 μM), 21 (IC₅₀ = 8.4 ± 0.15 μM), 23 (IC₅₀ = 9.0 ± 0.35 μM) and 13 (IC₅₀ = 15.22 ± 6.7 μM) showed an excellent antiglycation activity far better than the standard (rutin, IC₅₀ = 41.9 ± 2.3 μM). This study thus provides a series of potential molecules for further studies of antiglycation agents.     

Evaluation of bisindole as potent β-glucuronidase inhibitors: Synthesis and in silico based studies

Bisindole analogs 1–17 were synthesized and evaluated for their in vitro β-glucuronidase inhibitory potential. Out of seventeen compounds, the analog 1 (IC₅₀ = 1.62 ± 0.04 μM), 6 (IC₅₀ = 1.86 ± 0.05 μM), 10 (IC₅₀ = 2.80 ± 0.29 μM), 9 (IC₅₀ = 3.10 ± 0.28 μM), 14 (IC₅₀ = 4.30 ± 0.08 μM), 2 (IC₅₀ = 18.40 ± 0.09 μM), 19 (IC₅₀ = 19.90 ± 1.05 μM), 4 (IC₅₀ = 20.90 ± 0.62 μM), 7 (IC₅₀ = 21.50 ± 0.77 μM), and 3 (IC₅₀ = 22.30 ± 0.02 μM) showed superior β-glucuronidase inhibitory activity than the standard (d-saccharic acid 1,4-lactone, IC₅₀ = 48.40 ± 1.25 μM). In addition, molecular docking studies were performed to investigate the binding interactions of bisindole derivatives with the enzyme. This study has identified a new class of potent β-glucouronidase inhibitors.     

Synthesis of 6-chloro-2-Aryl-1H-imidazo[4,5-b]pyridine derivatives: Antidiabetic,antioxidant, β-glucuronidase inhibiton and their molecular docking studies

6-Chloro-2-Aryl-1H-imidazo[4,5-b]pyridine derivatives 1–26 were synthesized and characterized by various spectroscopic techniques. All these derivatives were evaluated for their antiglycation, antioxidant and β-glucuronidase potential followed their docking studies. In antiglycation assay, compound 2 (IC₅₀ = 240.10 ± 2.50 μM) and 4 (IC₅₀ = 240.30 ± 2.90 μM) was found to be most active compound of this series, while compounds 3 (IC₅₀ = 260.10 ± 2.50 μM), 6 (IC₅₀ = 290.60 ± 3.60 μM), 13 (IC₅₀ = 288.20 ± 3.00 μM) and 26 (IC₅₀ = 292.10 ± 3.20 μM) also showed better activities than the standard rutin (IC₅₀ = 294.50 ± 1.50 μM). In antioxidant assay, compound 1 (IC₅₀ = 69.45 ± 0.25 μM), 2 (IC₅₀ = 58.10 ± 2.50 μM), 3 (IC₅₀ = 74.25 ± 1.10 μM), and 4 (IC₅₀ = 72.50 ± 3.30 μM) showed good activities. In β-glucuronidase activity, compounds 3 (IC₅₀ = 29.25 ± 0.50 μM), compound 1 (IC₅₀ = 30.10 ± 0.60 μM) and compound 4 (IC₅₀ = 46.10 ± 1.10 μM) showed a significant activity as compared to than standard D-Saccharic acid 1,4-lactonec (IC₅₀ = 48.50 ± 1.25 μM) and their interaction with the enzyme was confirm by docking studies.     

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.     

Terpenoids with cytotoxic activity from the branches and leaves of Pyrus pashia

Twenty terpenoids, including a new triterpenoid (1) and a new monoterpenoid (20), were isolated from the branches and leaves of Pyrus pashia. The structures of two new compounds were determined to be 2α, 3β, 27-trihydroxyolean-12-en-28-oic acid (1) and (4α)-3-(5,5-dimethyltetrahydrofuranyl)-1-buten-3-ol 3-O-β-d-glucopyranoside (20) on the basis of spectroscopic analysis (IR, HRESIMS, 1D and 2D NMR) and chemical method. Some of the isolated compounds were evaluated for their cytotoxic activity against a panel of human cancer cell lines by MTT assay, using cisplatin as a positive control. Compound 14 exhibited cytotoxic activities against A549 (IC₅₀ = 19.18 ± 4.26 μM), Hela (IC₅₀ = 12.56 ± 3.89 μM), SGC7901 (IC₅₀ = 10.48 ± 1.95 μM) and NHI-1975 (IC₅₀ = 7.38 ± 2.31 μM) cell lines as well as compound 12 displayed cytotoxic activities against A549 (IC₅₀ = 14.71 ± 1.47 μM) and Hela (IC₅₀ = 12.22 ± 1.88 μM) cell lines.     

Synthesis of 2-methoxybenzoylhydrazone and evaluation of their antileishmanial activity

Compounds 1–25 showed varying degree of antileishmanial activities with IC₅₀ values ranging between 1.95 and 88.56 μM. Compounds 2, 10, and 11 (IC₅₀ = 3.29 ± 0.07 μM, 1.95 ± 0.04 μM, and 2.49 ± 0.03 μM, respectively) were found to be more active than standard pentamidine (IC₅₀ = 5.09 ± 0.04 μM). Compounds 7 (IC₅₀ = 7.64 ± 0.1 μM), 8 (IC₅₀ = 13.17 ± 0.46 μM), 18 (IC₅₀ = 13.15 ± 0.02 μM), and 24 (IC₅₀ = 15.65 ± 0.41 μM) exhibited good activities. Compounds 1, 3, 4, 5, 9, 12, 15, 18, and 19 were found to be moderately active. Compounds 13, 14, 16, 17, 20–25 showed weak activities with IC₅₀ values ranging between 57 and 88 μM.     

Schiff bases of 3-formylchromone as thymidine phosphorylase inhibitors

3-Formylchromone (1), 3-methyl-7-hydroxychromone (2) and Schiff bases of 3-formylchromone 3–19 have been synthesized and their anti-thymidine phosphorylase inhibitory activity was evaluated. Compounds 1–19 showed a varying degree of thymidine phosphorylase inhibition with IC₅₀ values 19.77 ± 3.25 to 480.21 ± 2.34 μM. Their activity was compared with the standard 7-deazaxanthine (IC₅₀ = 39.28 ± 0.76 μM). Compound 12 showed an excellent thymidine phosphorylase inhibitory activity with an IC₅₀ value of 19.77 ± 3.25 μM, better than the standard. Compound 4 also showed an excellent inhibitory activity (IC₅₀ = 40.29 ± 4.56 μM). The parent 3-formylchromone (1) and 3-methyl-7-hydroxychromone (2) were found to be inactive. The structures of the compounds were elucidated by using spectroscopic techniques, including ¹H NMR, EI MS, IR, UV and elemental analysis.     

Synthesis,molecular docking studies of hybrid benzimidazole as α-glucosidase inhibitor

Thiourea derivatives having benzimidazole 1–17 have been synthesized, characterized by ¹H NMR, ¹³C NMR and EI-MS and evaluated for α-glucosidase inhibition. Identification of potential α-glucosidase inhibitors were done by in vitro screening of 17 thiourea bearing benzimidazole derivatives using Baker’s yeast α-glucosidase enzyme. Compounds 1–17 exhibited a varying degree of α-glucosidase inhibitory activity with IC₅₀ values between 35.83 ± 0.66 and 297.99 ± 1.20 μM which are more better than the standard acarbose (IC₅₀ = 774.5 ± 1.94 μM). Compound 10 and 14 showed significant inhibitory effects with IC₅₀ value 50.57 ± 0.81 and 35.83 ± 0.66 μM, respectively better than the rest of the series. Structure activity relationships were established. Molecular docking studies were performed to understand the binding interaction of the compounds.     

Design,synthesis and preliminary activity assay of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives as novel Histone deacetylases (HDACs) inhibitors

Histone deacetylases (HDACs) are enzymes involved in tumor genesis and development. Herein, we report a novel series of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives as HDACs inhibitors. The preliminary biological screening showed that most of our compounds exhibited potent inhibitory activity against HDACs. Within this series, five compounds, 13a (IC₅₀ = 0.58 ± 0.10 μM), 7d (IC₅₀ = 1.00 ± 0.16 μM), 8l (IC₅₀ = 1.06 ± 0.14 μM), 7i (IC₅₀ = 1.17 ± 0.19 μM) and 7a (IC₅₀ = 1.29 ± 0.15 μM) possessed better HDACs inhibitory activity than Vorinostat (IC₅₀ = 1.48 ± 0.20 μM). So these five compounds could be used as novel lead compounds for further design of HDACs inhibitors. The anti-proliferative activities of a few compounds and the structure–activity relationships are also briefly discussed.     

Synthesis of bis-Schiff bases of isatins and their antiglycation activity

Bis-Schiff bases 1–27 have been synthesized and their in vitro antiglycation potential has been evaluated. Compounds 21 (IC₅₀ = 243.95 ± 4.59 μM), 20 (IC₅₀ = 257.61 ± 5.63 μM), and 7 (IC₅₀ = 291.14 ± 2.53 μM) showed an excellent antiglycation activity better than the standard (rutin, IC₅₀ = 294.46 ± 1.50 μM). This study has identified a series of potential molecules as antiglycation agents. A structure–activity relationship has been studied, and all the compounds were characterized by spectroscopic techniques.     

Isatin based Schiff bases as inhibitors of α-glucosidase: Synthesis,characterization, in vitro evaluation and molecular docking studies

Isatin base Schiff bases (1–20) were synthesized, characterized by ¹H NMR and EI/MS and evaluated for α-glucosidase inhibitory potential. Out of these twenty (20) compounds only six analogs showed potent α-glucosidase inhibitory potential with IC₅₀ value ranging in between 2.2 ± 0.25 and 83.5 ± 1.0 μM when compared with the standard acarbose (IC₅₀ = 840 ± 1.73 μM). Among the series compound 2 having IC₅₀ value (18.3 ± 0.56 μM), 9 (83.5 ± 1.0 μM), 11 (3.3 ± 0.25 μM), 12 (2.2 ± 0.25 μM), 14 (11.8 ± 0.15 μM), and 20 (3.0 ± 0.15 μM) showed excellent inhibitory potential many fold better than the standard acarbose. The binding interactions of these active analogs were confirmed through molecular docking.     

Design,synthesis and evaluation of novel metalloproteinase inhibitors based on l-tyrosine scaffold

A series of novel l-tyrosine derivatives were designed, synthesized and assayed for their inhibitory activities on matrix metalloproteinase 2 (MMP-2) and histone deacetylase 8 (HDAC-8). The results showed that these l-tyrosine derivatives exhibited inhibitory profiles against MMP-2 and HDAC-8. The compounds 6h (IC₅₀ = 0.013 ± 0.001 μM) and 6j (IC₅₀ = 0.017 ± 0.001 μM) were equal potent MMP-2 inhibitors to the positive control NNGH (IC₅₀ = 0.014 ± 0.001 μM). As for HDAC-8 inhibition, some of the hydroxamate compounds, such as 6d (IC₅₀ = 3.6 ± 0.2 μM) and 6c (IC₅₀ = 5.8 ± 0.5 μM), were equal potent to the positive control SAHA (IC₅₀ = 1.6 ± 0.1 μM). Structure–activity relationships were also briefly discussed.     

Synthesis of alpha amylase inhibitors based on privileged indole scaffold

Twenty five derivatives of indole carbohydrazide (1–25) had been synthesized. These compounds were characterized using ¹H NMR and EI-MS, and further evaluated for their α-amylase inhibitory potential. The analogs (1–25) showed varying degree of α-amylase inhibitory potential.ranging between 9.28 and 599.0 µM when compared with standard acarbose having IC₅₀ value 8.78 ± 0.16 µM. Six analogs, 25 (IC₅₀ = 9.28 ± 0.153 µM), 22 (IC₅₀ = 9.79 ± 0.43 µM), 4 (IC₅₀ = 11.08 ± 0.357 µM), 1 (IC₅₀ = 12.65 ± 0.169 µM), 8 (IC₅₀ = 21.37 ± 0.07 µM) and 14 (IC₅₀ = 43.21 ± 0.14 µM) showed potent α-amylase inhibition as compared to the standard acarbose (IC₅₀ = 8.78 ± 0.16 µM). All other analogs displayed good to moderate inhibitory potential. Structure-activity relationship was established through the interaction of the active compounds with enzyme active site with the help of docking studies.     

Synthesis of triazole Schiff bases: Novel inhibitors of nucleotide pyrophosphatase/phosphodiesterase-1

A series of Schiff base triazoles 1–25 was synthesized and evaluated for their nucleotide pyrophosphatase/phosphodiesterase-1 inhibitory activities. Among twenty-five compounds, three compounds 10 (IC₅₀ = 132.20 ± 2.89 μM), 13 (IC₅₀ = 152.83 ± 2.39 μM), and 22 (IC₅₀ = 251.0 ± 6.64 μM) were identified as potent inhibitors with superior activities than the standard EDTA (IC₅₀ = 277.69 ± 2.52 μM). The newly identified inhibitors may open a new avenue for the development of treatment of phosphodiesterase-I related disorders. These compounds were also evaluated for carbonic anhydrase, acetylcholinesterase and butyrylcholinesterase inhibitory potential and were found to be inactive. The compounds showed non-toxic effect towards PC3 cell lines.     

Facile synthesis of novel substituted aryl-thiazole (SAT) analogs via one-pot multi-component reaction as potent cytotoxic agents against cancer cell lines

In this study, twenty-five (25) substituted aryl thiazoles (SAT) 1–25 were synthesized, and their in vitro cytotoxicity was evaluated against four cancer cell lines, MCF-7 (ER^+ve breast), MDA-MB-231 (ER^−ve breast), HCT116 (colorectal) and HeLa (cervical). The activity was compared with the standard anticancer drug doxorubicin (IC₅₀ = 1.56 ± 0.05 μM). Among them, compounds 1, 4–8, and 19 were found to be toxic to all four cancer cell lines (IC₅₀ values 5.37 ± 0.56–46.72 ± 1.80 μM). Compound 20 was selectively active against MCF7 breast cancer cells with IC₅₀ of 40.21 ± 4.15 μM, whereas compound 19 was active against MCF7 and HeLa cells with IC₅₀ of 46.72 ± 1.8, and 19.86 ± 0.11 μM, respectively. These results suggest that substituted aryl thiazoles 1 and 4 deserve to be further investigated in vivo as anticancer leads.     

Thiadiazole derivatives as New Class of β-glucuronidase inhibitors

Thiadiazole derivatives 1–24 were synthesized via a single step reaction and screened for in vitro β-glucuronidase inhibitory activity. All the synthetic compounds displayed good inhibitory activity in the range of IC₅₀ = 2.16 ± 0.01–58.06 ± 1.60 μM as compare to standard d-saccharic acid 1,4-lactone (IC₅₀ = 48.4 ± 1.25 μM). Molecular docking study was conducted in order to establish the structure–activity relationship (SAR) which demonstrated that thiadiazole as well as both aryl moieties (aryl and N-aryl) involved to exhibit the inhibitory potential. All the synthetic compounds were characterized by spectroscopic techniques ¹H, ¹³C NMR, and EIMS.     

Synthesis and in silico studies of novel sulfonamides having oxadiazole ring: As β-glucuronidase inhibitors

Novel sulfonamides having oxadiazole ring were synthesized by multistep reaction and evaluated to check in vitro β-glucuronidase inhibitory activity. Luckily, except compound 13, all compounds were found to demonstrate good inhibitory activity in the range of IC₅₀ = 2.40 ± 0.01–58.06 ± 1.60 μM when compared to the standard d-saccharic acid 1,4-lactone (IC₅₀ = 48.4 ± 1.25 μM). Structure activity relationship was also presented. However, in order to ensure the SAR as well as the molecular interactions of compounds with the active site of enzyme, molecular docking studies on most active compounds 19, 16, 4 and 6 was carried out. All derivatives were fully characterized by ¹H NMR, ¹³C NMR and EI-MS spectroscopic techniques. CHN analysis was also presented.