Startseite Naturwissenschaften A new series of 2,4-thiazolidinediones endowed with potent aldose reductase inhibitory activity
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A new series of 2,4-thiazolidinediones endowed with potent aldose reductase inhibitory activity

  • Belgin Sever , Mehlika Dilek Altıntop EMAIL logo , Yeliz Demir , Cüneyt Türkeş , Kaan Özbaş , Gülşen Akalın Çiftçi , Şükrü Beydemir EMAIL logo und Ahmet Özdemir
Veröffentlicht/Copyright: 10. März 2021
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Open Chemistry
Aus der Zeitschrift Open Chemistry Band 19 Heft 1

Abstract

In an effort to identify potent aldose reductase (AR) inhibitors, 5-(arylidene)thiazolidine-2,4-diones (1–8), which were prepared by the solvent-free reaction of 2,4-thiazolidinedione with aromatic aldehydes in the presence of urea, were examined for their in vitro AR inhibitory activities and cytotoxicity. 5-(2-Hydroxy-3-methylbenzylidene)thiazolidine-2,4-dione (3) was the most potent AR inhibitor in this series, exerting uncompetitive inhibition with a K i value of 0.445 ± 0.013 µM. The IC50 value of compound 3 for L929 mouse fibroblast cells was determined as 8.9 ± 0.66 µM, pointing out its safety as an AR inhibitor. Molecular docking studies suggested that compound 3 exhibited good affinity to the binding site of AR (PDB ID: 4JIR). Based upon in silico absorption, distribution, metabolism, and excretion data, the compound is predicted to have favorable pharmacokinetic features. Taking into account the in silico and in vitro data, compound 3 stands out as a potential orally bioavailable AR inhibitor for the management of diabetic complications as well as nondiabetic diseases.

Graphical abstract

5-(2-Hydroxy-3-methylbenzylidene)thiazolidine-2,4-dione (3) was identified as the most potent AR inhibitor in this series, exerting uncompetitive inhibition with a K i value of 0.445 ± 0.013 µM.

Keywords: aldose reductase; thiazolidinedione; cytotoxicity; molecular docking

1 Introduction

Type 2 diabetes (T2D) is a chronic life-threatening disease characterized by abnormally high blood glucose levels resulting from impaired response of target tissues to insulin (insulin resistance) and/or progressively reduced function of pancreatic β cells. The global burden of T2D is increasing considerably, and therefore there is an urgent need to develop safe and potent antidiabetic agents [1,2,3,4,5].

Polyol pathway is a two-step metabolic pathway in which glucose is reduced to sorbitol, which is then converted to fructose. The abnormally activated polyol pathway has been reported to participate in the pathogenesis of T2D complications [5,6,7,8,9,10,11].

Aldose reductase (AR) catalyzes the NADPH-dependent reduction of glucose to sorbitol as the first and rate-limiting enzyme of the polyol pathway. Under euglycemic conditions, the reduction of glucose is a minor function of AR owing to the relatively low affinity (high K m) of AR for this substrate. However, under hyperglycemic conditions, excess intracellular glucose leads to an increase in the enzymatic conversion of glucose to sorbitol, NADPH-consuming reaction in tissues possessing insulin-independent glucose transport. Sorbitol does not diffuse readily through cell membranes due to its strong hydrophilic feature and accumulates in cells causing osmotic stress and cellular damage, particularly in lenses. Furthermore, the concurrent NADPH deprivation impairs the activity of other NADPH-dependent enzymes and causes an imbalance between the generation of intracellular reactive oxygen species and cellular antioxidant defense. Concomitantly, pseudohypoxia, which results from the NAD+ depletion during the oxidation of sorbitol to fructose by sorbitol dehydrogenase, causes further metabolic and signaling alterations by exacerbating redox imbalance. Fructose, the end product of the polyol pathway, is more reactive than glucose as a glycating agent; and the increased formation of fructose also gives rise to pathological conditions by promoting protein glycation and the formation of advanced glycation end products and thus leading to alterations in protein functions. Apart from its role in T2D complications, AR is an important mediator in oxidative and inflammatory-signaling pathways implicated in the pathophysiology of cardiovascular disorders, sepsis, and cancer. In this context, AR is identified as a multidisease target for the design of potent agents able to counteract the development of long-term T2D complications as well as nondiabetic diseases [5,6,7,8,9,10,11,12,13].

The recent findings related to the pathophysiological role of AR have led to the discovery of a great variety of AR inhibitors so far, and most of them have been evaluated in preclinical and clinical trials. However, their development is mostly hampered by low in vivo potency, adverse effects, or pharmacokinetic drawbacks [5,6,7,8,9,10,11,12,13].

2,4-Thiazolidinedione (TZD) stands out as a privileged scaffold for the identification of promising therapeutic agents for the management of T2D, targeting a plethora of crucial enzymes/receptors such as peroxisome proliferator-activated receptor gamma, AR, protein tyrosine phosphatase 1B, and so on [14,15,16,17,18,19,20,21,22,23,24,25,26]. In the search for novel AR inhibitors, 2,4-TZDs are of great importance as safer bioisosteres of hydantoin, which is considered as the main cause of hypersensitivity reactions provoked by some AR inhibitors, such as sorbinil. Currently, only epalrestat (EPR) bearing a 2-thioxo-4-thiazolidinone scaffold (Figure 1) is commercially available in few Asian countries (such as Japan and India) as an AR inhibitor approved for the management of diabetic neuropathy. This agent is able to slow the progression of diabetic neuropathy and ameliorate its symptoms without any serious side effects after long-term use. However, further long-term comparative studies should be carried out to elucidate its efficacy in different patient populations [5].

Figure 1 Epalrestat.
Figure 1

Epalrestat.

Taking into account the knowledge obtained so far [5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26] and the potential of TZD-based small molecules as AR inhibitors [14,15,16,17,18,19,20,21,22,23,24,25,26], herein we reported the preparation of new 2,4-TZDs and in vitro studies related to their AR inhibitory activities and cytotoxicity toward L929 mouse fibroblast cell line. In an effort to explore their possible binding modes in the binding site of AR, molecular docking studies were performed. In silico absorption, distribution, metabolism, and excretion (ADME) studies were also carried out to estimate their physicochemical parameters for the evaluation of their oral bioavailability and drug likeness.

2 Experimental section

2.1 Chemistry

2.1.1 General

2,4-TZD and urea were procured from Acros Organics (Geel, Belgium) and VWR Chemicals (Leuven, Belgium), respectively. Aromatic aldehydes were purchased from Alfa Aesar (Karlsruhe, Germany) or Sigma-Aldrich (St. Louis, MO, USA). Melting points (MPs) were detected using Electrothermal IA9200 MP apparatus (Staffordshire, UK). Infrared (IR), nuclear magnetic resonance (NMR; 1H and 13C), mass spectra, and elemental analyses were recorded on IRPrestige-21 FT-IR spectrophotometer (Shimadzu, Tokyo, Japan), Varian 400 MHz FT-NMR spectrometer (Agilent, Palo Alto, CA, USA), VG Quattro Mass spectrometer (Agilent, Minnesota, USA), and Perkin Elmer EAL 240 elemental analyzer (Perkin-Elmer, Norwalk, CT, USA), respectively.

2.1.2 Synthesis of 5-(arylidene)thiazolidine-2,4-diones (1–8)

A mixture of aromatic aldehyde (2 mmol) and 2,4-TZD (2 mmol) in the presence of urea (20 mmol) was heated in an oil bath at 150°C for 2 h. Upon completion of the reaction, it was then dispersed with hot water and collected by filtration. The product was crystallized from ethanol [27].

2.1.2.1 5-(2-Fluoro-4-methoxybenzylidene)thiazolidine-2,4-dione (1)

Yield: 88%. MP: 215–220°C.

IR ν max (cm−1): 3450.65, 3367.71, 3080.32, 3007.02, 2843.07, 1728.22, 1708.93, 1668.43, 1616.35, 1593.20, 1573.91, 1506.41, 1436.97, 1388.75, 1342.46, 1313.52, 1294.24, 1269.16, 1251.80, 1190.08, 1161.15, 1093.64, 1028.06, 950.91, 871.82, 858.32, 825.53, 806.25, 756.10, 729.09, 713.66, 692.44, and 646.15.

1H NMR (400 MHz, DMSO-d 6 ) δ (ppm): 3.80 (s, 3H), 6.38 (s, 1H), 6.86–6.89 (m, 1H), 7.68 (d, J = 9.6 Hz, 1H), 8.49 (s, 1H), 10.41, and 11.18 (2 s, 1H).

13C NMR (100 MHz, DMSO-d 6 ) δ (ppm): 55.76 (CH3), 101.61 (d, J = 25.0 Hz, CH), 110.79 (CH), 113.05 (d, J = 12.8 Hz, C), 116.12 (C), 127.85 (CH), 130.23 (d, J = 3.8 Hz, CH), 155.41 (C), 160.85 (d, J = 11.5 Hz, C), 165.23 (C), and 167.44 (C).

MS (FAB) m/z 254.11 [M + H]+.

Anal. Calcd. for C11H8FNO3S: C, 52.17; H, 3.18; and N, 5.53. Found: C, 52.15; H, 3.19; and N, 5.54.

2.1.2.2 5-(2-Fluoro-5-methoxybenzylidene)thiazolidine-2,4-dione (2)

Yield: 55%. MP: 235–240°C.

IR ν max (cm−1): 3466.08, 3045.60, 2945.30, 2835.36, 1728.22, 1666.50, 1593.20, 1496.76, 1463.97, 1419.61, 1382.96, 1323.17, 1282.66, 1211.30, 1099.43, 1031.92, 1012.63, 956.69, 877.61, 839.03, 804.32, 758.02, 711.73, 694.37, and 644.22.

1H NMR (400 MHz, DMSO-d 6 ) δ (ppm): 3.80 (s, 3H), 6.38 (s, 1H), 6.88–6.92 (m, 1H), 7.12–7.17 (m, 2H), 10.66, and 11.18 (2 brs, 1H).

13C NMR (100 MHz, DMSO-d 6 ) δ (ppm): 55.70 (CH3), 113.73 (d, J = 1.9 Hz, CH), 115.78 (CH), 115.88 (d, J = 3.2 Hz, CH), 116.12 (C), 121.23 (d, J = 14.1 Hz, C), 129.86 (d, J = 1.9 Hz, CH), 155.53 (C), 160.79 (C), 165.13 (C), and 167.44 (C).

MS (FAB) m/z 254.14 [M + H]+.

Anal. Calcd. for C11H8FNO3S: C, 52.17; H, 3.18; and N, 5.53. Found: C, 52.19; H, 3.17; and N, 5.52.

2.1.2.3 5-(2-Hydroxy-3-methylbenzylidene)thiazolidine-2,4-dione (3)

Yield: 36%. MP: 168–170°C.

IR ν max (cm−1): 3541.31, 3431.36, 3336.85, 3050.46, 2924.09, 2858.51, 1693.50, 1681.93, 1600.92, 1525.69, 1469.76, 1435.04, 1381.03, 1265.30, 1188.15, 1095.57, 1039.63, 765.74, 746.45, 680.87, and 650.01.

1H NMR (400 MHz, DMSO-d 6 ) δ (ppm): 2.30 (s, 3H), 6.66–7.44 (m, 3H), 8.50 (s, 1H), 10.12 (s, 1H), 10.41, and 11.18 (2 s, 1H).

13C NMR (100 MHz, DMSO-d 6 ) δ (ppm): 15.23 (CH3), 116.10 (C), 116.40 (C), 122.43 (CH), 125.82 (CH), 126.11 (C), 129.86 (CH), 131.20 (CH), 150.15 (C), 165.13 (C), and 167.44 (C).

MS (FAB) m/z 236.16 [M + H]+.

Anal. Calcd. for C11H9NO3S: C, 56.16; H, 3.86; and N, 5.95. Found: C, 56.13; H, 3.87; and N, 5.97.

2.1.2.4 5-(2-Hydroxy-5-methoxy-3-nitrobenzylidene)thiazolidine-2,4-dione (4)

Yield: 74%. MP: 245–246°C.

IR ν max (cm−1): 3562.52, 3425.58, 3334.92, 3076.46, 2945.30, 1693.50, 1681.93, 1668.43, 1598.99, 1537.27, 1531.48, 1454.33, 1344.38, 1307.74, 1242.16, 1197.79, 1166.93, 1095.57, 1041.56, 929.69, 837.11, 752.24, and 665.44.

1H NMR (400 MHz, DMSO-d 6 ) δ (ppm): 3.81 (s, 3H), 6.72–6.88 (m, 1H), 7.87–8.02 (m, 1H), 8.47 (s, 1H), 10.26 (s, 1H), and 11.10 (brs, 1H).

13C NMR (100 MHz, DMSO-d 6 ) δ (ppm): 55.78 (CH3), 108.20 (CH), 116.06 (C), 118.01 (CH), 118.42 (C), 135.55 (CH), 137.90 (C), 145.44 (C), 155.05 (C), 165.30 (C), and 167.40 (C).

MS (FAB) m/z 297.14 [M + H]+.

Anal. Calcd. for C11H8N2O6S: C, 44.60; H, 2.72; and N, 9.46. Found: C, 44.63; H, 2.71; and N, 9.44.

2.1.2.5 5-(3-Chloro-4-fluorobenzylidene)thiazolidine-2,4-dione (5)

Yield: 68%. MP: 218–224°C.

IR ν max (cm−1): 3444.87, 3387.00, 3037.89, 1737.86, 1708.93, 1668.43, 1591.27, 1504.48, 1435.04, 1346.31, 1263.37, 1195.87, 1126.43, 1091.71, 1060.85, 1024.20, 920.05, 898.83, 864.11, 819.75, 792.74, 756.10, 729.09, 709.80, 675.09, and 642.30.

1H NMR (400 MHz, DMSO-d 6 ) δ (ppm): 6.37 (s, 1H), 7.39 (t, J = 8.8 Hz, 1H), 7.83 (d, J = 5.6 Hz, 1H), 8.49 (s, 1H), 10.67, and 11.25 (2 brs, 1H).

13C NMR (100 MHz, DMSO-d 6 ) δ (ppm): 116.91 (C), 117.02 (d, J = 21.2 Hz, CH), 120.09 (d, J = 17.3 Hz, C), 128.70 (d, J = 1.9 Hz, CH), 130.15 (d, J = 7.0 Hz, CH), 130.72 (C), 130.96 (d, J = 3.8 Hz, CH), 155.38 (C), 165.27 (C), and 167.45 (C).

MS (FAB) m/z 258.06 [M + H]+.

Anal. Calcd. for C10H5ClFNO2S: C, 61.78; H, 4.75; and N, 6.00. Found: C, 61.81; H, 4.73; and N, 6.01.

2.1.2.6 5-(3-Chloro-4-methylbenzylidene)thiazolidine-2,4-dione (6)

Yield: 83%. MP: 225–230°C.

IR ν max (cm−1): 3456.44, 3375.43, 3028.24, 2929.87, 1728.22, 1710.86, 1660.71, 1589.34, 1496.76, 1440.83, 1392.61, 1361.74, 1334.74, 1284.59, 1253.73, 1219.01, 1188.15, 1124.50, 1087.85, 1053.13, 1031.92, 997.20, 906.54, 887.26, 860.25, 821.68, 756.10, 711.73, 675.09, 644.22, and 632.65.

1H NMR (400 MHz, DMSO-d 6 ) δ (ppm): 2.32 (s, 3H), 6.35 (s, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.66 (s, 1H), 8.48 (s, 1H), 10.61, and 11.21 (2 brs, 1H).

13C NMR (100 MHz, DMSO-d 6 ) δ (ppm): 19.35 (CH3), 116.91 (C), 127.94 (CH), 128.29 (CH), 128.97 (CH), 131.29 (C), 132.52 (C), 133.80 (C), 135.55 (CH), 165.35 (C), and 167.45 (C).

MS (FAB) m/z 254.17 [M + H]+.

Anal. Calcd. for C11H8ClNO2S: C, 52.08; H, 3.18; and N, 5.52. Found: C, 52.05; H, 3.20; and N, 5.52.

2.1.2.7 5-(3-Methoxy-2-nitrobenzylidene)thiazolidine-2,4-dione (7)

Yield: 43%. MP: 190–195°C.

IR ν max (cm−1): 3323.35, 3022.45, 2941.44, 2837.29, 1658.78, 1651.07, 1598.99, 1537.27, 1454.33, 1402.25, 1359.82, 1261.45, 1178.51, 1118.71, 1068.56, 1039.63, 995.27, 852.54, 732.95, and 642.30.

1H NMR (400 MHz, DMSO-d 6 ) δ (ppm): 3.83 (s, 3H), 6.85–7.90 (m, 3H), 8.69 (s, 1H), and 11.10 (brs, 1H).

13C NMR (100 MHz, DMSO-d 6 ) δ (ppm): 55.76 (CH3), 114.40 (CH), 116.50 (C), 119.69 (CH), 128.90 (C), 131.30 (C), 134.99 (CH), 136.56 (CH), 155.41 (C), 165.36 (C), and 167.47 (C).

MS (FAB) m/z 281.16 [M + H]+.

Anal. Calcd. for C11H8N2O5S: C, 47.14; H, 2.88; and N, 10.00. Found: C, 47.11; H, 2.89; and N, 10.02.

2.1.2.8 5-(5-Chloro-2-hydroxy-3-methylbenzylidene)thiazolidine-2,4-dione (8)

Yield: 40%. MP: 160–165°C.

IR ν max (cm−1): 3541.31, 3454.51, 3334.92, 3076.46, 2927.94, 1693.50, 1681.93, 1598.99, 1566.20, 1514.12, 1469.76, 1435.04, 1381.03, 1311.59, 1192.01, 1120.64, 1043.49, 900.76, 864.11, 752.24, 731.02, 651.94, and 634.58.

1H NMR (400 MHz, DMSO-d 6 ) δ (ppm): 2.26 (s, 3H), 6.92–7.68 (m, 2H), 8.51 (s, 1H), 10.21 (s, 1H), and 11.10 (brs, 1H).

13C NMR (100 MHz, DMSO-d 6 ) δ (ppm): 15.25 (CH3), 116.61 (C), 117.89 (C), 124.78 (CH), 126.76 (C), 129.39 (CH), 132.80 (C), 135.56 (CH), 150.15 (C), 165.31 (C), and 167.42 (C).

MS (FAB) m/z 270.12 [M + H]+.

Anal. Calcd. for C11H8ClNO3S: C, 48.99; H, 2.99; and N, 5.19. Found: C, 48.98; H, 2.97; and N, 5.21.

2.2 Biochemistry

2.2.1 AR activity assay

Purification of sheep liver AR was done according to the previous studies [28,29,30,31,32]. Bradford method was utilized to determine the quantitative protein [33]. The enzyme purity was checked according to Laemmli’s procedure [34,35]. AR activity was spectrophotometrically evaluated based on the decrease in absorbance of NADPH at 340 nm [36,37,38].

2.2.2 In vitro inhibition studies

The AR activity was determined in the presence of different concentrations of compounds 1–8. The IC50 value of each compound was calculated from activity%–[Compound] graphs [36]. For determining the inhibition types of the compounds, Lineweaver–Burk graph was plotted [39] according to the previous works [40,41,42].

2.2.3 Cell culture and drug treatment

The L929 mouse fibroblast cells (ATCC, CCL-1TM) (Manassas, VA, USA) were cultured and drug treatments were performed as previously reported [42].

2.2.4 MTT assay

MTT test was performed to examine the cytotoxic effects of compounds 1–8 on the L929 cells as previously explained [43] but with minor modifications [42].

The percentage of the viable cells was calculated using the following formula: (%) = [100 × (sample absorbance)/(control absorbance)].

2.2.5 Statistical studies

GraphPad Prism version 7 for Mac (GraphPad Software, La Jolla, CA, USA) was used for data analysis and graphs. SigmaPlot version 12 for Windows (Systat Software, San Jose, CA, USA) was performed to calculate the inhibition constants. The fit of enzyme inhibition models was compared using the extra sum-of-squares F test and the Akaike’s corrected Information Criterion (AICc) approach. The results were expressed as mean ± standard error of the mean (95% confidence intervals). Differences between data sets were considered statistically significant when the p value was less than 0.05.

2.3 Molecular docking studies

Molecular docking simulations were conducted using panels (LigPrep [44], Maestro [45], Prime molecular mechanics–generalized Born surface area [MM-GBSA] [46], Protein Preparation Wizard [47], and Receptor Grid Generation [48]) in the Schrödinger Suite 2020-2 for Mac. The high-resolution 3D crystal structure of AR (PDB ID: 4JIR; 2.00 Å) [49] was downloaded from RCSB Protein Data Bank [50] and used for molecular docking. Protein Preparation Wizard [51] was used to prepare the crystal structure [52]. The 3D structures of compounds 1–8 were sketched using ChemDraw Pro version 19.1 for Mac [53] (PerkinElmer, Inc., Waltham, MA, USA). The molecules were subjected to ligand preparation using LigPrep tool [54] in default conditions at pH 7.4 ± 0.5 [55] with Epik [56] in the OPLS3e force field [57,58]. Receptor Grid Generation tool [59] was used to generate the grid for docking. Binding sites were defined using cocrystallized natural ligand (EPR). Glide extra precision (Glide XP) [60,61] was used for docking [62]. Docked poses were rescored using the MM-GBSA approach [63,64].

2.4 In silico ADME studies

QikProp, a predictive ADME module within the Maestro suite produced by Schrödinger, was performed to predict the ADME properties of compounds 1–8.

  1. Ethical approval: The conducted research is not related to either human or animal use.

3 Results and discussion

3.1 Chemistry

The preparation of the hitherto unreported 5-(arylidene)thiazolidine-2,4-diones (1–8) was carried out through the solvent-free reaction of 2,4-TZD with aromatic aldehydes in the presence of urea (Scheme 1).

Scheme 1 The synthetic route for the preparation of compounds 1–8. Reagents and conditions: (i) NH2CONH2, oil bath, 150°C, 2 h.
Scheme 1

The synthetic route for the preparation of compounds 1–8. Reagents and conditions: (i) NH2CONH2, oil bath, 150°C, 2 h.

The structures of compounds 1–8 were verified by IR, 1H NMR, 13C NMR, mass spectrometry and elemental analyses. In their IR spectra, the C═O stretching vibrations resulted in the formation of two characteristic bands at 1737.86–1651.07 cm−1. The N–H stretching vibration belonging to the N–H proton of the thiazolidine scaffold gave rise to the bands in the region 3466.08–3323.35 cm−1. In the IR spectra of compounds 3, 4, and 8, the O–H stretching band appeared at 3562.52–3541.31 cm−1. In the 1H NMR spectra of all compounds except compound 2, the signal due to the benzylidene CH proton was observed at 8.47–8.69 ppm as a singlet. In the 1H NMR spectra of compounds 4, 7, and 8, the signal due to the N–H proton appeared at 11.10 ppm as a broad singlet, whereas in the 1H NMR spectra of other compounds, the signal due to the N–H proton appeared in the region 10.41–11.25 ppm as two singlets or broad singlets. In the 1H NMR spectra of methoxy-substituted compounds 1, 2, 4, and 7, the signal due to the methoxy protons was observed in the region 3.80–3.83 ppm as a singlet. In the 1H NMR spectra of methyl-substituted compounds 3, 6, and 8, the signal due to the methyl protons occurred in the region 2.26–2.32 ppm as a singlet. The O–H proton gave rise to a singlet peak at 10.12–10.26 ppm in the 1H NMR spectra of compounds 3, 4, and 8. In the 13C NMR spectra of compounds 1–8, the signals due to the carbons of two C═O groups were observed in the region 165.13–167.47 ppm. The signal due to the benzylidene CH carbon appeared at 129.86–136.56 ppm. In the 13C NMR spectra of methoxy-substituted compounds 1, 2, 4, and 7, the methoxy carbon gave rise to the peak at 55.70–55.78 ppm. In the 13C NMR spectra of methyl-substituted compounds 3, 6, and 8, the signal due to the methyl carbon occurred in the region 15.23–19.35 ppm.

3.2 In vitro AR inhibitory activity and cytotoxicity

The IC50, K i, and inhibition types of compounds 1–8 were determined to investigate their ability to inhibit AR (Table 1). According to in vitro data, compounds 1–8 showed inhibitory effects on AR, with IC50 values ranging from 0.273 to 0.533 µM and K i values ranging from 0.445 to 0.943 µM (Figure 2). Compounds 1, 3, and 5 were found to act as uncompetitive AR inhibitors, whereas other compounds were identified as noncompetitive AR inhibitors. The order of 2,4-TZD-based AR inhibitors (1–8) (from the most active to the least active) according to their K i values was noted to be as follows: compound 3 > compound 1 > compound 2 > compound 7 > compound 6 > compound 4 > compound 5 > compound 8. The in vitro data pointed out the significance of the arylidene group at the fifth position of 2,4-TZD scaffold. The introduction of a chlorine group into the fifth position of the benzylidene moiety of compound 3 (IC50 = 0.382 ± 0.010 µM, K i = 0.445 ± 0.013 µM) led to a substantial decrease in AR inhibitory potency (IC50 = 0.533 ± 0.015 µM, K i = 0.943 ± 0.024 µM for compound 8) and an alteration in inhibition type (the inhibition type of compound 3 was uncompetitive, while the inhibition type of compound 8 was noncompetitive).

Table 1

AR inhibition data of compounds 1–8

Compound R IC50 (µM) R 2 K i (µM) R 2 Inhibition type
1 2-F-4-OCH3 0.375 ± 0.007 0.9970 0.462 ± 0.015 0.9964 Uncompetitive
2 2-F-5-OCH3 0.273 ± 0.004 0.9981 0.549 ± 0.023 0.9923 Non-competitive
3 2-OH-3-CH3 0.382 ± 0.010 0.9955 0.445 ± 0.013 0.9982 Uncompetitive
4 2-OH-5-OCH3-3-NO2 0.349 ± 0.003 0.9994 0.769 ± 0.017 0.9977 Non-competitive
5 3-Cl-4-F 0.398 ± 0.011 0.9920 0.892 ± 0.020 0.9983 Uncompetitive
6 3-Cl-4-CH3 0.411 ± 0.005 0.9991 0.729 ± 0.019 0.9957 Non-competitive
7 3-OCH3-2-NO2 0.455 ± 0.008 0.9963 0.713 ± 0.014 0.9976 Non-competitive
8 2-OH-3-CH3-5-Cl 0.533 ± 0.015 0.9935 0.943 ± 0.024 0.9960 Non-competitive

The test results were indicated as mean ± standard deviation.

Figure 2 (a) Percentage activity versus inhibitor concentration graph of compound 3 at five different concentrations. (b) Lineweaver–Burk plot of compound 3.
Figure 2

(a) Percentage activity versus inhibitor concentration graph of compound 3 at five different concentrations. (b) Lineweaver–Burk plot of compound 3.

In the search for AR inhibitors for the management of T2D and its complications, the identification of potent therapeutic agents endowed with favorable pharmacokinetic profiles as well as devoid of severe unwanted effects is an uphill task for researchers [5]. On this basis, herein the cytotoxic activities of compounds 1–8 against L929 mouse fibroblast (healthy) cells were determined (Table 2). According to the MTT assay, all compounds did not show significant cytotoxicity toward L929 cells at their effective concentrations. The IC50 values of compounds 2–6 for L929 cells were found to be between 1.43 and 8.9 µM, while the IC50 values of compounds 7 and 8 for L929 cell line were higher than 25 µM, pointing out the safety of compounds 2–8 as AR inhibitors. However, the IC50 value of compound 1 for L929 cells (IC50 = 0.55 ± 0.07 µM) was slightly close to its IC50 value for AR inhibition (IC50 = 0.375 ± 0.007 µM). The effects of compound 1 on percentages of L929 cell viability at different concentrations (0.39, 0.78, and 6.26 µM) were found as 68.85 ± 2.47, 38.61 ± 14.71, and 31.60 ± 3.15, respectively (p < 0.05). These results showed that compound 1 caused dose-dependent cytotoxicity on L929 cell line at tested concentrations. On the other hand, the effects of compound 3 on percentages of L929 cell viability at different concentrations (0.78, 6.26, and 12.5 µM) were determined as 92.22 ± 5.43, 91.99 ± 13.69, and 22.72 ± 2.39, respectively (p < 0.05). The cytotoxicity of compound 3 was low at 0.78 and 6.26 µM. This outcome indicated that compound 3 displayed low cytotoxicity toward L929 cell line at its IC50 value for AR inhibition (IC50 = 0.382 ± 0.010 µM).

Table 2

IC50 values of compounds 1–8 for L929 cell line after 24 h incubation

Compound IC50 (µM)a
1 0.55 ± 0.07
2 2.63 ± 0.15
3 8.9 ± 0.66
4 2.25 ± 0.35
5 3.47 ± 0.84
6 1.43 ± 0.06
7 >25
8 >25
  1. a

    Results were given as mean ± SD.

3.3 Molecular docking studies

In an effort to gain insight into the binding mode of the TZD scaffold in the enzyme binding site, compound 3 carrying 2-hydroxy-3-methylbenzylidene moiety at the fifth position of 2,4-TZD scaffold was docked into the binding site of AR (PDB ID: 4JIR) as a representative of compounds 1–8 (Figure 3). The best poses for ligand according to score and binding interactions were refined by the MM-GBSA-based approach to assess the electrostatic contribution of the variable dielectric surface generalized born (VSGB) solvation model. For validation of molecular docking simulations, the cocrystalized ligand EPR was extracted and redocked into the binding site. Their root mean square deviation (RMSD) score was computed to evaluate the quality of the cocrystallized ligand. The results were compared with EPR derived from the corresponding 4JIR, and the docking poses were superimposed. The RMSD score was found as 1.20 Å. The docking pattern of EPR was compared with that of compound 3.

Figure 3 Interactions of the ligands with the key amino acids within the binding site of AR (PDB ID: 4JIR, 2.00 Å). (a) 2D ligand interaction diagram of 4JIR with native ligand EPR (epalrestat). (b) 2D ligand interaction diagram of 4JIR with compound 3.
Figure 3

Interactions of the ligands with the key amino acids within the binding site of AR (PDB ID: 4JIR, 2.00 Å). (a) 2D ligand interaction diagram of 4JIR with native ligand EPR (epalrestat). (b) 2D ligand interaction diagram of 4JIR with compound 3.

According to Zhang et al. [49], the native ligand EPR (with an MM-GBSA value of –33.42 kcal/mol and a docking score of –7.19) formed three H-bonds with Tyr48, His110, and Trp111 (with distances 1.56, 1.83, and 2.25 Å, respectively), in the catalytic domain of 4JIR. Moreover, the most prominent amino acid residues accommodating hydrophobic fragments were Tyr48 and Trp111 as well as Trp20, Val47, Trp79, Phe122, Trp219, and Cys298. Compound 3 (with an MM-GBSA value of –33.69 kcal/mol and a docking score of –7.19) exhibited two interactions with the target enzyme. Asn160 and Cys298 showed H-acceptor interactions with the hydroxyl and carbonyl groups (with distances 2.10 and 2.41 Å, respectively) of the ligand. The weak π–π stacking between Trp20, His110, and Tyr209 residues and the benzylidene moiety was observed in the 2D ligand interaction diagram (Figure 3). The results provided insights into the interactions between compounds 1–8 and AR and rationalized the experimental data.

3.4 In silico pharmacokinetic studies

The discovery of AR inhibitors with favorable ADME profiles represents a crucial turning point in the challenging route to develop a new generation of safer AR inhibitors [5]. On this basis, the pharmacokinetic features of compounds 1–8 were assessed by means of QikProp (Table 3). According to in silico prediction, their SASA, QPlogPo/w, CIQPlogS, and QPlogKhsa values were within the recommended range. Their human oral absorption percentages were found to range from 56.281 to 89.199%. All compounds comply with Lipinski’s rule of five and Jorgensen’s rule of three, and therefore they are expected to have favorable oral bioavailability and drug-like features.

Table 3

Predicted ADME profiles of compounds 1–8

Compound SASAa QPlogPo/wa CIQPlogSa QPlogKhsaa Human oral absorption%b Rule of fivec Rule of threec
1 428.912 1.786 −3.528 −0.236 86.866 0 0
2 421.221 1.746 −3.528 −0.240 86.630 0 0
3 423.671 1.156 −3.130 −0.293 77.063 0 0
4 465.209 0.375 −3.705 −0.406 56.281 0 0
5 417.076 2.184 −3.892 −0.145 89.199 0 0
6 436.250 2.144 −3.813 −0.044 88.965 0 0
7 456.458 1.058 −3.691 −0.304 70.607 0 0
8 448.637 1.694 −3.791 −0.188 81.474 0 0
  1. a

    Recommended values for the total solvent accessible surface area (SASA): 300–1,000 Å2; the predicted octanol/water partition coefficient (QPlogPo/w): −2 to 6.5; the conformation-independent predicted aqueous solubility (CIQPlogS): −6.5 to 0.5; the predicted binding to human serum albumin (QPlogKhsa): −1.5 to 1.5.

  2. b

    Predicted human oral absorption on 0 to 100% scale. Human oral absorption higher than 80% is considered to be high, while human oral absorption lower than 25% is considered to be poor.

  3. c

    Rule of Five: Number of violations of Lipinski’s rule of five. The rules are molecular weight of the molecule < 500, QPlogPo/w < 5, hydrogen-bond donor atoms ≤5, hydrogen-bond acceptor atoms ≤ 10. Compounds that provide these rules are considered as drug-like molecules. Rule of Three: Number of violations of Jorgensen’s rule of three. The three rules are QPlogS (predicted aqueous solubility) > −5.7, QPPCaco > 22 nm/s, # primary metabolites < 7. Compounds with fewer (and preferably no) violations of these rules are more likely to be orally available agents (Schrödinger Release 2016-2: Schrödinger, LLC, New York, NY, USA).

4 Conclusions

In conclusion, a facile and versatile synthetic procedure was performed to obtain new 5-(arylidene)thiazolidine-2,4-diones, which were evaluated for their AR inhibitory effects and cytotoxic effects on L929 cells. According to in vitro assay, compounds 1–8 showed inhibitory effects on AR with K i values ranging from 0.445 to 0.943 µM. Taking into account the K i values, compound 3 was found as the most promising AR inhibitor with a K i value of 0.445 ± 0.013 µM and its inhibition type was determined as uncompetitive. The MTT assay indicated that compound 3 did not exert cytotoxicity toward L929 cells at its effective concentration. Based on molecular docking studies, compound 3 interacted with crucial amino acid residues in the binding site of AR (PDB ID: 4JIR). Taking into account in silico ADME studies, this compound is expected to have a favorable pharmacokinetic profile. In vitro and in silico studies pointed out the potential of compound 3 as an orally bioavailable AR inhibitor for the management of T2D complications as well as nondiabetic diseases.

  1. Funding: This work was supported by the Research Fund of Anadolu University (grant numbers: 2005S019 and 1610S681), the Research Fund of Ardahan University (grant number: 2019-008), and the Research Fund of Erzincan Binali Yıldırım University (grant number: FBA-2017-501).

  2. Author contributions: BS was involved in conceptualization, investigation, formal analysis, methodology, software, writing of the original draft, reviewing, and editing; MDA was in charge of conceptualization, data curation, formal analysis, funding acquisition, investigation, methodology, project administration, resources, software, writing –  writing of the original draft, reviewing, and editing; YD contributed to data curation, formal analysis, funding acquisition, methodology, project administration, resources, software, validation, visualization, writing of the original draft, reviewing, and editing; CT was involved in data curation, formal analysis, funding acquisition, methodology, project administration, resources, software, validation, visualization, writing of the original draft, reviewing, and editing; KÖ contributed to investigation, methodology, writing, reviewing, and editing; GAÇ was in charge of data curation, formal analysis, methodology, software, validation, writing, reviewing, and editing; ŞB was involved in conceptualization, methodology, software, project administration, resources, writing, reviewing, and editing; AÖ contributed to conceptualization, methodology, software, resources, writing, reviewing, and editing.

  3. Conflict of interest: Belgin Sever, the coauthor of this article, is a current Editorial Board member of Open Chemistry. This fact did not affect the peer-review process. The authors declare no other conflict of interest.

  4. Data availability statement: All data generated or analyzed during this study are included in this published article [and its supplementary information files].

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Received: 2020-12-02
Revised: 2021-01-26
Accepted: 2021-02-09
Published Online: 2021-03-10

© 2021 Belgin Sever et al., published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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  10. Effects of different extraction methods on antioxidant properties of blueberry anthocyanins
  11. Modeling the removal of methylene blue dye using a graphene oxide/TiO2/SiO2 nanocomposite under sunlight irradiation by intelligent system
  12. Antimicrobial and antioxidant activities of Cinnamomum cassia essential oil and its application in food preservation
  13. Full spectrum and genetic algorithm-selected spectrum-based chemometric methods for simultaneous determination of azilsartan medoxomil, chlorthalidone, and azilsartan: Development, validation, and application on commercial dosage form
  14. Evaluation of the performance of immunoblot and immunodot techniques used to identify autoantibodies in patients with autoimmune diseases
  15. Computational studies by molecular docking of some antiviral drugs with COVID-19 receptors are an approach to medication for COVID-19
  16. Synthesis of amides and esters containing furan rings under microwave-assisted conditions
  17. Simultaneous removal efficiency of H2S and CO2 by high-gravity rotating packed bed: Experiments and simulation
  18. Design, synthesis, and biological activities of novel thiophene, pyrimidine, pyrazole, pyridine, coumarin and isoxazole: Dydrogesterone derivatives as antitumor agents
  19. Content and composition analysis of polysaccharides from Blaps rynchopetera and its macrophage phagocytic activity
  20. A new series of 2,4-thiazolidinediones endowed with potent aldose reductase inhibitory activity
  21. Assessing encapsulation of curcumin in cocoliposome: In vitro study
  22. Rare norisodinosterol derivatives from Xenia umbellata: Isolation and anti-proliferative activity
  23. Comparative study of antioxidant and anticancer activities and HPTLC quantification of rutin in white radish (Raphanus sativus L.) leaves and root extracts grown in Saudi Arabia
  24. Comparison of adsorption properties of commercial silica and rice husk ash (RHA) silica: A study by NIR spectroscopy
  25. Sodium borohydride (NaBH4) as a high-capacity material for next-generation sodium-ion capacitors
  26. Aroma components of tobacco powder from different producing areas based on gas chromatography ion mobility spectrometry
  27. The effects of salinity on changes in characteristics of soils collected in a saline region of the Mekong Delta, Vietnam
  28. Synthesis, properties, and activity of MoVTeNbO catalysts modified by zirconia-pillared clays in oxidative dehydrogenation of ethane
  29. Synthesis and crystal structure of N,N′-bis(4-chlorophenyl)thiourea N,N-dimethylformamide
  30. Quantitative analysis of volatile compounds of four Chinese traditional liquors by SPME-GC-MS and determination of total phenolic contents and antioxidant activities
  31. A novel separation method of the valuable components for activated clay production wastewater
  32. On ve-degree- and ev-degree-based topological properties of crystallographic structure of cuprite Cu2O
  33. Antihyperglycemic effect and phytochemical investigation of Rubia cordifolia (Indian Madder) leaves extract
  34. Microsphere molecularly imprinted solid-phase extraction for diazepam analysis using itaconic acid as a monomer in propanol
  35. A nitric oxide-releasing prodrug promotes apoptosis in human renal carcinoma cells: Involvement of reactive oxygen species
  36. Machine vision-based driving and feedback scheme for digital microfluidics system
  37. Study on the application of a steam-foam drive profile modification technology for heavy oil reservoir development
  38. Ni–Ru-containing mixed oxide-based composites as precursors for ethanol steam reforming catalysts: Effect of the synthesis methods on the structural and catalytic properties
  39. Preparation of composite soybean straw-based materials by LDHs modifying as a solid sorbent for removal of Pb(ii) from water samples
  40. Synthesis and spectral characterizations of vanadyl(ii) and chromium(iii) mixed ligand complexes containing metformin drug and glycine amino acid
  41. In vitro evaluation of lactic acid bacteria with probiotic activity isolated from local pickled leaf mustard from Wuwei in Anhui as substitutes for chemical synthetic additives
  42. Utilization and simulation of innovative new binuclear Co(ii), Ni(ii), Cu(ii), and Zn(ii) diimine Schiff base complexes in sterilization and coronavirus resistance (Covid-19)
  43. Phosphorylation of Pit-1 by cyclin-dependent kinase 5 at serine 126 is associated with cell proliferation and poor prognosis in prolactinomas
  44. Molecularly imprinted membrane for transport of urea, creatinine, and vitamin B12 as a hemodialysis candidate membrane
  45. Optimization of Murrayafoline A ethanol extraction process from the roots of Glycosmis stenocarpa, and evaluation of its Tumorigenesis inhibition activity on Hep-G2 cells
  46. Highly sensitive determination of α-lipoic acid in pharmaceuticals on a boron-doped diamond electrode
  47. Synthesis, chemo-informatics, and anticancer evaluation of fluorophenyl-isoxazole derivatives
  48. In vitro and in vivo investigation of polypharmacology of propolis extract as anticancer, antibacterial, anti-inflammatory, and chemical properties
  49. Topological indices of bipolar fuzzy incidence graph
  50. Preparation of Fe3O4@SiO2–ZnO catalyst and its catalytic synthesis of rosin glycol ester
  51. Construction of a new luminescent Cd(ii) compound for the detection of Fe3+ and treatment of Hepatitis B
  52. Investigation of bovine serum albumin aggregation upon exposure to silver(i) and copper(ii) metal ions using Zetasizer
  53. Discoloration of methylene blue at neutral pH by heterogeneous photo-Fenton-like reactions using crystalline and amorphous iron oxides
  54. Optimized extraction of polyphenols from leaves of Rosemary (Rosmarinus officinalis L.) grown in Lam Dong province, Vietnam, and evaluation of their antioxidant capacity
  55. Synthesis of novel thiourea-/urea-benzimidazole derivatives as anticancer agents
  56. Potency and selectivity indices of Myristica fragrans Houtt. mace chloroform extract against non-clinical and clinical human pathogens
  57. Simple modifications of nicotinic, isonicotinic, and 2,6-dichloroisonicotinic acids toward new weapons against plant diseases
  58. Synthesis, optical and structural characterisation of ZnS nanoparticles derived from Zn(ii) dithiocarbamate complexes
  59. Presence of short and cyclic peptides in Acacia and Ziziphus honeys may potentiate their medicinal values
  60. The role of vitamin D deficiency and elevated inflammatory biomarkers as risk factors for the progression of diabetic nephropathy in patients with type 2 diabetes mellitus
  61. Quantitative structure–activity relationship study on prolonged anticonvulsant activity of terpene derivatives in pentylenetetrazole test
  62. GADD45B induced the enhancing of cell viability and proliferation in radiotherapy and increased the radioresistance of HONE1 cells
  63. Cannabis sativa L. chemical compositions as potential plasmodium falciparum dihydrofolate reductase-thymidinesynthase enzyme inhibitors: An in silico study for drug development
  64. Dynamics of λ-cyhalothrin disappearance and expression of selected P450 genes in bees depending on the ambient temperature
  65. Identification of synthetic cannabinoid methyl 2-{[1-(cyclohexylmethyl)-1H-indol-3-yl] formamido}-3-methylbutanoate using modern mass spectrometry and nuclear magnetic resonance techniques
  66. Study on the speciation of arsenic in the genuine medicinal material honeysuckle
  67. Two Cu(ii)-based coordination polymers: Crystal structures and treatment activity on periodontitis
  68. Conversion of furfuryl alcohol to ethyl levulinate in the presence of mesoporous aluminosilicate catalyst
  69. Review Articles
  70. Hsien Wu and his major contributions to the chemical era of immunology
  71. Overview of the major classes of new psychoactive substances, psychoactive effects, analytical determination and conformational analysis of selected illegal drugs
  72. An overview of persistent organic pollutants along the coastal environment of Kuwait
  73. Mechanism underlying sevoflurane-induced protection in cerebral ischemia–reperfusion injury
  74. COVID-19 and SARS-CoV-2: Everything we know so far – A comprehensive review
  75. Challenge of diabetes mellitus and researchers’ contributions to its control
  76. Advances in the design and application of transition metal oxide-based supercapacitors
  77. Color and composition of beauty products formulated with lemongrass essential oil: Cosmetics formulation with lemongrass essential oil
  78. The structural chemistry of zinc(ii) and nickel(ii) dithiocarbamate complexes
  79. Bioprospecting for antituberculosis natural products – A review
  80. Recent progress in direct urea fuel cell
  81. Rapid Communications
  82. A comparative morphological study of titanium dioxide surface layer dental implants
  83. Changes in the antioxidative properties of honeys during their fermentation
  84. Erratum
  85. Erratum to “Corrosion study of copper in aqueous sulfuric acid solution in the presence of (2E,5E)-2,5-dibenzylidenecyclopentanone and (2E,5E)-bis[(4-dimethylamino)benzylidene]cyclopentanone: Experimental and theoretical study”
  86. Erratum to “Modified TDAE petroleum plasticiser”
  87. Corrigendum
  88. Corrigendum to “A nitric oxide-releasing prodrug promotes apoptosis in human renal carcinoma cells: Involvement of reactive oxygen species”
  89. Special Issue on 3rd IC3PE 2020
  90. Visible light-responsive photocatalyst of SnO2/rGO prepared using Pometia pinnata leaf extract
  91. Antihyperglycemic activity of Centella asiatica (L.) Urb. leaf ethanol extract SNEDDS in zebrafish (Danio rerio)
  92. Selection of oil extraction process from Chlorella species of microalgae by using multi-criteria decision analysis technique for biodiesel production
  93. Special Issue on the 14th Joint Conference of Chemistry (14JCC)
  94. Synthesis and in vitro cytotoxicity evaluation of isatin-pyrrole derivatives against HepG2 cell line
  95. CO2 gas separation using mixed matrix membranes based on polyethersulfone/MIL-100(Al)
  96. Effect of synthesis and activation methods on the character of CoMo/ultrastable Y-zeolite catalysts
  97. Special Issue on Electrochemical Amplified Sensors
  98. Enhancement of graphene oxide through β-cyclodextrin composite to sensitive analysis of an antidepressant: Sulpiride
  99. Investigation of the spectroelectrochemical behavior of quercetin isolated from Zanthoxylum bungeanum
  100. An electrochemical sensor for high sensitive determination of lysozyme based on the aptamer competition approach
  101. An improved non-enzymatic electrochemical sensor amplified with CuO nanostructures for sensitive determination of uric acid
  102. Special Issue on Applied Biochemistry and Biotechnology 2020
  103. Fast discrimination of avocado oil for different extracted methods using headspace-gas chromatography-ion mobility spectroscopy with PCA based on volatile organic compounds
  104. Effect of alkali bases on the synthesis of ZnO quantum dots
  105. Quality evaluation of Cabernet Sauvignon wines in different vintages by 1H nuclear magnetic resonance-based metabolomics
  106. Special Issue on the Joint Science Congress of Materials and Polymers (ISCMP 2019)
  107. Diatomaceous Earth: Characterization, thermal modification, and application
  108. Electrochemical determination of atenolol and propranolol using a carbon paste sensor modified with natural ilmenite
  109. Special Issue on the Conference of Energy, Fuels, Environment 2020
  110. Assessment of the mercury contamination of landfilled and recovered foundry waste – a case study
  111. Primary energy consumption in selected EU Countries compared to global trends
  112. Modified TDAE petroleum plasticiser
  113. Use of glycerol waste in lactic acid bacteria metabolism for the production of lactic acid: State of the art in Poland
  114. Topical Issue on Applications of Mathematics in Chemistry
  115. Theoretical study of energy, inertia and nullity of phenylene and anthracene
  116. Banhatti, revan and hyper-indices of silicon carbide Si2C3-III[n,m]
  117. Topical Issue on Agriculture
  118. Occurrence of mycotoxins in selected agricultural and commercial products available in eastern Poland
  119. Special Issue on Ethnobotanical, Phytochemical and Biological Investigation of Medicinal Plants
  120. Acute and repeated dose 60-day oral toxicity assessment of chemically characterized Berberis hispanica Boiss. and Reut in Wistar rats
  121. Phytochemical profile, in vitro antioxidant, and anti-protein denaturation activities of Curcuma longa L. rhizome and leaves
  122. Antiplasmodial potential of Eucalyptus obliqua leaf methanolic extract against Plasmodium vivax: An in vitro study
  123. Prunus padus L. bark as a functional promoting component in functional herbal infusions – cyclooxygenase-2 inhibitory, antioxidant, and antimicrobial effects
  124. Molecular and docking studies of tetramethoxy hydroxyflavone compound from Artemisia absinthium against carcinogens found in cigarette smoke
  125. Special Issue on the Joint Science Congress of Materials and Polymers (ISCMP 2020)
  126. Preparation of cypress (Cupressus sempervirens L.) essential oil loaded poly(lactic acid) nanofibers
  127. Influence of mica mineral on flame retardancy and mechanical properties of intumescent flame retardant polypropylene composites
  128. Production and characterization of thermoplastic elastomer foams based on the styrene–ethylene–butylene–styrene (SEBS) rubber and thermoplastic material
  129. Special Issue on Applied Chemistry in Agriculture and Food Science
  130. Impact of essential oils on the development of pathogens of the Fusarium genus and germination parameters of selected crops
  131. Yield, volume, quality, and reduction of biotic stress influenced by titanium application in oilseed rape, winter wheat, and maize cultivations
  132. Influence of potato variety on polyphenol profile composition and glycoalcaloid contents of potato juice
  133. Carryover effect of direct-fed microbial supplementation and early weaning on the growth performance and carcass characteristics of growing Najdi lambs
  134. Special Issue on Applied Biochemistry and Biotechnology (ABB 2021)
  135. The electrochemical redox mechanism and antioxidant activity of polyphenolic compounds based on inlaid multi-walled carbon nanotubes-modified graphite electrode
  136. Study of an adsorption method for trace mercury based on Bacillus subtilis
  137. Special Issue on The 1st Malaysia International Conference on Nanotechnology & Catalysis (MICNC2021)
  138. Mitigating membrane biofouling in biofuel cell system – A review
  139. Mechanical properties of polymeric biomaterials: Modified ePTFE using gamma irradiation
https://doi.org/10.1515/chem-2021-0032
Schlagwörter für diesen Artikel
aldose reductase; thiazolidinedione; cytotoxicity; molecular docking
Creative Commons
BY 4.0

Artikel in diesem Heft

  1. Regular Articles
  2. Qualitative and semi-quantitative assessment of anthocyanins in Tibetan hulless barley from different geographical locations by UPLC-QTOF-MS and their antioxidant capacities
  3. Effect of sodium chloride on the expression of genes involved in the salt tolerance of Bacillus sp. strain “SX4” isolated from salinized greenhouse soil
  4. GC-MS analysis of mango stem bark extracts (Mangifera indica L.), Haden variety. Possible contribution of volatile compounds to its health effects
  5. Influence of nanoscale-modified apatite-type calcium phosphates on the biofilm formation by pathogenic microorganisms
  6. Removal of paracetamol from aqueous solution by containment composites
  7. Investigating a human pesticide intoxication incident: The importance of robust analytical approaches
  8. Induction of apoptosis and cell cycle arrest by chloroform fraction of Juniperus phoenicea and chemical constituents analysis
  9. Recovery of γ-Fe2O3 from copper ore tailings by magnetization roasting and magnetic separation
  10. Effects of different extraction methods on antioxidant properties of blueberry anthocyanins
  11. Modeling the removal of methylene blue dye using a graphene oxide/TiO2/SiO2 nanocomposite under sunlight irradiation by intelligent system
  12. Antimicrobial and antioxidant activities of Cinnamomum cassia essential oil and its application in food preservation
  13. Full spectrum and genetic algorithm-selected spectrum-based chemometric methods for simultaneous determination of azilsartan medoxomil, chlorthalidone, and azilsartan: Development, validation, and application on commercial dosage form
  14. Evaluation of the performance of immunoblot and immunodot techniques used to identify autoantibodies in patients with autoimmune diseases
  15. Computational studies by molecular docking of some antiviral drugs with COVID-19 receptors are an approach to medication for COVID-19
  16. Synthesis of amides and esters containing furan rings under microwave-assisted conditions
  17. Simultaneous removal efficiency of H2S and CO2 by high-gravity rotating packed bed: Experiments and simulation
  18. Design, synthesis, and biological activities of novel thiophene, pyrimidine, pyrazole, pyridine, coumarin and isoxazole: Dydrogesterone derivatives as antitumor agents
  19. Content and composition analysis of polysaccharides from Blaps rynchopetera and its macrophage phagocytic activity
  20. A new series of 2,4-thiazolidinediones endowed with potent aldose reductase inhibitory activity
  21. Assessing encapsulation of curcumin in cocoliposome: In vitro study
  22. Rare norisodinosterol derivatives from Xenia umbellata: Isolation and anti-proliferative activity
  23. Comparative study of antioxidant and anticancer activities and HPTLC quantification of rutin in white radish (Raphanus sativus L.) leaves and root extracts grown in Saudi Arabia
  24. Comparison of adsorption properties of commercial silica and rice husk ash (RHA) silica: A study by NIR spectroscopy
  25. Sodium borohydride (NaBH4) as a high-capacity material for next-generation sodium-ion capacitors
  26. Aroma components of tobacco powder from different producing areas based on gas chromatography ion mobility spectrometry
  27. The effects of salinity on changes in characteristics of soils collected in a saline region of the Mekong Delta, Vietnam
  28. Synthesis, properties, and activity of MoVTeNbO catalysts modified by zirconia-pillared clays in oxidative dehydrogenation of ethane
  29. Synthesis and crystal structure of N,N′-bis(4-chlorophenyl)thiourea N,N-dimethylformamide
  30. Quantitative analysis of volatile compounds of four Chinese traditional liquors by SPME-GC-MS and determination of total phenolic contents and antioxidant activities
  31. A novel separation method of the valuable components for activated clay production wastewater
  32. On ve-degree- and ev-degree-based topological properties of crystallographic structure of cuprite Cu2O
  33. Antihyperglycemic effect and phytochemical investigation of Rubia cordifolia (Indian Madder) leaves extract
  34. Microsphere molecularly imprinted solid-phase extraction for diazepam analysis using itaconic acid as a monomer in propanol
  35. A nitric oxide-releasing prodrug promotes apoptosis in human renal carcinoma cells: Involvement of reactive oxygen species
  36. Machine vision-based driving and feedback scheme for digital microfluidics system
  37. Study on the application of a steam-foam drive profile modification technology for heavy oil reservoir development
  38. Ni–Ru-containing mixed oxide-based composites as precursors for ethanol steam reforming catalysts: Effect of the synthesis methods on the structural and catalytic properties
  39. Preparation of composite soybean straw-based materials by LDHs modifying as a solid sorbent for removal of Pb(ii) from water samples
  40. Synthesis and spectral characterizations of vanadyl(ii) and chromium(iii) mixed ligand complexes containing metformin drug and glycine amino acid
  41. In vitro evaluation of lactic acid bacteria with probiotic activity isolated from local pickled leaf mustard from Wuwei in Anhui as substitutes for chemical synthetic additives
  42. Utilization and simulation of innovative new binuclear Co(ii), Ni(ii), Cu(ii), and Zn(ii) diimine Schiff base complexes in sterilization and coronavirus resistance (Covid-19)
  43. Phosphorylation of Pit-1 by cyclin-dependent kinase 5 at serine 126 is associated with cell proliferation and poor prognosis in prolactinomas
  44. Molecularly imprinted membrane for transport of urea, creatinine, and vitamin B12 as a hemodialysis candidate membrane
  45. Optimization of Murrayafoline A ethanol extraction process from the roots of Glycosmis stenocarpa, and evaluation of its Tumorigenesis inhibition activity on Hep-G2 cells
  46. Highly sensitive determination of α-lipoic acid in pharmaceuticals on a boron-doped diamond electrode
  47. Synthesis, chemo-informatics, and anticancer evaluation of fluorophenyl-isoxazole derivatives
  48. In vitro and in vivo investigation of polypharmacology of propolis extract as anticancer, antibacterial, anti-inflammatory, and chemical properties
  49. Topological indices of bipolar fuzzy incidence graph
  50. Preparation of Fe3O4@SiO2–ZnO catalyst and its catalytic synthesis of rosin glycol ester
  51. Construction of a new luminescent Cd(ii) compound for the detection of Fe3+ and treatment of Hepatitis B
  52. Investigation of bovine serum albumin aggregation upon exposure to silver(i) and copper(ii) metal ions using Zetasizer
  53. Discoloration of methylene blue at neutral pH by heterogeneous photo-Fenton-like reactions using crystalline and amorphous iron oxides
  54. Optimized extraction of polyphenols from leaves of Rosemary (Rosmarinus officinalis L.) grown in Lam Dong province, Vietnam, and evaluation of their antioxidant capacity
  55. Synthesis of novel thiourea-/urea-benzimidazole derivatives as anticancer agents
  56. Potency and selectivity indices of Myristica fragrans Houtt. mace chloroform extract against non-clinical and clinical human pathogens
  57. Simple modifications of nicotinic, isonicotinic, and 2,6-dichloroisonicotinic acids toward new weapons against plant diseases
  58. Synthesis, optical and structural characterisation of ZnS nanoparticles derived from Zn(ii) dithiocarbamate complexes
  59. Presence of short and cyclic peptides in Acacia and Ziziphus honeys may potentiate their medicinal values
  60. The role of vitamin D deficiency and elevated inflammatory biomarkers as risk factors for the progression of diabetic nephropathy in patients with type 2 diabetes mellitus
  61. Quantitative structure–activity relationship study on prolonged anticonvulsant activity of terpene derivatives in pentylenetetrazole test
  62. GADD45B induced the enhancing of cell viability and proliferation in radiotherapy and increased the radioresistance of HONE1 cells
  63. Cannabis sativa L. chemical compositions as potential plasmodium falciparum dihydrofolate reductase-thymidinesynthase enzyme inhibitors: An in silico study for drug development
  64. Dynamics of λ-cyhalothrin disappearance and expression of selected P450 genes in bees depending on the ambient temperature
  65. Identification of synthetic cannabinoid methyl 2-{[1-(cyclohexylmethyl)-1H-indol-3-yl] formamido}-3-methylbutanoate using modern mass spectrometry and nuclear magnetic resonance techniques
  66. Study on the speciation of arsenic in the genuine medicinal material honeysuckle
  67. Two Cu(ii)-based coordination polymers: Crystal structures and treatment activity on periodontitis
  68. Conversion of furfuryl alcohol to ethyl levulinate in the presence of mesoporous aluminosilicate catalyst
  69. Review Articles
  70. Hsien Wu and his major contributions to the chemical era of immunology
  71. Overview of the major classes of new psychoactive substances, psychoactive effects, analytical determination and conformational analysis of selected illegal drugs
  72. An overview of persistent organic pollutants along the coastal environment of Kuwait
  73. Mechanism underlying sevoflurane-induced protection in cerebral ischemia–reperfusion injury
  74. COVID-19 and SARS-CoV-2: Everything we know so far – A comprehensive review
  75. Challenge of diabetes mellitus and researchers’ contributions to its control
  76. Advances in the design and application of transition metal oxide-based supercapacitors
  77. Color and composition of beauty products formulated with lemongrass essential oil: Cosmetics formulation with lemongrass essential oil
  78. The structural chemistry of zinc(ii) and nickel(ii) dithiocarbamate complexes
  79. Bioprospecting for antituberculosis natural products – A review
  80. Recent progress in direct urea fuel cell
  81. Rapid Communications
  82. A comparative morphological study of titanium dioxide surface layer dental implants
  83. Changes in the antioxidative properties of honeys during their fermentation
  84. Erratum
  85. Erratum to “Corrosion study of copper in aqueous sulfuric acid solution in the presence of (2E,5E)-2,5-dibenzylidenecyclopentanone and (2E,5E)-bis[(4-dimethylamino)benzylidene]cyclopentanone: Experimental and theoretical study”
  86. Erratum to “Modified TDAE petroleum plasticiser”
  87. Corrigendum
  88. Corrigendum to “A nitric oxide-releasing prodrug promotes apoptosis in human renal carcinoma cells: Involvement of reactive oxygen species”
  89. Special Issue on 3rd IC3PE 2020
  90. Visible light-responsive photocatalyst of SnO2/rGO prepared using Pometia pinnata leaf extract
  91. Antihyperglycemic activity of Centella asiatica (L.) Urb. leaf ethanol extract SNEDDS in zebrafish (Danio rerio)
  92. Selection of oil extraction process from Chlorella species of microalgae by using multi-criteria decision analysis technique for biodiesel production
  93. Special Issue on the 14th Joint Conference of Chemistry (14JCC)
  94. Synthesis and in vitro cytotoxicity evaluation of isatin-pyrrole derivatives against HepG2 cell line
  95. CO2 gas separation using mixed matrix membranes based on polyethersulfone/MIL-100(Al)
  96. Effect of synthesis and activation methods on the character of CoMo/ultrastable Y-zeolite catalysts
  97. Special Issue on Electrochemical Amplified Sensors
  98. Enhancement of graphene oxide through β-cyclodextrin composite to sensitive analysis of an antidepressant: Sulpiride
  99. Investigation of the spectroelectrochemical behavior of quercetin isolated from Zanthoxylum bungeanum
  100. An electrochemical sensor for high sensitive determination of lysozyme based on the aptamer competition approach
  101. An improved non-enzymatic electrochemical sensor amplified with CuO nanostructures for sensitive determination of uric acid
  102. Special Issue on Applied Biochemistry and Biotechnology 2020
  103. Fast discrimination of avocado oil for different extracted methods using headspace-gas chromatography-ion mobility spectroscopy with PCA based on volatile organic compounds
  104. Effect of alkali bases on the synthesis of ZnO quantum dots
  105. Quality evaluation of Cabernet Sauvignon wines in different vintages by 1H nuclear magnetic resonance-based metabolomics
  106. Special Issue on the Joint Science Congress of Materials and Polymers (ISCMP 2019)
  107. Diatomaceous Earth: Characterization, thermal modification, and application
  108. Electrochemical determination of atenolol and propranolol using a carbon paste sensor modified with natural ilmenite
  109. Special Issue on the Conference of Energy, Fuels, Environment 2020
  110. Assessment of the mercury contamination of landfilled and recovered foundry waste – a case study
  111. Primary energy consumption in selected EU Countries compared to global trends
  112. Modified TDAE petroleum plasticiser
  113. Use of glycerol waste in lactic acid bacteria metabolism for the production of lactic acid: State of the art in Poland
  114. Topical Issue on Applications of Mathematics in Chemistry
  115. Theoretical study of energy, inertia and nullity of phenylene and anthracene
  116. Banhatti, revan and hyper-indices of silicon carbide Si2C3-III[n,m]
  117. Topical Issue on Agriculture
  118. Occurrence of mycotoxins in selected agricultural and commercial products available in eastern Poland
  119. Special Issue on Ethnobotanical, Phytochemical and Biological Investigation of Medicinal Plants
  120. Acute and repeated dose 60-day oral toxicity assessment of chemically characterized Berberis hispanica Boiss. and Reut in Wistar rats
  121. Phytochemical profile, in vitro antioxidant, and anti-protein denaturation activities of Curcuma longa L. rhizome and leaves
  122. Antiplasmodial potential of Eucalyptus obliqua leaf methanolic extract against Plasmodium vivax: An in vitro study
  123. Prunus padus L. bark as a functional promoting component in functional herbal infusions – cyclooxygenase-2 inhibitory, antioxidant, and antimicrobial effects
  124. Molecular and docking studies of tetramethoxy hydroxyflavone compound from Artemisia absinthium against carcinogens found in cigarette smoke
  125. Special Issue on the Joint Science Congress of Materials and Polymers (ISCMP 2020)
  126. Preparation of cypress (Cupressus sempervirens L.) essential oil loaded poly(lactic acid) nanofibers
  127. Influence of mica mineral on flame retardancy and mechanical properties of intumescent flame retardant polypropylene composites
  128. Production and characterization of thermoplastic elastomer foams based on the styrene–ethylene–butylene–styrene (SEBS) rubber and thermoplastic material
  129. Special Issue on Applied Chemistry in Agriculture and Food Science
  130. Impact of essential oils on the development of pathogens of the Fusarium genus and germination parameters of selected crops
  131. Yield, volume, quality, and reduction of biotic stress influenced by titanium application in oilseed rape, winter wheat, and maize cultivations
  132. Influence of potato variety on polyphenol profile composition and glycoalcaloid contents of potato juice
  133. Carryover effect of direct-fed microbial supplementation and early weaning on the growth performance and carcass characteristics of growing Najdi lambs
  134. Special Issue on Applied Biochemistry and Biotechnology (ABB 2021)
  135. The electrochemical redox mechanism and antioxidant activity of polyphenolic compounds based on inlaid multi-walled carbon nanotubes-modified graphite electrode
  136. Study of an adsorption method for trace mercury based on Bacillus subtilis
  137. Special Issue on The 1st Malaysia International Conference on Nanotechnology & Catalysis (MICNC2021)
  138. Mitigating membrane biofouling in biofuel cell system – A review
  139. Mechanical properties of polymeric biomaterials: Modified ePTFE using gamma irradiation
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