Synthesis and Quantitative Structure-Antioxidant Activity Relationship Analysis of Thiazolidine-2,4-dione Analogues

 

Swathi N^1,2,*, Subrahmanyam CVS³ and Satyanarayana K⁴

¹Department of Pharmaceutical Chemistry, Gokaraju Rangaraju College of Pharmacy, Hyderabad, 500090, Telangana, India

²Centre for Pharmaceutical Sciences, Jawaharlal Nehru Technological University, Hyderabad, 500072, Telangana, India

³Faculty of Technology, Osmania University, Hyderabad, 500007, Telangana, India

⁴Natco Research Centre, Natco Pharma Ltd, B-13, Industrial Estate, Sanath Nagar, Hyderabad, 500018, Telangana, India

*Corresponding Author E-mail: swa.pharma@gmail.com

Three series of thiazolidine-2,4-dione analogues (1-17, 14a-h, 15a-h, 16a-h, 17a-h) were synthesized by Knoevenagel condensation/N-alkylation/combination of both the reactions. The structure of the compounds was established based on IR, ¹H NMR and Mass spectral data analysis. In the in vitro antioxidant potential evaluation, the compound 14g bearing 4-hydroxyl,3-methoxyl substitution on 5-aryl functionality shown significant reducing power (IC₅₀ 22.7±0.43 μM). Descriptor-based QSAR analysis was utilized to study the structural contribution to the radical scavenging potential. Among various QSAR models, model 12 was found to be best and the R² value 0.858 is indicative of good correlation between in vitro and in silico activity. The QSAR studies revealed the potential contribution of the descriptors HOMO, HBD, DM and SASA towards the antioxidant activity.

 

 

 

INTRODUCTION:

Defective insulin secretion, resistance to insulin action and reduction in the bio-antioxidant potential leads to diabetes mellitus. The imbalance between the pro-oxidant and antioxidant homeostasis results in oxidative stress (OS). The role of OS in the pathogenesis of diabetes and its associated diseases (retinopathy, nephropathy, atherosclerosis and coronary artery disease) is well characterized.^1,2 Oral hypoglycemic agents, such as glibenclamide, glipizide and metformin scavenge free radicals and decreases intracellular reactive oxygen species level.^3,4 The antioxidant potential of various 5-substituted and N, 5-disubstituted-1,3-thiazolidine-2,4-diones were reported in the literature.^5,6 Hence, the molecules having both hypoglycemic and antioxidant potential offers a novel gateway in the diabetes therapy.

 

Prompted by the above mentioned facts and in continuation of our research affords, the in vitro reducing potential of thiazolidine-2,4-diones analogues was evaluated.

 

The descriptor-based QSAR analysis was utilized to identify the molecular properties contributing to the antioxidant activity.

 

MATERIALS AND METHODS:

Melting points were determined in open capillaries using DBK melting point apparatus, expressed in ˚C and are uncorrected. Analytical thin layer chromatography (TLC) was performed on silica gel 60 F₂₅₄ plates (Merck) with visualization by UV light and staining with iodine. The elemental analyses for C, H and N were done on Perkin-Elmer analyzer. The IR spectrum was run on Shimadzu IR affinity 1 spectrophotometer and the absorption bands were expressed in cm^-1. ¹H NMR (300 and 400 MHz) and ¹³C NMR (300 MHz) spectra were recorded on Avance spectrometers using DMSO-d₆ as solvent and the chemical shifts were reported in ppm. The absorbance values were recorded using UV-1800 Shimadzu UV-Visible spectrophotometer.

 

General procedure:

Synthesis of 5-substitutedarylidene-1,3-thiazolidine-2,4-diones (1-13)

To the suspension of substituted arylaldehydes (4.2 mmol) and 1,3-thiazolidine-2,4-dione (0.5 g, 4.2 mmol) in dry toluene (15 mL), catalytic amount of piperidine was added. The flask was equipped with Dean-Stark apparatus fitted with a drying tube to provide azeotropic condition. The mixture was refluxed for 6 h with stirring. The progression and completion of the reaction was monitored by TLC. The product precipitated on cooling was filtered under vacuum and washed with a mixture of cold dry toluene and ethanol (1:1).

 

The details of the compounds 1-10 were given in our previous communication.⁷

 

5-(4-Hydroxybenzylidene)-1,3-thiazolidine-2,4-dione (11):

Colorless crystals, Yield 69%, m.p.: 253-256 °C; FT-IR (KBr): v(cm^-1) 3428 (OH), 3162 (aromatic CH), 3033 (CH), 1739 (CO), 1681 (CO), 1365 (C-N), 1281 (C-O), 676 (C-S). ¹H NMR (300 MHz, DMSO-d₆): δ ppm = 9.70 (br, s, 2H, OH, NH), 7.58 (s, 1H, =CH), 7.40 (d, 2H, aromatic, 8.49 Hz), 6.87 (d, 2H, aromatic, 8.49 Hz); Mass (221.237): m/z 221 (M⁺).

 

5-(4-Hydroxy,3-methoxybenzylidene)-1,3-thiazolidine-2,4-dione (12):

Pale yellow crystals, Yield 72%, m.p.: 194-195 °C; FT-IR (KBr): v(cm^-1) 3480 (OH), 3192 (NH), 3034 (aromatic CH), 1737 (C=O), 1678 (C=O), 1516 (C=C), 1290 (C-O). ¹H NMR (400 MHz, DMSO-d₆): δ ppm = 9.77 (br, s, 1H, OH, NH), 7.57 (s, 1H, =CH), 7.15 (d, 1H, J = 1.6 Hz, aromatic), 7.02 (dd, 1H, aromatic), 6.89 (d, 1H, J = 8.0 Hz, aromatic); Mass (251.263): m/z 251.1 (M⁺).

 

5-(3,4-Dimethoxybenzylidene)-1,3-thiazolidine-2,4-dione (13):

Pale yellow crystals, Yield 75%, m.p.: 190-191 °C; FT-IR (KBr): v(cm^-1) 3216 (NH), 3044 (aromatic CH), 1731 (C=O), 1693 (C=O), 1501 (C=C), 1332 (C-O), 1315 (C-N), 714 (C-S). ¹H NMR (400 MHz, DMSO-d₆): δ ppm = 12.52 (s, 1H, NH), 7.75 (s, 1H, =CH), 7.17 (d, 2H, J = 6.8 Hz, aromatic), 7.11 (d, 2H, J = 12.0 Hz, aromatic), 3.81 (d, 6H, two OCH₃); Mass (265.29): m/z 265.2 (M⁺).

 

Synthesis of N-substituted-1,3-thiazolidine-2,4-diones (14-17):

A solution of potassium hydroxide in ethanol (4.2 mmol) was added drop wise to a suspension of   1,3-thiazolidine-2, 4-dione (4.2 mmol) in ethanol (10 mL).  The mixture was stirred at room temperature for 15 min and then p-chloro/p-fluorobenzyl chloride (4.2 mmol) was added. The reaction mixture was refluxed with stirring. The progression and completion of the reaction is monitored by TLC and taken 6 h for completion. The separated solid was filtered, washed with water and diethyl ether. The residue obtained was recrystallized from ethanol.

 

The details of the compounds 14, 15 were given in our previous communication.⁸

 

N-(4-Chlorobenzyl)-1,3-thiazolidine-2,4-dione  (16):

Colorless crystals, Yield 80%, m.p.: 95-96 °C (Lo et al., 1953, 97-98 °C); FT-IR (KBr): v(cm^-1) 3115 (aromatic CH), 2999 (CH), 1743 (C=O), 1676 (C=O), 715 (C-S), 671 (C-Cl). ¹H NMR (300 MHz, DMSO-d₆): δ ppm = 7.39 (d, 2H, J = 8.4 Hz, aromatic), 7.28 (d, 2H, J = 8.4 Hz, aromatic), 4.65 (s, 2H, side chain CH₂), 4.27 (s, 2H, ring CH₂).

 

N-(4-Fluorobenzyl)-1,3-thiazolidine-2,4-dione (17):

Colorless shiny crystals, Yield 76%, m.p.: 81-83°C; FT-IR (KBr): v(cm^-1) 3000 (aromatic CH), 2780 (CH),1762 (C=O), 1681 (C=O), 1516 (C=C), 993 (C-F). ¹H NMR (300 MHz, DMSO-d₆): δ ppm = 7.12-7.30 (m, 4H, aromatic), 4.64 (s, 2H, side chain CH₂), 4.25 (s, 2H, ring CH₂).

 

Synthesis of N-(4-halobenzyl)-5-(substituted benzylidene)-1,3-thiazolidine-2,4-diones (16a-h, 17a-h): 

To the suspension of substituted aryl aldehydes (4.2 mmol) and N-(4-chlorobenzyl/4-fluorobenzyl)-1,3-thiazolidine-2,4-dione (16/17) (4.2 mmol) in dry toluene (12 mL), catalytic amount of piperidine were added. The reaction mixture was refluxed with stirring for 6 h. Azeotropic condition was maintained with the aid of a Dean-Stark apparatus fitted with a drying tube. The product, precipitated on cooling was filtered under vacuum and washed with a mixture of cold toluene and ethanol (1:1). The physical, analytical and spectral details of the compounds 14a-h, 15a-h were given in our previous communication.⁸

 

5-Benzylidene-N-(4-chlorobenzyl)-1, 3-thiazolidine-2,4-dione (16a):

Colorless crystals, Yield 75%, m.p. 164-165 °C; FT-IR (KBr, cm^-1): 3066, 2916, 1747, 1685, 1312, 682. ¹H NMR (300 MHz, DMSO-d₆) δ in ppm: 7.90 (s, 1H, =CH), 7.29-7.72 (m, 9H, Ar-H), 4.86 (s, 2H, CH₂).

 

N-(4-Chlorobenzyl)-5-(4-chlorobenzylidene)-1,3-thiazolidine-2,4-dione (16b):

Colorless crystals, Yield 71%, m.p. 174-175 °C; FT-IR (KBr, cm^-1):  3088, 1737, 1676, 1323, 657. ¹H NMR (300 MHz, DMSO-d₆) δ in ppm: 7.91 (s, 1H, =CH), 7.39 (d, 2H, J = 8.4 Hz, Ar-H), 7.21 (d, 2H, J = 8.37 Hz, Ar-H), 7.11 (m, 4H, Ar-H), 4.81 (s, 2H, CH₂).

 

N-(4-Chlorobenzyl)-5-(4-nitrobenzylidene)-1,3-thiazolidine-2,4-dione (16c):

Colorless solid, Yield 65%, m.p. 209-211 °C; FT-IR (KBr, cm^-1): 2976, 1742, 1689, 1562, 1233, 653. ¹H NMR (300 MHz, DMSO-d₆) δ in ppm: 8.03 (s, 1H, =CH), 7.52-8.21 (m, 8H, Ar-H), 4.78 (s, 2H, CH₂).

N-(4-Chlorobenzyl)-5-(4-methoxybenzylidene)-1,3-thiazolidine-2,4-dione (16d):

Colorless crystals, Yield 68%, m.p. 185-187 °C; FT-IR (KBr, cm^-1):  2985, 1726, 1670, 1174, 685; ¹H NMR (300 MHz, DMSO-d₆) δ in ppm: 7.91(s, 1H, =CH), 7.58 (d, 2H, J = 8.76 Hz, Ar-H), 7.39 (d, 2H, J = 8.46 Hz Ar-H), 7.31 (d, 2H, J = 8.43 Hz, Ar-H), 7.09 (d, 2H, J = 8.76 Hz, Ar-H), 4.81 (s, 2H, CH₂), 3.82 (s, 3H, OCH₃); ¹³C NMR (300 MHz, DMSO-d₆) δ in ppm: 165.57 (C=O), 167.57 (C=O), 161.25 (C, aromatic), 134.53 (C, aromatic),133.55 (=CH), 132.34 (C, aromatic), 129.57 (C, aromatic), 128.61 (C, aromatic), 128.12 (C, aromatic), 127.10 (C, aromatic), 125.33 (C-5), 117.71 (C, aromatic), 114.99 (C, aromatic), 55.51 (OCH₃), 43.88 (CH₂Ph).  

 

N-(4-Chlorobenzyl)-5-(4-(dimethylamino)benzylidene)-1,3-thiazolidine-2,4-dione (16e):

Yellow solid, Yield 77%, m.p. 196-198 °C; FT-IR (KBr, cm^-1): 2978, 1723, 1672, 1365, 1167, 664; ¹H NMR (300 MHz, DMSO-d₆) δ in ppm: 7.83 (s, 1H, =CH), 7.45 (d, 2H, J = 8.8 Hz, Ar-H), 7.40 (d, 2H, J = 8.4 Hz, Ar-H), 7.31 (d, 2H, J = 8.4 Hz, Ar-H), 6.81 (d, 2H, J = 8.8 Hz, Ar-H), 4.81 (s, 2H, CH₂), 3.02 (s, 6H, 2CH₃).

 

N-(4-Chlorobenzyl)-5-(4-hydroxybenzylidene)-1,3-thiazolidine-2,4-dione (16f):

Colorless solid, Yield 74%, m.p. 201-202 °C; FT-IR (KBr, cm^-1): 3001, 1743, 1678, 1408, 1183, 658. ¹H NMR (300 MHz, DMSO-d₆) δ in ppm: 8.92 (s, 1H, OH), 7.84 (s, 1H, =CH), 7.45 (d, 2H, J = 8.8 Hz, Ar-H), 7.40 (d, 2H, J = 8.4 Hz, Ar-H), 7.31 (d, 2H, J = 8.4 Hz, Ar-H), 6.84 (d, 2H, J = 8.8 Hz, Ar-H), 4.81 (s, 2H, CH₂).

 

N-(4-Chlorobenzyl)-5-(4-hydroxy-3-methoxybenzylidene)-1,3-thiazolidine-2,4-dione (16g):

Pale yellow solid, Yield 76%, m.p. 181-182 °C; FT-IR (KBr, cm^-1): 2992, 1737, 1686, 1410, 1194, 652. ¹H NMR (300 MHz, DMSO-d₆) δ in ppm: 9.03 (s, 1H, OH), 7.87 (s, 1H, =CH), 7.41 (d, 2H, J = 8.4 Hz, Ar-H), 7.32 (d, 2H, J = 8.4 Hz, Ar-H), 6.90-7.19 (m, 3H, Ar-H), 4.82 (s, 2H, CH₂), 3.81 (s, 3H, OCH₃).

 

N-(4-Chlorobenzyl)-5-(3,4-dimethoxybenzylidene)-1,3-thiazolidine-2,4-dione (16h):

Pale yellow solid, Yield 69%, m.p. 172-173 °C; FT-IR (KBr, cm^-1): 2989, 1772, 1697, 1451, 1202, 1156, 645; ¹H NMR (300 MHz, DMSO-d₆) δ in ppm: 7.93 (s, 1H, =CH), 7.41 (d, 2H, J = 8.4 Hz, Ar-H), 7.32 (d, 2H, J = 8.4 Hz, Ar-H), 7.13-7.22 (m, 4H,  Ar-H), 4.83 (s, 2H, CH₂), 3.81 (s, 6H, two OCH₃).

 

5-(Benzylidene)-N-(4-fluorobenzyl)-1,3-thiazolidine-2,4-dione (17a):

Beige solid, Yield 76%, m.p. 155-156 °C; FT-IR (KBr, cm^-1): 2975, 1739, 1672, 1338, 1078; ¹H NMR (400 MHz, DMSO-d₆) δ in ppm: 7.97 (s, 1H, =CH), 7.63 (d, 2H, J = 7.2 Hz, Ar-H), 7.36-7.57 (m, 5H, Ar-H), 7.16 (t, 2H, Ar-H), 4.82 (s, 2H, CH₂).

 

5-(4-Chlorobenzylidene)-N-(4-fluorobenzyl)-1,3-thiazolidine-2,4-dione (17b):

Pale yellow crystals, Yield 85%, m.p. 178-179 °C; FT-IR (KBr, cm^-1): 3001, 1735, 1670, 1082, 650. ¹H NMR (400 MHz, DMSO-d₆) δ in ppm: 7.97 (s, 1H, =CH), 7.65 (d, 2H, J = 8.4 Hz, Ar-H), 7.61 (d, 2H, J = 8.4 Hz, Ar-H), 7.35 (q, 2H, Ar-H), 7.16 (t, 2H, Ar-H), 4.82 (s, 2H, CH₂).

 

N-(4-Fluorobenzyl)-5-(4-nitrobenzylidene)-1,3-thiazolidine-2,4-dione (17c):

Colorless crystals, Yield 52%, m.p. 224-225 °C; FT-IR (KBr, cm^-1): 3008, 1762, 1668, 1538, 1104; ¹H NMR (300 MHz, DMSO-d₆) δ in ppm: 8.15 (d, 2H, J = 8.1 Hz, Ar-H,), 7.95 (s, 1H, =CH), 7.74-7.82 (m, 6H, Ar-H), 4.83 (s, 2H, CH₂).

 

N-(4-Fluorobenzyl)-5-(4-methoxybenzylidene)-1,3-thiazolidine-2,4-dione (17d):

Colorless solid, Yield 82%, m.p. 143-144 °C; FT-IR (KBr, cm^-1): 3001, 1732, 1683, 1338, 1096. ¹H NMR (400 MHz, DMSO-d₆) δ in ppm: 7.92 (s, 1H, =CH), 7.59 (d, 2H, J = 8.8 Hz, Ar-H), 7.16-7.38 (m, 4H, Ar-H), 7.10 (d, 2H, J = 8.8 Hz, Ar-H), 4.82 (s, 2H, CH₂), 3.83 (s, 3H, OCH₃).

 

5-(4-(Dimethylamino)benzylidene)-N-(4-fluorobenzyl)-1,3-thiazolidine-2,4-dione (17e):

Yellowish orange solid, Yield 75%, m.p. 205-206 °C; FT-IR (KBr, cm^-1): 2949, 1726, 1672, 1375, 1103; ¹H NMR (300 MHz, DMSO-d₆) δ in ppm: 7.82 (s, 1H, =CH), 7.43 (d, 2H, 8.94 Hz, Ar-H), 7.13-7.31 (m, 4H, Ar-H), 6.79 (d, 2H, 8.97 Hz, Ar-H), 4.79 (s, 2H, CH₂), 3.01 (s, 6H, two CH₃).

 

5-(4-Hydroxybenzylidene)-N-(4-fluorobenzyl)-1,3-thiazolidine-2,4-dione (17f):

Pale yellow solid, Yield 64%, m.p. 213-214 °C; FT-IR (KBr, cm^-1): 3003, 1748, 1625, 1514, 1357, 655. ¹H NMR (300 MHz, DMSO-d₆) δ in ppm: 8.90 (s, 1H, OH), 8.15 (d, 2H, J = 8.7 Hz, Ar-H), 7.70 (s, 1H, =CH), 6.82-7.60 (m, 6H, Ar-H), 5.25 (s, 2H, CH₂).

 

N-(4-Fluorobenzyl)-5-(4-(hydroxy-3-methoxy)benzylidene)-1,3-thiazolidine-2,4-dione (17g):

Pale yellow solid, Yield 61%, m.p. 175-176 °C; FT-IR (KBr, cm^-1): 2977, 1706, 1644, 1157, 1427, 1322; ¹H NMR (300 MHz, DMSO-d₆) δ in ppm: 9.11 (s, 1H, OH), 8.18 (d, 2H, J = 9.0 Hz, Ar-H), 7.84 (s, 1H, =CH), 6.81-7.50 (m, 6H, Ar-H), 4.92 (s, 2H, CH₂), 3.73 (s, 3H, OCH₃).

 

5-(3,4-Dimethoxybenzylidene)-N-(4-fluorobenzyl)-1,3-thiazolidine-2,4-dione (17h):

Pale yellow solid, Yield 71%, m.p. 168-170 °C; FT-IR (KBr, cm^-1): 2984, 1678, 1631, 1523, 1403, 1154. ¹H NMR (300 MHz, DMSO-d₆) δ in ppm:  8.05 (d, 2H, J = 8.4 Hz, Ar-H), 7.93 (s, 1H, =CH), 7.10-7.55 (m, 6H, Ar-H), 4.96 (s, 2H, CH₂), 3.82 (s, 6H, two OCH₃).

 

Evaluation of antioxidant activity:

Reducing power activity:

The reducing property of the synthesized compounds (1-17, 14a-h, 15a-h, 16a-h, 17a-h) was determined by using the Oyaizu method (1986).⁹ Different concentrations of test and reference compounds in dimethyl formamide (1 mL) were mixed with potassium ferricyanide (1% w/v, 2.5 mL) and phosphate buffer (pH 6.6, 2.5 mL). The reaction mixture was incubated at 50 °C for 20 min and then centrifuged at 3000 rpm for 10 min. The upper layer of the solution (2.5 mL) was mixed with distilled water (2.5 mL) and ferric chloride (0.1% w/v, 0.5 mL) and the absorbance was measured at 700 nm.  Baseline correction was done using phosphate buffer pH 6.6. The percentage of reducing power of the antioxidant was calculated using the formula given below. The activity was expressed as mean IC₅₀ (µM) ±SD of triplicate measurements.

 

A_control: Optical density of control; A_test: Optical density of test/reference compound.

 

QSAR analysis:

A data set containing twenty five thiazolidinedione analogues and reference ascorbic acid were considered for QSAR analysis. The thermodynamic, electronic and steric properties of the compounds, such as partition coefficient (Log P), hydrogen bond donors and acceptors (HBD, HBA), energy of highest occupied molecular orbital (HOMO), energy of lowest unoccupied molecular orbital (LUMO), dipole moment (DM), molecular weight (MW), polar surface area (PSA), solvent-accessible surface area (SASA), molecular volume (MV), ionization potential (IP) and electron affinity (EA) were considered as the independent variables. The reducing power of test compounds (PIC₅₀) was considered as the dependent variable and was calculated from the IC₅₀ values of the individual compounds. All compound structures were sketched with Marvin Sketch and geometry optimization was performed with LigPrep 2.4 program using MMFF force field at pH 7 ± 2.0. Molecular properties, such as MW, Log P, HBD, HBA, HOMO, LUMO, DM, PSA, MV, IP and EA were calculated for optimized structures. HOMO and LUMO were determined from MOPAC using the PM3 method. Remaining properties were calculated using quickprop 3.3. Multiple Linear Regression (MLR) analysis was performed using Strike 1.9 (Schrodinger, 2010).¹⁰ Various QSAR models were generated and were validated by internal validation measures.

 

RESULTS AND DISCUSSION:

Various 5-substituted aryl/heteroaryl-1,3-thiazolidine-2,4-diones (1-13), N-substituted (14-17) and N,5-disubstituted-1,3-thiazolidine-2,4-diones (14a-h, 15a-h, 16a-h, 17a-h) were prepared as shown in Scheme 1. The appearance of benzylidene (=CH) proton in the range of δ 7.4-8.04 ppm indicated the occurrence of Knoevenagel condensation (formation of 1-13), while absence of -NH proton in the ¹H NMR spectra indicated the formation of N-substituted-1,3-thiazolidine-2,4-diones (14-17). The appearance of benzylidene proton in the range of δ 7.80-8.13 ppm and disappearance of -NH proton peak ensured the substitution at both 3^rd and 5^th positions. 

 

The substances with reductive potential reduce potassium ferric cyanide (Fe³⁺) to ferro cyanide, which on further complexing with ferric chloride forms ferric-ferrous complex. The formed complex has an absorption maximum at 700 nm. An increased absorbance at this wavelength is the measure of reductive capacity of compounds. The reducing power profile of the synthesized compounds was given in table 1. Among the 5-substituted thiazolidinedione analogues (1-13), compound 12 with electron-donating groups shown significant reducing activity (47.1±2.92). In case of N-substituted analogues (14-17), N-[2-(4-methoxyphenyl)-2-oxoethyl]-1,3-thiazolidine-2,4-dione (14) alone shown mild activity (98.2±4.53 µM). The compound 14g with a 4-hydroxy,3-methoxy benzylidene group showed highest reducing power activity (32.6±1.58 µM) among the all test compounds. Compounds with electron-withdrawing -NO₂ and -Cl groups and those with unsubstituted benzylidene group on thiazolidinedione ring have shown poor activity (IC₅₀ > 100 µM).

 

QSAR analysis was performed to identify the molecular descriptors necessary for the antioxidant activity. A number of QSAR models were generated by considering the molecular descriptors in different combinations. The best model is selected from the various statistically significant equations on the basis of squared correlation coefficient (R²), standard deviation (SD), sequential Fischer test (F) and pearson-r (P). The QSAR equation with the lowest SD, and pearson-r value and the R² value reaching to unity is considered as best. A high F value explains the strong relation between the variables under study. The model 12 with lowest SD (0.0733), higher R² value (0.858) and higher F (30.3) values was considered as the best QSAR model (Table 2). QSAR equation for model 12 in reducing power activity is

 

A perusal to Table 2 indicated that model 6 is equally a good fit, because it contained only three parameters, yet the R² value (0.834) was appreciable. Since for calculation of each descriptor 5 to 6 molecules are required, as the present study involves a total of 26 molecules, it would be appropriate to consider the model 12 with four descriptors. The experimental antioxidant activity results were well correlated with the predicted activity with R² value of 0.858 (Fig 1). Compound 14 was identified as outlier and the correlation without this outlier slightly increased (R² = 0.884). In this analysis, compounds 11, 12, 14e and 14g shown good fit (the residual value is zero), indicating their potential to act as lead molecules.

 

The QSAR equation (1) reveals that molecular properties like, HOMO, HBD, DM and SASA were positively contributed to the reducing power activity. The QSAR model was validated internally for its robustness and predictive ability based on the value of leave-one-out cross-validated squared correlation coefficient (LOO-Q²). The model 12 has shown LOO-Q² value of 0.86 (greater than 0.5) and considered to be a good model.

 

Table No:1 Experimental and Strike 1.9 predicted reducing power activity of compounds

Compound Code	Experimental		Predicted  PIC50b	Residualc
	IC50 (µM)±SD	PIC50
6	96.1±3.71	4.02	4.07	-0.05
7	73.2±3.63	4.14	4.23	-0.09
11	50.8±2.68	4.29	4.29	0
12	47.1±2.92	4.33	4.33	0
13	83.4±3.73	4.08	4.07	0.01
14a	98.2±4.53	4.01	3.87	0.14
14a	84.7±3.61	4.07	4.13	-0.06
14d	71.3±3.55	4.15	4.23	-0.08
14e	40.8±2.82	4.39	4.39	0
14f	34.2±1.7	4.47	4.45	0.02
14g	32.6±1.58	4.49	4.49	0
14h	68.4±3.47	4.16	4.19	-0.03
15d	83.8±3.9	4.08	4.16	-0.08
15e	44.7±2.82	4.35	4.34	0.01
15f	38.8±1.91	4.41	4.38	0.03
15g	39.3±1.78	4.40	4.43	-0.03
15h	71.8±3.63	4.15	4.22	-0.07
16e	45.2±2.58	4.34	4.29	0.05
16f	39.8±2.62	4.40	4.32	0.08
16g	39.1±2.76	4.41	4.38	0.03
16h	82.3±4.61	4.08	4.18	-0.1
17e	42.6±2.87	4.37	4.26	0.11
17f	38.1±1.46	4.42	4.3	0.12
17g	41±2.52	4.39	4.36	0.03
17h	85.1±3.48	4.07	4.15	-0.08
Ascorbic acid	21.3±0.58	4.67	4.71	-0.04
a Outlier.  bPredicted values are given as per model 12.  cResidual = Experimental-predicted activity.

 

Fig 1.A plot showing experimental versus predicted activity of compounds with residual representation using QSAR model.

Table No: 2 The statistical relevance of QSAR models in reducing power activity (n = 26)

Model No.	Descriptors	SD	R2	F	P
1	Log P, HOMO, HBA	0.18	0.0981	0.8	5.283X10-1
2	Log P, MW, HOMO	0.175	0.148	1.2	3.270X10-1
3	Log P, MW, HBD	0.0997	0.724	18.4	4.341X10-6
7	HBD, DM, MV	0.0793	0.826	33.1	3.765X10-8
5	HBD, HOMO, SASA	0.0777	0.833	34.9	2.436X10-8
6	HBD, DM, SASA	0.0774	0.834	35.1	2.286X10-8
7	HBD, LUMO, DM, MV	0.081	0.827	23.9	2.230X10-7
8	Log P, HBD, DM, MV	0.0779	0.84	26.2	1.036X10-7
9	HBD, DM, SASA, MV	0.0774	0.842	26.6	9.145X10-8
10	HBD, HOMO, DM, MV	0.0759	0.848	27.9	6.217X10-8
11	Log P, HBD, DM, SASA	0.0758	0.848	27.9	6.173X10-8
12*	HBD, HOMO, DM, SASA	0.0733	0.858	30.3	3.157X10-8
13	HBD, HOMO, DM, MV, PSA	0.0758	0.856	22.6	2.177X10-7
14	HBD, HOMO, DM, SASA, HBA	0.0731	0.866	24.6	1.108X10-7
15	HBD, HOMO, DM, SASA, MV	0.0712	0.873	26.1	6.797X10-8
*Best model

 

 

CONCLUSION:

The antioxidant potential of forty nine thiazolidine-2,4-dione analogues (1-17, 14a-h, 15a-h, 16a-h, 17a-h) was assessed by in vitro reducing power assay. The statistical relevance between molecular descriptors and antioxidant activity was established through descriptor-based QSAR analysis. The compounds with electron-donating groups at the benzylidene portion of the analogues have shown predominant antioxidant activity in comparison of molecules with electron-withdrawing groups. The QSAR studies revealed the contribution of HOMO, HBD, DM and SASA towards the reducing ability of the thiazolidine-2,4-dione analogues. Synthesis of a few more analogues of similar kind, exploring their in vitro, in silico and in vivo activity correlations is under investigation.

 

ACKNOWLEDGMENTS:

The authors are thankful to Gokaraju Rangaraju Educational Society (GRES) and Natco Pharma Ltd., Hyderabad. The Schrodinger software facility was supported by AICTE, New Delhi (RPS-102/2009-10).

 

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Received on 04.11.2014         Modified on 07.11.2014

Accepted on 14.12.2014         © AJRC All right reserved