Insights on the Antioxidant Potential of 1, 2, 4-Triazoles: Synthesis, Screening & QSAR Studies
Sateesh Pokuria, Rajeev K. Singlab,*, Varadaraj G. Bhata* and Gautham G. Shenoya
aDepartment of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal-576104, Karnataka, India; bDivision of Biotechnology, Netaji Subhas Institute of Technology, Azad Hind Fauz Marg, Sector-3, Dwarka, New Delhi-110078, India
Abstract: The aligned manuscript reports synthesis, screening and QSAR analysis of twenty six 1, 2, 4-triazole analogues from their re-spective aromatic carboxylic acids. The structures of synthesized analogues were characterized using physical and spectral analysis. 1, 2, 4-Triazole analogs antioxidant capacity was determined using DPPH radical scavenging assay. Results revealed that out of L, T & VRT series, VRT series of 1, 2, 4-triazoles have significant antioxidant activities when compared with standard ascorbic acid. To obtain struc-tural insights for development of new antioxidants a 2D-QSAR analysis of this dataset of 26 molecules was performed. The 2D-QSAR models correlate with the in vitro results and explain the salient structural features predominant in the molecules responsible for antioxi-dant activity.
1. STATE OF ART & INTRODUCTION “The paradox of aerobic life is that oxygen is both essential and deleterious for cell function.” [1]. Antioxidants have a good role in the prevention and treatment of many disorders by acting as scav-engers of free radicals. Reactive Oxygen Species (ROS) like hy-droxyl radicals (·OH), superoxide anion radicals (O2·-) are produced in living organisms by different mechanisms and are responsible for the bodily complications. Normal aerobic respiration and the stimu-lation of polymorphonuclear leukocytes, macrophages and perox-isomes constitute prominent sources of ROS [2]. It is a well-known fact that antioxidants are body`s defense mechanism which act against harmful byproducts (ROS) produced during normal cell aerobic respiration. The usual method to detect antioxidant activity of compounds is DPPH radical scavenging method which works on the scavenging of 2, 2-diphenyl-1-picrylhydrazyl(DPPH) radicals by antioxidant, followed by absorbance reading at 515-520 nm [3]. Five membered heterocyclic rings have been extensively re-ported for various pharmaceutical applications; it has been shown that nitrogen at 1, 2 and 4 position activates the ring [4]. The 1,2,4-triazole ring has been widely used for antiinflammatory [5, 6], anti-tumor, antiviral [7-10], analgesic [11], anticonvulsant [12], cytotox-icity [13], antifungal [14], antioxidant & urease inhibition [15], antitubercular [16] etc. The above facts strongly suggest making an all out effort to provide effective remedies for silent killers like ROS rendering it worthwhile to design novel 1,2,4-triazoles for antioxidant activity. Development of quantitative structure activity relationship (QSAR) is undoubtedly a landmark in modern chemistry and bio-chemistry. 2D-QSAR makes it easy to interpret the correlation of biological activity with different molecular properties called as *Address correspondence to these authors at the Division of Biotechnology, Netaji Subhas Institute of Technology, Sector-3, Dwarka, New Delhi-110078, India; Tel: +91 98186 03719; Fax: 011 - 2509 9022; E-mails: [email protected]; [email protected] Department of Pharmaceutical Chemistry, Manipal College of Pharmaceuti-cal Sciences, Manipal University, Manipal-576104, Karnataka, India; E-mail: [email protected]
Fig. (1). Scavenging action of 1, 2, 4- triazole analogs on the DPPH radical.
descriptors providing insights in structural features which augment the biological nature of the molecules. A careful molecular manipu-lation will help in obtaining new drugs of real therapeutic merit. In the quest to apply modern tools of computational chemistry for design of novel antioxidants we have developed molecules with 1, 2, 4-triazole moiety and evaluate their ability for scavenging the radical of DPPH as depicted in (Fig. 1).
2. MATERIALS & METHODS The compounds in this study are synthesized as indicted in the Schemes 1, 2 and 3 respectively for series L, T and VRT respec-tively for which the general procedure of synthesis is mentioned in the following sections. Melting points of these triazole analogs were determined by Toshniwal melting point system and are uncor-rected. Infrared spectra were taken on FTIR-8310 Shimadzu spec-trometer using potassium bromide (KBr) pellets and PMR spectra by using AMX 400 at frequency 200 MHz, keeping TMS as inter-nal standard and deuterated DMSO as solvent, chemical shifts in ppm. Solvent system adopted in ascending thin layer chromatogra-phy was ethyl acetate: chloroform (15:85).
390 Current Drug Metabolism, 2014, Vol. 15, No. 4 Pokuri et al.
2.1. Synthesis of L & T Series of 1, 2, 4-Triazoles as per Scheme 1 and 2
2.1.1. Synthesis of Morpholin-4-yl Benzoates (5a and 5b; as in
Scheme 1) [17]
In a sealed tube, solution of methyl substituted benzoate in dry DMSO (25 mL) was mixed with K2HPO4 (10.4 g, 60 mM), fol-lowed by the addition of morpholine (1 mL, 12 mM). Reaction mixture was heated to 95ºc for 20 h. To monitor the progress of reaction, TLC technique with Benzine: Ethylacetate (8:2) as solvent was adopted. Reaction mixture was cooled, followed by dilution with dichloromethane. Dichloromethane layer was then washed with cold water, followed by its drying over anhydrous sodium sulfate. Its concentration under reduced pressure yielded a liquid.
2.1.2. Synthesis of Acid Hydrazide (6a and 6b, as in Scheme 1 and
13a-13d as in Scheme 2) [18]
The respective ester (1.2 g, 5 mM,) was then dissolved in methanol in RBF. Reaction mixture was to be kept free from mois-ture and to maintain it, CaCl2 drying tube was used. Hydrazine
hydrate 99% (0.304 mL, 5 mM) was added slowly, followed by refluxing. To monitor the progress of reaction, TLC technique with Benzine: Ethylacetate (8:2) as solvent was adopted. The reaction mixture was concentrated under reduced pressure upon reaction completion and it yielded crude solid. The residue was then filtered, washed with water, followed by its recrystallization using aqueous ethanol.
2.1.3. Synthesis of Thiosemicarbazides(7a, 7b and 7c, as in
Scheme 1 and 14a-14i as in Scheme 2) [18]
The substituted carboxylic acid hydrazide (0.478 g, 2 mM) was dissolved in ethanol (4 mL) and the substituted phenyl isothiocy-anate (0.340 g, 2 mM) was separately added drop wise with con-tinuous stirring, followed by refluxing for 5 minutes. To monitor the progress of reaction, TLC technique with Benzine: Ethylacetate (8:2) as solvent was adopted. Upon reaction completion, reaction mixture was to be cooled to room temperature. The organic solvent was evaporated under reduced pressure and it yielded crude solid thiosemicarbazide. Ethylacetate: Benzine mixture was also used as recrystallization solvent.
Scheme 1.
1, 2, 4- Triazoles & Antioxidant Action Current Drug Metabolism, 2014, Vol. 15, No. 4 391
2.1.4. Synthesis of 1,2,4-Triazole-3-Thione (L1-3 as in Scheme 1
and T1-9 as in Scheme 2) [18]
The respective thiosemicarbazide (0.300 g, 7 mM) in 4N aque-ous NaOH solution was refused. To monitor the progress of reac-tion, TLC technique with Benzine: Ethylacetate (8:2) as solvent was adopted. Upon reaction completion, reaction mixture was to be cooled to room temperature followed by its filtration. Neutralization of this filtrate by 6N HCl resulted in precipitation of respective triazole. The precipitates were then filtered, washed with water, followed by their recrystallization using aqueous ethanol.
2.1.5. Synthesis of S- Methylated 1,2,4-Triazole (L4 and L5 as in
Scheme 1) [19]
The respective triazole (0.230 g, 0.58 mM) was mixed with Methyl iodide (0.163 g, 1.6 mM), potassium carbonate (58 mg, 5.8 mM) and acetonitrile (3 mL) at room temperature for 3h with regu-lar stirring. The mixture was then partitioned between chloroform and water. The organic layer was decanted, followed by its washing with brine was dried over sodium sulfate. Chloroform was then evaporated under vacuum to afford a solid, which was then recrys-tallized by CH3CN/EtOAC.
2.1.6. Synthesis of 3-Sulphonated- 1,2,4-Triazole (L6 and L7 as in
Scheme 1) [19]
To the respective s-methylated triazole (100 mg, 0.2 M,) methanol(3 mL) and water(1 mL) were added. Oxone (245 mg, 0.8 mM) and mixture were stirred at 700c for 12 hours. To precipitate 3-sulphonated-1,2,4-triazoles, water was added in the reaction mix-ture. The precipitates were then filtered, washed with water to yield a sulphonated triazole as colorless powder.
2.2. Synthesis of VRT-01 – VRT-08 as in Scheme 3 2.2.1. Step 1
2.2.1.a. Synthesis of Methyl Pyridine-3- Carboxylate (VR-1e as in
Scheme 3)
Thionyl chloride (12ml) was added in an RBF containing 7gm of nicotinic acid. It was then heated to reflux for 4 hrs, followed by vacuum to remove excess of SOCl2. HPLC grade CH3OH (30 ml) was added, followed by refluxing for addition 5 hours. It was then kept overnight at room temperature, heated over heating mantle and poured in a china dish while hot. To monitor the progress of reac-tion, TLC technique with Benzine: Ethylacetate (8:2) as solvent was adopted. The crystallized product was filtered off and dried in vacuum desiccator.
Scheme 2.
392 Current Drug Metabolism, 2014, Vol. 15, No. 4 Pokuri et al.
2.2.1.b. Synthesis of Pyridine-3-carbohydrazide (VR-1 as in
Scheme 3)
Hydrazine hydrate (99%) (20 ml) was taken in an RBF contain-ing 6.9 gm of VR-1e. The contents were heated to reflux for 6Hrs. It was then transferred in to a china dish while it was hot. The crys-tallized product so obtained was recrystallized using absolute etha-nol. The reaction was monitored on TLC using solvent system Methanol: Benzene (10:90).
2.2.1.c. Synthesis of [2-(pyridin-3-ylcarbonyl)hydrazinecarbodi-
thioato-S]potassate(1-)[VRD-1 as in Scheme 3]
To a continuously stirred solution of KOH (16.8gm, 0.3 mol) & VR-1(0.2 mol) in absolute ethanol (150ml), CS2 (22.4 gm, 0.3 mol) was added drop by drop, followed by dilution with 100 ml of absolute ethanol with occasional shaking for 4-6 hours. To monitor the pro-
gress of reaction, TLC technique with benzine: ethylacetate (8:2) as solvent was adopted. It was then diluted with dry ether (200 ml) to precipitate VRD-1. The precipitates were filtered and washed with ether. VRD-1 was then used for further reaction without purification.
2.2.2. Step 2 2.2.2.a. Synthesis of ethyl(2,3,4-trisubstitutedphenoxy)acetate[VR-
IIe – VR-IXe as in Scheme 3]
To a 2 gm of free flowing pre-heated potassium carbonate in 20ml of dry acetone, phenol derivatives (0.1 mol) followed by the addition of ethyl chloroacetate (0.15 mol) were added. The contents were heated to reflux for 16-18hrs. To monitor the progress of reac-tion, TLC technique was adopted. After reaction completion, the mixture was filtered while it was hot. Then the residue was washed with warm acetone. Excess of acetone was removed by vacuum.
Scheme 3.
1, 2, 4- Triazoles & Antioxidant Action Current Drug Metabolism, 2014, Vol. 15, No. 4 393
2.2.2.b. Synthesis of 2-(2,3,4-trisubstitutedphenoxy)acetohydra-
zide [VR-II – VR-IX as in Scheme 3]
Hydrazine hydrate (99-100%) (0.1 mol) was taken in an RBF containing VR-IIe – VR-IXe (0.032 mol). The contents were heated to reflux for a period of 6 hours. It was then transferred to a china dish while it was hot. The crystallized product was recrystallized using absolute ethanol. The reaction was monitored on TLC using solvent system Methanol: Benzene (10:90).
2.2.3. Step 3
Synthesis of N-[3-(pyridin-3-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-2-(2,3,4-trisubstitutedphenoxy)acetamide [VRT-01 –VRT-07 as in Scheme 3]: The mixture of VRD-1(0.01 mol) and 2-(2,3,4-trisubstitutedphenoxy)acetohydrazide (0.014 mol) was re-fused for 4 hrs. To monitor the progress of reaction, TLC technique was adopted. The reaction mixture was with 100 ml of ice cold water, followed by acidification with concentrated HCl. The pre-cipitates were then filtered, washed with water, and recrystallized using absolute ethanol to yield desired triazole. Column purified 1,2,4-triazoles were then used for further studies. Synthesis of N-(3-(pyridine-3-yl)-5-thioxo-1H-1,2,4-triazol-4(5H)- yl)nicotinamide[VRT-08 as in Scheme 3]: The mixture of VRD-1(0.01 mol) and nicotinohydrazine (0.012 mol) was refused for 4 hrs. To monitor the progress of reaction, TLC technique was adopted. The reaction mixture was diluted with 100 ml of ice cold water, followed by acidification with concentrated HCl. The pre-cipitates were then filtered, washed with water, and recrystallized using absolute ethanol to yield desired triazole. Column purified VRT-08 was then used for further studies.
2.3. DPPH Radical Scavenging Activity The DPPH radical scavenging assay was carried out in a 96 well microtiter plate. To 100 l of DPPH solution, 100 l of each of the test sample or the standard drug, in case of standard, was added separately in wells of the micro-titter plate. The nal concentrations in the wells for test and standard solutions were 1000-15.625 g/ml. The plates were incubated at 37 ºC for 20 min and the absorbance of each solution was measured at 540 nm, using ELISA micro-titter plate reader. The experiment was performed in triplicate and % scavenging activity was calculated using the general formula. IC50 (Inhibitory concentration) is the concentration of the sample required to scavenge 50% of DPPH free radicals and it was calculated from the graph, % scavenging vs. concentration” [20, 21].
2.4. QSAR Analysis In the quest for identifying structural features responsible for antioxidant activity of twenty six analogs of 1,2,4-triazole analogs, two dimensional QSAR studies of these analogs were carried out using the Vlife Molecular Design Suite 4.3 [5, 22, 23]. In order to perform 2D QSAR, the biological activity was converted to Loge (IC50) or In (IC50). The structures were sketched using the 2D- Draw app of VLife MDS 4.3, and were converted to 3D, followed by batch energy minimization using the Merck Molecular Force Field. Energy minimized structures of these 1, 2, 4-triazoles were ported to the 2D-QSAR Module of VLIFE MDS 4.3, for computing the descriptors corresponding to the physicochemical and alignment independent topological descriptors. Total 309 descriptors were calculated out of which 56 descriptors were invariable, henceforth removed from the experimentation. The calculated properties were further used to delineate a relationship between properties of the molecules and their biological activity using regression methods. The data prior to model building were classified into training and test sets using Sphere exclusion, which classifies the data dependent on the dissimilarity between molecules defined by Euclidean dis-
tances. The Multiple Linear regression model with stepwise for-ward backward variable selection (MLR-SFB), a “Filter” based approach was used, the filters applied were. 1) Cross Correlation Limit (<0.5) in order to eliminate terms with
high inter-correlation; 2) Number of variable in final equation (upto 4); 3) F test In (2.00); and 4) F Test Out (1.99) indicating signifi-
cance of to be selected variable; 5) r2 as Term selection criteria; 6) Variance cut-off (0.00) with auto scaling indicating variation
in selected variables; 7) Number of random iterations (100) indicating iterations carried
out to build models.
3. RESULTS & DISCUSSION 3.1. Chemistry A total of 26 molecules (Fig. 2) in three series L, T & VRT were synthesized as depicted in Schemes 1, 2 & 3 respectively. The com-pounds were characterized using spectral data. The IR absorptions in the region of 1570-1550 cm-1 due to N=N and in the region of 1640-1560 cm-1 due to C=N functions are the diagnostic features for the compounds. 1, 2, 4- triazoles show the characteristic strong N-H stretching of a secondary amine at 3400-3200 cm-1. In 5-substituted-3-mercapto-1,2,4-triazoles, the thiol-thione tautomeric forms can also be differentiated in the IR spectra by the presence of C=S absorption band at about 1325-1300 cm-1 for thione and by characteristic SH absorption band at about 2600-2550 cm-1 for thiol forms. The L and VRT series of 1, 2, 4-triazole have thione form of 5-mercapto group while T series has thiol form. In EIMS of 1, 2, 4-triazoles, a strong molecular ion peak is always observed. In the series of L, T and VRT of 1,2,4-triazole, N(1) –H proton was found to be a singlet and was seen to be most downfield due to the delocalization of the lone pair of nitrogen on the alpha, -unsaturated double bond. 3,4-dihydro-4,5-diphenyl-2H-1,2,4-triazole-3-thiol(T1): IR(KBr Disc) cm-1- 3442(N-H), 2563(S-H), 3103(Ar C-H), 1593 & 1544(C=C), 1502(C=N), 1332(C-N); MS- 252[M+], 220[M+ - SH], 194[M+ - CHNS], 149[M+ -C7H5N], 118[M+ -C7H5NS], 103[M+ -C7H6N2S], 91[M+ -C8H5N2S]. 4-(2,4-dichlorophenyl)-3,4-dihydro-5-phenyl-2H-1,2,4-triazole-3-thiol(T2): IR(KBr Disc) cm-1- 3441 & 3406(N-H), 3080 & 3406(Ar C-H), 2549(S-H), 1600(C=C), 1560(N-H), 1494(C=N), 1332(C-N); MS- 322[M+], 286[M+ - SH], 266[M+ - CHNS], 171[M+ - C13H8N2Cl2], 149[M+ - C7H3NCl2], 91[M+ - C8H3NCl2]. 5-(4-fluorophenyl)-3,4-dihydro-4-phenyl-2H-1,2,4-triazole-3-thiol(T3): IR(KBr Disc) cm-1- 3444(N-H), 3089 & 3012(Ar C-H), 2563(S-H), 1608(C=C), 1550(N-H), 1514(C=N), 1334(C-N); MS- 271[M+], 253[M+ - F], 212[M+ - CHNS], 149[M+ - C7H4NF], 91[M+ - C7H4NF- CHNS], 77[M+ - C7H4N2F- CHNS]. 5-(4-chlorophenyl)-3,4-dihydro-4-phenyl-2H-1,2,4-triazole-3-thiol (T4): IR(KBr Disc) cm-1- 3446(N-H), 3055 & 3026(Ar C-H), 2557(S-H), 1597 & 1475(C=C), 1541(N-H), 1498(C=N), 1328(C-N); MS- 286[M+], 253[M+ -SH], 152[M+ - C7H5NS], 149[M+ -C7H4ClN], 137[M+ - C7H6N2S], 91[M+ - C7H4ClN- CHSN]. 4-(4-chlorophenyl)-3,4-dihydro-5-phenyl-2H-1,2,4-triazole-3-thiol (T5): IR(KBr Disc) cm-1- 3444 & 3427(N-H), 3107 & 3080(Ar C-H), 2563(S-H), 1544(C=C), 1498(C=N), 1330(C-N); MS- 286[M+], 252[M+ -SH], 183[M+ -C7H5N], 167[M+ -C7H6N2], 125[M+ -C7H5N- CHNS], 118[M+ -C7H4NSCl], 103[M+ -C7H5N2SCl]. 4-(2,4-dichlorophenyl)-3,4-dihydro-5-phenyl-2H-1,2,4-triazole-3-thiol (T6): IR(KBr Disc) cm-1- 3363 & 3324(N-H), 3084(Ar C-H), 2549(S-H), 1566(C=C), 1485(C=N), 1355(C-N); MS- 322[M+], 286[M+ -SH], 266[M+ -CHNS], 219[M+ -C7H5N], 189[M+ -CHNS- C6H5].
394 Current Drug Metabolism, 2014, Vol. 15, No. 4 Pokuri et al.
3.2. Antioxidant Activity Antioxidant activity of the synthesized compounds evaluated by DPPH assay is as shown in Table 1. The compounds from L (L1-L5) & T (T1-T11) series did not exhibit significant antioxidant activity for except compound T4 while compounds in the VRT series (VRT-01 – VRT-08) possessed excellent antioxidant capac-ity. The insignificant antioxidant capacity of L & T series of 1, 2, 4-triazoles may be attributed to the ideal electronic configuration in the scaffold to reduce the free radical by disassociation.
3.3. Quantitative Structure Activity Relationship A QSAR model was developed for 26 analogs of 1,2,4-triazole for antioxidant applying stepwise forward backward method coupled with multiple linear regression. The generated model was selected based on statistical parameters like correlation coefficient (r2), cross validation correlation coefficient (q2) and predicted r2. The best model for the identification of significant descriptors is as follows:
Table 1. Observed and modeled antioxidant action of 1, 2, 4-triazole using DPPH radical scavenging assay and simulated (QSAR) technique respectively. (Refer to Fig. 1).
Code Experimental Activity [Loge(IC50)]
Predicted Activity [Loge(IC50)]
VRT-01 -1.96 -1.96
VRT-02t 2.769 6.56
VRT-03t 2.96 2.68
VRT-04 1.73 2.29
VRT-05 6.02 6.02
VRT-06 3.12 2.01
VRT-07 1.11 1.88
VRT-08 3.83 3.61
T1 5.69 6.09
T2 5.85 5.93
T3t 6.24 6.31
T4 4.89 5.95
T5 5.58 5.87
T6 5.98 5.74
T7t 5.24 5.86
T8 6.42 5.87
T9 5.47 5.74
T10 6.91 6.16
T11t 6.91 5.89
L1 5.739 5.28
L2t 6.03 5.62
L3t 5.72 5.27
L4 5.49 5.43
L5t 5.79 5.82
L6 5.61 5.43
L7 5.56 5.69
t = Test Molecule
LogIC50 = -1.8161(±0.0270) T_N_N_3 - 3.4415(±0.3090) T_O_Cl_4 + 1.8465(±0.2733) T_N_O_1 - 9.8325(±3.3166) SAMostHydrophobic + 8.4566. From the statistical point of view, this is a robust model. Statis-tical parameters for this equation were as follows: N = 18, r2 = 0.9449, q2 = 0.6067, F-Test= 55.6963, r2se = 0.6087, pred_r2 = 0.1456. The generated model is able to classify 94% variation within the training set molecules. The actual and predicted activities are as indicated in Table 1, relationship between the experimental and predicted LogIC50 values is depicted in the fitness plot is shown in (Fig. 3). The descriptors selected in the model are as follows:
396 Current Drug Metabolism, 2014, Vol. 15, No. 4 Pokuri et al.
Fig. (3). Observed vs. predicted antioxidant activity of 1, 2, 4-triaozle analogs.
Fig. (4). Contribution Plot revealing the proportional of physicochemical and alignment independent topological descriptors influencing the antioxi-dant activity of 1, 2, 4- triazoles.
Fig. (5). Observed activity vs residual value in relation to QSAR model.
“T_N_N_3: This is the count of number of nitrogen atoms (sin-gle, double or triple bonded) separated from any other nitrogen atom (single, double or triple bonded) by 3 bonds in a mole-cule” [23].
“T_O_Cl_4: This is the count of oxygen atoms (single,double or triple bonds) separated from chlorine atom(single, double or triple bonded) by four bonds in a molecule” [23].
“T_N_O_1: This is the count of number of nitrogen atoms (sin-gle, double or triple bond) separated from any oxygen atom (single, double or triple bond) by single bonds in a molecule” [23].
“SAMostHydrophobic: This is the most hydrophobic value on the vdw surface. (By Audry method using SLogP)” [23].
Contribution plot of significant descriptors is shown in (Fig. 4). The descriptor positively contributing to activity is T_N_O_1 which represents the number of nitrogen atoms attached to oxygen atom conducive to the activity. The highest contribution of the de-scriptors SAMostHydrophobic, indicates that higher value of the most hydrophobic point on the molecule is hostile for activity. The second most contributing descriptor T_O_Cl_4 indicating the num-ber of oxygen atoms separated from chlorine atom by 4 bonds is hostile for activity. The descriptor T_N_N_3 represents the number of nitrogen atoms separated from other nitrogen by 3 bonds indicat-ing that two nitrogen atoms near each other except for the nitrogen forming a triazole ring are hostile for activity.
Along with this, relationship between observed antioxidant activity and residual value is also graphically represented by (Fig. 5).
4. CONCLUSION
A total of twenty six NCEs were synthesized having 1,2,4-triazole motif and evaluated for their antioxidant activity using DPPH radical scavenging method. Based on these results, quantita-tive structure activity relationship model has been modeled, so as to ease the design of newer antioxidant molecules.
FUNDING AGENCY Wet lab work was supported by Manipal University and com-putational studies were supported by Netaji Subhas Institute of Technology. QSAR studies were performed on VLife MDS 4.3 funded by Science & Engineering Research Board vide project no. SR/FT/LS-149/2011.
CONTRIBUTION OF EACH AUTHOR Sateesh Pokuri: Synthesis & antioxidant evaluation of T & L series of 1,2,4-Triazoles. Rajeev K Singla: Synthesis & antioxidant evaluation of VRT series of 1,2,4-Triazoles. Varadaraj Bhat G: QSAR studies & Data Analysis. Gautham G Shenoy: Data Analysis & supervision of Sateesh Pokuri & Rajeev K Singla.
CONFLICT OF INTEREST The authors confirm that this article content has no conflict of interest.
ACKNOWLEDGEMENTS The author would like to express his gratitude towards IISc, Bangalore for providing NMR Data as well as management of Ma-nipal University for supporting this research. The author Rajeev K. Singla received SERB-Young Scientist Fellowship from Science & Engineering Research Board, Govt. of India(vide project no. SR/FT/LS-149/2011). We would to express our sincere thanks to
1, 2, 4- Triazoles & Antioxidant Action Current Drug Metabolism, 2014, Vol. 15, No. 4 397
Dr. Kundan Ingale, Application Scientist, Vlife Sciences Pvt. Ltd and his technical team for the technical check during revision of our manuscript.
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