SYNTHESIS, CHARACTERIZATION, AND PHARMACOLOGICAL EVALUATION OF SOME NOVEL HYDRAZONE DERIVATIVES DERIVED FROM 3-((4-FORMYL-2-METHOXYPHENOXY) METHYL) BENZONITRILEHTML Full Text
SYNTHESIS, CHARACTERIZATION, AND PHARMACOLOGICAL EVALUATION OF SOME NOVEL HYDRAZONE DERIVATIVES DERIVED FROM 3-((4-FORMYL-2-METHOXYPHENOXY) METHYL) BENZONITRILE
Kantlam Chamakuri 1, Srinivasa Murthy Muppavarapu *2 and Narsimha Reddy Yellu 3
School of Pharmaceutical Sciences 1, Jawaharlal Nehru Technological University, Kakinada-533 003, Andhra Pradesh, India.
Department of Pharmaceutical Chemistry 2, Vignan Institute of Pharmaceutical Sciences, Deshmukhi, Nalgonda-508 284, Telangana State, India.
Department of Pharmacology 3, University College of Pharmaceutical Sciences, Kakatiya University, Warangal-506 009, Telangana State, India
ABSTRACT: Hydrazones are an important classe of biologically active compounds found in many synthetic compounds. In view of their importance in synthetic chemistry, the present article reported that a new series of novel hydrazone derivatives (4a-e) were synthesized by condensation of 3-((4-formyl-2-methoxyphenoxy)methyl)benzonitrile(3) with different benzohydrazides and confirmed by their IR, 1H NMR, and Mass spectral data. Further these synthesized derivatives (4a-e) were evaluated for their biological activities such as antiinflammatory, analgesic, and antibacterial activities. All the derivatives were showing the pharmacological activities mainly due to the presence of pharmacophore, azomethine group (CONH- N=CH) and were modified with various substituents. Among all the compounds 4a, 4d, and 4e incorporated with 4-methoxy, 4-chloro and 2,4-dichloro moieties exhibited more antiinflammatory activity and the remaining compounds 4b and 4c incorporated with 4-bromo and 2-bromo substituents showed moderate activity when compared with standard reference, indomethacin. The compounds 4d, 4e and 4b showed good analgesic activity and remaining compounds 4a and 4c showed moderate activity comparable to that of standard drug diclofenac. The compounds 4a and 4e exhibited excellent antibacterial activity and the compounds 4b, 4c and 4d showed less activity when compared with standard drug, Gentamycin
Hydrazone, Antiinflammatory, Analgesic, Antibacterial
INTRODUCTION: Hydrazones constitute biologically active drug molecules. Hydrazone derivatives are containing highly reactive azomethine group (CONH- N=CH) and thus useful in new drug development 1.Recently, a lot of biologically important hydrazone derivatives with a number of functional groups have been synthesized from aromatic and aliphatic compounds 2.
New compounds are being synthesized as drugs in order to combat diseases with maximal therapeutic effects and minimal toxicity. Hydrazones are used for the synthesis of novel heterocyclic compounds 3. Hydrazones have attracted a considerable attention of medicinal chemists due to their wide range of biological importance in medicinal chemistry. Many studies have confirmed that hydrazone derivatives exhibit a wide spectrum of biological activities including anti-inflammatory 4, 5 analgesic 6, 7 antibacterial 8, 9 antifungal10, 11, anticancer 12, antioxidant13, 14 antidepressant 15, antitubercular 16, cytotoxicity 17, antiamoebic 18, antitumor 19, antiplatelet 20, anticonvulsant 21, antimycobacterial 22, antihypertensive 23 and antinociceptive 24 activities. Encouraged by the biological applications of hydrazones, the present research work is aspired to describe synthesis, characterization and antiinflammatory, analgesic and antibacterial activities of novel hydrazone derivatives 4a-e derived from vanillin.
MATERIALS AND METHODS:
Chemicals and solvents used were purchased from Fluka and Merck. All the reagents used were of analytical grade. For thin-layer chromatography (TLC) analysis, Merck precoated silica gel 60 F254 Plates were used and spots were visualized with UV light. Melting point determinations were performed by using Mel-temp apparatus and are uncorrected. Infrared (IR) spectra were recorded on a Perkin Elmer FT-IR spectrometer. 1H NMR spectra were recorded in Varian MR-400 MHz instrument. Chemical shifts were reported in δ parts per million (ppm) downfield from tetramethylsilane (TMS) with reference to internal standard and the signals were reported as s (singlet), d (doublet), dd (doublet of doublet), t (triplet), q (quartet), m (multiplet) and coupling constants in Hz. The Mass spectra were recorded on Agilent ion trap MS.
Preparation of 3-((4-formyl-2-methoxyphenoxy) methyl)benzonitrile(3) from vanillin(1) with 3-(bromomethyl) benzonitrile(2):
Vanillin was used as a starting material for the preparation of hydrazones. K2CO3 (0.905g, 6.55mmol) was added to the DMF solution containing vanillin(1) (1g, 6.57mmol), and then added 3-(bromomethyl) benzonitrile (2) (1.41g, 7.23mmol). The reaction mixture was stirred at 80 oC, for 2h. After the reaction reached completion, the mixture was cooled to room temperature and the precipitate obtained was filtered and washed with petroleum ether, to obtain the pure compound(3). The 3-((4-formyl – 2 - methoxy phenoxy) methyl)benzonitrile(3) was synthesized and the quantified data along with the spectral data has been presented.
A white solid was obtained in 95% yield. mp 88 oC; FT-IR (KBr): υmax 3448, 3348, 2973, 2824, 2739, 2229, 1680, 1590, 1517, 1451, 1425, 1386, 1341, 1318, 1275, 1244, 1177, 1125, 1029, 887, 870, 816, 796, 785, 683, 639, 619, 551 cm-1; 1H NMR (400 MHz, DMSO-d6): δ 3.85 (s, 3H), 5.28 (s, 2H), 7.26 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 1.6 Hz, 1H), 7.55 (dd, J = 2.0, 8.4 Hz, 1H), 7.64 (t, J = 8.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.94 (s, 1H), 9.85 (s, 1H); MS (ESI) m/z 267.8 (M+H)+.
Synthesis of Hydrazone Derivatives (4a-e) from 3-((4-formyl - 2 - methoxy phenoxy) methyl) benzonitrile (3) reacting with different Benzohydrazide derivatives (a – e):
The hydrazone derivatives (4a-e) were synthesized by addition of benzohydrazide derivatives (a-e) to the solution of ethanol containing the 3-((4-formyl-2-methoxyphenoxy) methyl) benzonitrile (3), and refluxed for 1h. The reaction mixture was cooled to room temperature and the precipitate obtained was filtered and washed with petroleum ether, to obtain the pure compounds 4a-e. The yield of products varied from 89 – 97%. The hydrazone derivatives 4a-e were synthesized and the quantified data along with the spectral data was presented.
(E)-N'-(4-(3-cyanobenzyloxy) - 3 - methoxy benzylidene)-4-methoxybenzohydrazide(4a):
White solid; Yield: 96%; mp 198-206 oC; FT- IR (KBr): υmax 3435, 3232, 2939, 2838, 2230, 1644, 1605, 1576, 1542, 1507, 1462, 1417, 1377, 1295, 1269, 1256, 1232, 1178, 1139, 1052, 1030, 1010, 971, 899, 839, 810, 793, 760, 690, 627, 537 cm-1; 1H NMR (400 MHz, DMSO-d6): δ 3.83 (s, 3H), 3.85 (s, 3H), 5.21 (s, 2H), 7.20-7.05 (m, 4H), 7.37 (s, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.92-7.80 (m, 5H), 8.38 (s, 1H), 11.64 (s, 1H); MS (ESI) m/z, 416 (M+1).
(E)-N - (4-(3-cyanobenzyloxy) – 3 - methoxy benzylidene)-4-bromobenzohydrazide(4b):
White solid; Yield: 92%; mp 195-200 oC; FT- IR (KBr): υmax 3431, 3221, 3064, 2936, 2234, 1649, 1605, 1544, 1510, 1483, 1453, 1418, 1376, 1270, 1233, 1198, 1166, 1138, 1034, 1009, 970, 895, 867, 795, 754, 687, 623, 535 cm-1; 1H NMR (400 MHz, DMSO-d6): δ 3.85 (s. 3H), 5.22 (s, 2H), 7.14 (d, J = 8.4 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 7.38 (s, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.93-7.74 (m, 7H), 8.38 (s, 1H), 11.83 (s, 1H); MS (ESI) m/z, 463.9 (M-1).
(E)-N'-(4-(3-cyanobenzyloxy) – 3 - methoxy benzylidene)-2-bromobenzohydrazide(4c):
White solid; Yield: 97%; mp 185-190 oC; FT- IR (KBr): υmax 3448, 3185, 3047, 3008, 2230, 1657, 1600, 1557, 1509, 1463, 1420, 1390, 1375, 1301, 1268, 1226, 1171, 1138, 1068, 1029, 1004, 901, 863, 831, 808, 793, 757, 737, 693, 655, 555 cm-1; 1H NMR (400 MHz, DMSO-d6): δ 3.85 (*3.63, s, 3H), 5.21 (*5.14, s, 2H), 7.00 (*6.95, J = 8.6 Hz, 1H), 7.20 (*7.10, d, J = 8.6 Hz, 1H), 7.55-7.35 (m, 4H), 7.76-7.52 (m, 3H), 7.93-7.80 (m, 2H), 8.19 (*7.95, s, 1H), 11.94 (*11.82, s, 1H); MS (ESI) m/z, 463.9 (M+H).
(E)-N'-(4-(3-cyanobenzyloxy) – 3 - methoxy benzylidene)-4-chlorobenzohydrazide(4d):
White solid; Yield: 94%; mp 185-190 oC; FT-IR (KBr): υmax 3223, 3078, 3055, 2976, 2938, 2879, 2236, 1649, 1605, 1596, 1542, 1509, 1485, 1454, 1419, 1376, 1329, 1271, 1233, 1198, 1166, 1139,1093, 1033, 1006, 970, 896, 866, 841, 795, 755, 687, 624, 538 cm-1; 1H NMR (400 MHz, DMSO-d6): δ 3.86 (s, 3H), 5.22(s, 3H), 7.14 (d, J = 8.4 Hz, 1H), 7.22 (d, J = 7.2 Hz, 1H), 7.38 (s, 1H), 7.66 - 7.60 (m, 3H), 7.83 (t, J = 7.6 Hz, 2H), 7.92 (d, J = 8.0 Hz, 3H), 8.38 (s, 1H), 11.83 (s, 1H); MS (ESI) m/z, 419.9 (M+H)+.
(E)-N'-(4-(3-cyanobenzyloxy) - 3 - methoxy benzylidene)-2,4-dichlorobenzohydrazide(4e):
White solid; Yield: 89%; mp 185-190 oC; FT-IR (KBr): υmax 3431, 3190, 3056, 2932, 2836, 2232, 1652, 1599, 1561, 1515, 1467, 1386, 1331, 1268, 1234, 1172, 1133, 1103, 1034, 1010, 943, 899, 854, 793, 689, 571, 534 cm-1; 1H NMR (400 MHz, DMSO-d6): δ 3.85 (*3.66, s, 1H), 5.21 (*5.15, s, 1H), 7.03 (*6.98, d, J = 8.8 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.38 (d, J = 1.6 Hz, 1H), 7.66-7.48 (m, 3H), 7.93-7.74 (m, 3H), 8.18 (*7.95, s, 1H), 12.03 (*11.87, s, 1H); MS (ESI) m/z, 453.9 (M+1).
4a; R= 4-Methoxy
4b; R= 4-Bromo
4c; R= 2-Bromo
4d; R= 4-Chloro
4e; R= 2,4-Dichloro
Animals and Instruments used:
Adult Wistar rats of either sex weighing between 150-200g were used for the study of anti-inflammatory activity. Adult Wistar mice of either sex (20-25 g) were used for the study of the analgesic activity. All experimental procedures were carried out according to the guidelines given by the Committee for the Purpose of Control and Supervision on Experiments on Animals (CPCSEA) and were approved by the Institutional Animal Ethics Committee with registration number. 1722/RO/ERe/S/13/CPCSEA.
All the synthesized compounds were tested for in vivo antiinflammatory activity 25 in adult wistar rats by paw edema method and edema was produced by using Carrageenan, foot volume measured by using plethysmometer. Analgesic activity 26 was carried in adult wistar mice by using Eddy's hot plate method. In vitro antibacterial activity 27 was done by the disk diffusion technique.
The synthesized compounds were screened for anti inflammatory, analgesic, and antimicrobial activities. The test dose for the synthesized compounds was fixed as 10 mg/kg for anti inflammatory and analgesic activities and fixed as 100 and 200 µg ̸ mL for antimicrobial activity. Indomethacin was taken as the standard drug for anti inflammatory activity and Diclofenac sodium was taken as the standard drug for analgesic activity. Gentamycin was used as standard drug for antimicrobial activity.
Anti inflammatory activity by paw edema method:
Adult Wistar rats of either sex with a body weight between 150-200g were used to study anti inflammatory activity. The animals were starved overnight. The test drug and standard were suspended in 1%CMC (control) and given orally. Thirty minutes later, 0.05 ml of 1% solution of carrageenan was given by a subcutaneous injection into the plantar side of the left hind paw of all the rats. The paw volume was measured by using plethysmometer after injection. Then the paw volume was again measured after 1h, 2h, 3h and 4h time intervals. The results were summarized in Table 1.
Analgesic activity by Eddy's hot plate:
Adult Wistar mice of either sex (20-25 g) Were weighed and numbered, the basal reaction-time was noted by observing hind paw licking in animals when placed on the hot plate maintained at constant temperature (55ºC). Drug was given by oral route to animals and noted the reaction time of animals on the hot plate at 30, 60, 90, 120 and 180 min after the drug administration. The percent increase in reaction-time (as index of analgesia) was calculated at each time interval. The results were shown in Table 2.
Antibacterial activity by disk diffusion method:
The antibacterial activity of the synthesized compounds was determined by the standard disk diffusion method. The test organism chosen were Escherichia coli and Bacillus subtillis. The concentration of the sample compounds and the standard was prepared as 100 and 200 µg ̸ mL in DMSO. Gentamycin was used as standard drug. The antimicrobial study was conducted for the determination of following parameters like, Zone of Inhibition and MIC (minimum inhibitory concentration), Different concentrations of synthetic chemical compounds were tested for anti-microbial activity by disc diffusion method. Nutrient agar medium was inoculated with different microorganisms and once the media was solidified, it was punched with a 6 mm diameter well. The tested compounds solutions were prepared in DMSO and evaluated them for their in vitro antibacterial activity against Bacillus subtillis, and Escherichia coli respectively. Agar plates containing bacteria and synthetic chemical compounds were incubated at 37ºC for 24 hrs. Antimicrobial activity was evaluated by measuring the inhibition zone. The zone of inhibition obtained by different synthesized compounds was compared with that of standard drug Gentamycin. The results were given in Table 3.
RESULTS AND DISCUSSION:
The synthesized hydrazone derivatives 4a–e explained in this paper were prepared according to the synthetic Scheme 1. Vanillin 1 present in the solution mixture of K2CO3 and DMF was condensed with 3-(bromomethyl) benzonitrile (2) by stirring at 80oc, for 2h to get the pure compounds (3) in 95% yield. To the solution of 3-((4-formyl - 2 - methoxyphenoxy) methyl) benzonitrile (3) in ethanol, add Benzohydrazide derivatives (a-e) and refluxed for 1h to obtain the pure compounds 4a-e. The yield of the product varied from 89 – 97%. The structures of the synthesized hydrazone derivatives 4a-e were confirmed by IR, 1H NMR and Mass spectral data. The 1H NMR data for the derivatives 4a–e were in agreement with the assigned structures. All the aliphatic and aromatic protons were observed at expected regions. The mass spectra of compounds 4a-e showed (M+1) peaks, in agreement with their molecular formula.
The newly prepared hydrazone derivatives 4a-e were screened for anti-inflammatory activity at concentration 10 mg/kg by carrageenan paw edema method. Among all tested compounds, 4a, 4d and 4e exhibited maximum activity, while compounds 4b and 4c showed moderate activity when compared with standard indomethacin, anti inflammatory agent. In general, it is observed from Table 1 and that the compounds having 4-methoxy, 4-chloro, and 2, 4-dichloro exhibited excellent anti inflammatory activity and remaining compounds showed moderate activity. As all the tested compounds emerged as active against inflammation, it indicates that this basic moiety can be a promising scaffold for anti inflammatory drugs.
The newly prepared chalcone derivatives 4a-e were screened for analgesic activity at concentration 10 mg/kg by using hot plate method. Among all tested compounds, 4d, 4e and 4b showed maximum activity, while compounds 4a and 4c showed moderate activity when comparable with disease control. In general, it is observed from Table-2 and that the compounds having 4-chloro, 2, 4-dichloro and 4-bromo, exhibited excellent analgesic activity and remaining compounds showed moderate activity. As all the tested compounds emerged as active against analgesia, it indicates that this basic moiety can be a promising nucleus for analgesic drugs. It may be suggested that this basic moiety can be a promising scaffold for analgesic drugs.
Anti- Bacterial Activity:
The anti-bacterial activity of 4a–e compounds was determined by the disc diffusion method with Gentamycin (100 & 200µg ̸ mL) as the reference standard. The synthesized compounds were screened against two Gram positive bacterial strains viz., Escherichia coli, and Bacillus subtillis. The outcome of the results are presented in the Table-3, it is evident from the results that, compounds 4a, 4d and 4e exhibited high activity against the Escherichia Coli bacteria, the rest of the compounds were found to be moderately active (4b and 4c) against the Escherichia Coli. The compound 4a exhibited high activity against the Bacillus subtilis bacteria, the rest of the compounds were found to be moderately active (4b, 4c, 4d and 4e) against the Bacillus subtilis. It is observed from the above anti-bacterial data that within the hydrazone derivatives 4a-e, compounds incorporated with the substituents such as 4-methoxy, and 2, 4-dichloro exhibited excellent antibacterial activity.
TABLE 1: ANTIINFLAMMATORY ACTIVITY OF SYNTHESIZED COMPOUNDS 4 a-e IN CARRAGEENAN-INDUCED RAT PAW EDEMA.
|Compounds||R||Volume of paw edema (ml)*|
|After 1 hr After 2hr After3hr After4hr|
|Control||0.63 ±0.021||0.70 ±0.036||0.80 ±0.000||0.80 ±0.000|
|Standard||0.55 ±0.034 ns||0.41 ±0.016 ***||0.30 ±0.044***||0.25±0.034***|
|4a||4-Methoxy||0.46 ±0.033*||0.40 ±0.044 ***||0.30 ±0.044***||0.26 ±0.033***|
|4b||4-Bromo||0.48 ±0.040ns||0.38 ±0.060 ***||0.33 ±0.049***||0.32±0.042***|
|4c||2-Bromo||0.48 ±0.040ns||0.36 ±0.055 ***||0.30 ±0.036***||0.31±0.040***|
|4d||4-Chloro||0.46 ±0.033*||0.38 ±0.016 ***||0.31 ±0.040***||0.28±0.040***|
|4e||2,4-Dichloro||0.53 ±0.033ns||0.43 ±0.021***||0.35 ±0.050***||0.28±0.040***|
All the values were expressed as mean ±SEM, n=6.
* p <0.05, **p <0.01, ***p <0.001, ns p>0.05 followed by Tukey’s test when compared with Disease control (Carrageenan Treated).
TABLE 2: ANALGESIC ACTIVITY OF THE HYDRAZONE DERIVATIVES 4 a-e BY HOT PLATE METHOD IN ALBINO MICE.
|After administration(paw licking response)|
|30 min 60min 90min 120min 180min|
|Control||8.33±0.33ns||8.50 ±0.22**||8.33 ±0.33**||8.16±0.16**||8.17±0.30**||8.33±0.21**|
All the values were represented as MEAN ±SEM, n=6.
P value *p<0.05, **p<0.01,***p<0.001, ns p>0.05 followed by Dunnet’s test
Compare with normal control (treated with vehicle)
TABLE 3: RESULTS OF ANTIBACTERIAL BIOASSAY OF COMPOUNDS 4a-e (CONCENTRATION USED (100&200 µg ̸ mL) OF DMSO)
Compound Code R
|In vitro antibacterial activity
Zones of inhibition of compounds 4a-e in mm
|Escherichia Coli||Bacillus subtilis|
|(100 µg ̸mL)||(200 µg ̸mL)||(100 µg ̸mL)||(200 µg ̸mL)|
(100&200µg ̸ mL)
Zones of inhibition were measured in mm
CONCLUSION: In conclusion the new hydrazone derivatives were synthesized and the synthesized compounds were confirmed by spectral analysis such as IR, 1HNMR and MS spectroscopy. However the newly synthesized compounds were screened for antiinflammatory and analgesic activities by in vivo methods. Antiinflammatory activity was found to be more for compound 4a. The rest of the compounds were found to have moderate antiinflammatory activity. All the compounds exhibited analgesic activity and more activity was found in 4d. The compounds were subjected to their antibacterial activity by in vitro method, and 4a and 4e were found to be more effective against gram positive bacteria and remaining compounds exhibited equipotent activity.
ACKNOWLEDGEMENT: The authors gratefully thank Dr. B. Ram, Director, Green Evolution Laboratories Wangapally Village, Nalgonda District, Telangana State, India, for his helpful suggestions and supporting the work.
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How to cite this article:
Kantlam Ch, Srinivasa Murthy M and Narsimha Reddy Y:: Synthesis, Characterization, and Pharmacological Evaluation of Some Novel Hydrazone Derivatives Derived from 3-((4-Formyl-2-Methoxyphenoxy) Methyl) Benzonitrile. Int J Pharm Sci Res 2016; 7(4): 1633-39.doi: 10.13040/IJPSR.0975-8232.7(4).1633-39.
All © 2013 are reserved by International Journal of Pharmaceutical Sciences and Research. This Journal licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.
Kantlam Chamakuri , Srinivasa Murthy Muppavarapu * and Narsimha Reddy Yellu
Department of Pharmaceutical Chemistry, Vignan Institute of Pharmaceutical Sciences, Deshmukhi, Nalgonda, Telangana State, India
03 November, 2015
30 December, 2015
18 March, 2016
01 April, 2016