Synthesis and anti-inflammatory activity of hydrazones bearing biphenyl moiety and vanillin based hybrids

Article abstract of DOI:10.13005/ojc/330250

The intense research work in the field of medicinal chemistry has enhanced the significance of Biphenyl moiety as pharmacologically important compound. Some of the compounds bearing Biphenyl moiety possess important medicinal properties like antihypertensive and calcium channel blocker, anti-inflammatory, diuretic, anti-diabetic activity, antipsychotic and anxiolytic activity. The present article describes the synthesis of novel benzohydrazides and 2-phenylacetohydrazides bearing Biphenyl moiety and vanillin hybrid. The synthesized compounds (31-40) were characterized by ¹H NMR, Mass and IR spectroscopic techniques and were evaluated for anti-inflammatory activity by carrageenan paw edema method. The results of the study revealed that compounds 39 and 40 (bearing 2-(4-nitrophenyl)acetohydrazide and 2-(2,3-dihydrobenzofuran-5-yl)acetohydrazide) showed maximum anti-inflammatory activity while the compounds 31, 32, 33, 34 and 38 bearing benzohydrazides displayed moderate anti-inflammatory activity.

Full text of DOI:10.13005/ojc/330250

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ISSN: 0970-020 X
CODEN: OJCHEG
2017, Vol. 33, No. (2):
Pg. 971-978
ORIENTAL JOURNAL OF CHEMISTRY
An International Open Free Access, Peer Reviewed Research Journal
www.orientjchem.org
Synthesis and Anti-Inflammatory Activity of Hydrazones
Bearing Biphenyl Moiety and Vanillin Based Hybrids
A.L.V. KUMAR REDDY1, 2* and NIREN E KATHALE1
1Department of Chemistry, Sardar Patel Mahavidyalaya, Chandrapur, Gondwana
University, Gadchiroli, Maharashtra, India.
2Department of Uranium Oxide Plant, Nuclear Fuel Complex, ECIL Post, 500062,
Hyderabad, Telangana State, India.
* Corresponding author E-mail: alvkumar2016@gmail.com
http://dx.doi.org/10.13005/ojc/330250
(Received: March 08, 2017; Accepted: April 05, 2017)
ABSTRACT
The intense research work in the field of medicinal chemistry has enhanced the significance
of Biphenyl moiety as pharmacologically important compound. Some of the compounds bearing
Biphenyl moiety possess important medicinal properties like antihypertensive and calcium channel
blocker, anti-inflammatory, diuretic, anti-diabetic activity, antipsychotic and anxiolytic activity. The
present article describes the synthesis of novel benzohydrazides and 2-phenylacetohydrazides
bearing Biphenyl moiety and vanillin hybrid.The synthesized compounds (31-40) were characterized
by 1H NMR, Mass and IR spectroscopic techniques and were evaluated for anti-inflammatory activity
by carrageenan paw edema method. The results of the study revealed that compounds 39 and
40 (bearing 2-(4-nitrophenyl)acetohydrazide and 2-(2,3-dihydrobenzofuran-5-yl)acetohydrazide)
showed maximum anti-inflammatory activity while the compounds 31, 32, 33, 34 and 38 bearing
benzohydrazides displayed moderate anti-inflammatory activity.
Keywords: Biphenyl, Vanillin, Hydrazones, Synthesis, Anti-inflammatory
INTRODUCTION
of microbes to the obtainable drugs. Further, the
infection caused by such microorganism pretense
severe confronts to medicinal scientists and required
for development of efficient drugs.
Theadvancementofnovelchemotherapeutic
agent is an imperative and demanding task for the
medicinal chemist. Many research programs are
aimed towards design and synthesis of new drugs.
Research on new substances possessing better
antimicrobial activity has fascinated significant
attention due to continuous increase in the resistance
The intense research work in the field of
medicinal chemistry has enhanced the significance
of Biphenyl moiety as pharmacologically important
compound. Some of the compounds bearing

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REDDY & KATHALE, Orient. J. Chem., Vol. 33(2), 971-978 (2017)
Biphenyl moiety possess important medicinal
properties like antihypertensive and calcium channel
blocker1,2, anti-inflammatory3, diuretic4, anti-diabetic5 Chemistry
activity, antipsychotic and anxiolytic activity6. Some
RESULTS AND DISCUSSION
The approach for the synthesis of novel
of the Biphenyl hydrazide-hydrazone are known to hydrazones (31-40) bearing biphenyl moiety and
exhibit very good antimicrobial activity7,8.
vanillin hybrid is illustrated in Scheme 1.Esterification
of aromatic carboxylic acids (1-5) and substituted
Va n i l l i n ( 4 - h y d r o x y - 3 - m e t h o x y 2-phenyl acetic acids (6-10) was accomplished in
benzaldehyde), a dietary flavoring agent, has been presence of catalytic quantity of conc;sulphuric in
reported to show antioxidant and anti-mutagenic ethanol at reflux for 12-14h resulted in the formation
activities, and has also been proved to be an of corresponding ethylbenzoates (11-15) and
anticarcinogen against a variety of chemical and ethyl-2-phenylacetates (16-20). Treatment of
physical agents9–14. Besides its flavor qualities, these ethylesters (11-20) with hydrazine-hydrate
vanillin exhibits the antimicrobial potential and has in ethanol at reflux for 8-10 h produced the
been used as a natural food preservative15. In old corresponding benzohydrazides (21-25) and
medicinal literature, vanilla was described as a 2-phenyl-acetohydrazides (16-20). On the other
remedy for fevers16,17
.
hand, condensation of vanillin A and the biphenyl
intermediate B25in presences of potassium in
Hydrazones consisting of azomethine acetonitrile at 85-90oC resulted in the formation of key
–NH-N=CH- proton signify an imperative class of intermediate aldehyde C in 88% yield25. Coupling of
compounds for a therapeutic drug development aldehyde C with benzohydrazides (21-25) in ethanol
program in the branch of medicinal chemistry. at reflux for 1h gave the corresponding hydrazide-
These compounds possess varied biological and hydrazone derivatives (31-35) in quantitative yields,
pharmacological properties such as antiinflammatory, while the preparation of acetohydrazide-hydrazone
antihelmintic, cardioprotective, antiviral, antimicrobial, (36-40) was reported by us recently. The structural
antischistosomiasis, analgesic, anticancer, determination of the synthesized benzohydrazides
antiplatelet, anticonvulsant, antitubercular, antifungal, 31-35 was established by spectroscopic techniques
antiprotozoal, antimalarial, antitrypanosomal, like 1H NMR, IR and mass.
etc.18-22. In recent years, a number of hydrazone
derivatives have been developed and evaluated for
their antibacterial activity23, 24
The structure of the key aldehyde
intermediate C was confirmed by the presence of
signal in 1H NMR at 9.82 ppm as a singlet with one
.
Combination of different pharmacophores proton integration corresponds to the presence
in the same molecule may perhaps guide for of carbonyl group, this was further confirmed by
the development of new compounds in the drug the presence of characteristic peak in the region
development program in order to attain a higher 1739 cm-1 in IR spectra. The m/z peak at 337.0 in
biological activity. Therefore the combination of the mass spectra determines the desired molecular
Biphenyl,Vanilinandhydrazonetypecompoundsmight formulae. On the other hand, the 1H NMR of‘Benzoic
offer new effectual drugs against multidrugresistant acid [4-(4’-fluoro-biphenyl -4-ylmethoxy)-3-methoxy-
microbial infections.
benzylidene]-hydrazide’is characterized as follows,
the proton signals at 11.74 ppm and 8.38 ppm as
Inspired by the various pharmacological singlets is assigned to the groups –CO-NH- and
activities of the above discussed moieties and –HC=N- respectively and the aromatic proton signals
in continuation to our research program on appeared in the expected region.The methylene and
acetohydrazide-hydrazone derivatives25, we report the methoxy groups appeared at 5.20 ppm (-OCH2-)
here in the synthesis, characterization and anti- and 3.85 ppm (-OCH3) as singlets.The peaks in the IR
inflammatory activity of novel benzohydrazides spectra at 3236, 1647 and 1548 cm-1 corresponds to
and 2-phenylacetohydrazide-hydrazone derivatives –C=O (str), C=N (str) and –NH (def) respectively.The
(31-40).
mass spectra of the compound showed, m/z 455.1
(M+1) and is in agreement with the desired molecular

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REDDY & KATHALE, Orient. J. Chem., Vol. 33(2), 971-978 (2017)
formulae. Similarly, the structural elucidation of the
remaining benzohydrazide-hydrazone derivative
(31-35) was characterized as described above.The
structural characterization of the acetohydrazide-
hydrazones derivatives (36-40) was discussed by
us in our previous published article25.
EXPERIMENTAL SECTION
Materials and Methods
The solvents were purified according
to standard procedures prior to use and all
commercial chemicals were used as received. For
thin-layer chromatography (TLC) analysis, Merck
pre-coated Plates (silica gel 60 F254) were used
and spots were visualized under UV light. Merck
silica gel 60 (230-400 mesh) was used for flash
column chromatography and the eluting solvents
are indicated in the procedures. Melting point (mp)
determinations were performed by using Mel-temp
Anti-inflammatory activity
The synthesized benzohydrazide-
hydrazones and 2-phenylacetohydrazide-hydrazone
were evaluated for anti-inflammatory activity at 10
mg/Kg po by carrageenan paw edema method and
the results are tabulated in Table 1. From table 1,
it is observed that compounds 35, 36, 37 showed
good anti-inflammatory activity and compounds
39 and 40 showed maximum anti-inflammatory
activity while the compounds 31, 32, 33, 34 and 38
bearing benzohydrazidesdisplayed moderate anti-
inflammatory activity. In general, with in the series
of the synthesized hydrazones, compounds bearing
2-phenylacetohydrazides exhibited pronounced
anti-inflammatory activity when compared to 31, 32,
33,34 bearingbenzohydrazides.
1
apparatus and are uncorrected. H NMR spectra
were recorded in Varian MR-400 MHz instrument.
Chemical shifts are reported in parts per million
(ppm) downfield from tetramethylsilane (TMS) as
internal standard reference and the signals were
reported as s (singlet), d (doublet), dd (doblet of
doblet), t (triplet), q (quartet), m (multiplet) and
coupling constants are measured in Hz. The mass
spectra were recorded on Agilent ion trap MS and
Infrared (IR) spectra were recorded on a Perkin
Elmer FT-IR spectrometer.
n = 0, 1
n = 0, 1
n = 0, 1
H
OEt
OH
N
NH2
O
O
O
R
R
R
1. n = 0, R = H
2. n = 0, R = 4-OMe
3. n = 0, R = 4-Cl
4. n = 0, R = 3,5-Cl
5. n = 0, R = 3,4,5-OMe
6. n = 1, R = H
7. n = 1, R = 3,5-CH3
8. n = 1, R = 2-Cl, 4-F
9. n = 1, R = 4-NO2
10. n = 1, R = tetrahydrofuran
11. n = 0, R = H
21. n = 0, R = H
12. n = 0, R = 4-OMe
13. n = 0, R = 4-Cl
14. n = 0, R = 3,5-Cl
22. n = 0, R = 4-OMe
23. n = 0, R = 4-Cl
24. n = 0, R = 3,5-Cl
15. n = 0, R = 3,4,5-OMe
16. n = 1, R = H
17. n = 1, R = 3,5-CH3
18. n = 1, R = 2-Cl, 4-F
19. n = 1, R = 4-NO2
20. n = 1, R = tetrahydrofuran
25. n = 0, R = 3,4,5-OMe
26. n = 1, R = H
27. n = 1, R = 3,5-CH3
28. n = 1, R = 2-Cl, 4-F
29. n = 1, R = 4-NO2
30. n = 1, R = tetrahydrofuran
F
F
F
O
O
OH
MeO
MeO
MeO
21 - 30
+
CHO
CHO
N
n = 0, 1
C
HN
A
Br
R
O
B
31. n = 0, R = H
32. n = 0, R = 4-OMe
33. n = 0, R = 4-Cl
34. n = 0, R = 3,5-Cl
35. n = 0, R = 3,4,5-OMe
36. n = 1, R = H
37. n = 1, R = 3,5-CH3
38. n = 1, R = 2-Cl, 4-F
39. n = 1, R = 4-NO2
40. n = 1, R = tetrahydrofuran
Scheme 1: Synthesis of novel hydrazide-hydrazone derivatives 31-40

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REDDY & KATHALE, Orient. J. Chem., Vol. 33(2), 971-978 (2017)
Experimental conditions
a) conc; H2SO4, Ethanol, reflux, 10-12h;
4-Chlorobenzohydrazide (23)
Off white solid; Yield: 82%; M.p.: 160-162
b) Hydrazine-hydrate, Ethanol, reflux, 8-12h; c) oC;1H NMR (CDCl3, 400 MHz): d 9.86 (s, 1H), 7.85
B, K2CO3, Acetonitrile, 85-90oC, 2h; d) 21-25 and (d, J = 6.8 Hz, 2H), 7.52 (d, J = 8.8 Hz, 2H), 4.52
26-30, ethanol, reflux, 2-3h.
(s, 2H); ESI-MS: m/z, 169.1 (M+H)+.
General method for the preparation of 3,5-dichlorobenzohydrazide (24)
ethylbenzoates(11-15)andethyl-2-phenylacetates
(16-20)
White solid;Yield: 88 %; M.p.: 128-129 oC;
1H NMR (DMSO-d6, 300 MHz): d 9.98 (s, 1H), 7.82
Benzoicacids (1-5, 2g, 16.40mmol) and (s, 1H), 7.78 (s, 1H), 4.57 (br.s, 2H); ESI-MS: m/z,
2-phenylaceticacid (6-10, 2g, 14.69 mmol) was 203.1 (M+1)+.
dissolved in ethanol (25 mL) and then catalytic
quantity of concentrated sulphuric acid was added 3, 4, 5-Trimethoxybenzohydrazide (25)
and refluxed for 10-12h.Ethanol was concentrated up
Off white solid; Yield: 85 %; M.p.: 158-160
to 80% and diluted with ethylacetate (50 mL) followed oC;1H NMR (CDCl3, 400 MHz): d 9.50 (s, 1H), 6.42
by water (25 mL). The organic layer was washed (s, 1H), 4.45 (br.s, 2H), 3.84 (s, 3H), 3.80 (s, 6H).
with saturated NaHCO3solution (4 X 20 mL), water
and brine solution.The separated organic layer was 2-phenylacetohydrazide (26)
dried on sodium sulphate, filtered and concentrated
Off-white solid;Yield;85%;M.p:116-117oC;
to obtain the corresponding ethylbenzoates (11-15) 1H NMR (400 MHz, CDCl3): d 7.10 (d, J = 6.8 Hz,
and ethyl-2-phenylacetates (16-20) in 75-80% yield. 1H), 6.82 (d, J = 6.8 Hz, 2H), 6.70 (d, J = 6.6 Hz,
The isolated compounds were utilized in the next step 1H0, 5.80 (d, J = 6.6 Hz, 1H), 5.30 (br.s, 1H), 3.56
without any further purification.
(s, 2H).
General method for the preparation 2-(3,5-dimethylphenyl)acetohydrazide (27)
o f b e n z o h y d r a z i d e s ( 2 1 - 2 5 ) a n d
2-phenylbenzohydrazides (26-30)
Pale brown solid;Yield:88%;M.p.:94-95oC;
1H NMR (400 MHz, CDCl3): d 6.90 (s, 1H), 6.82
Ethylbenzoates (11-15, 1.5g, 9.98 mmol) (s, 2H), 6.70 (br.s, 1H), 3.90 (br.s, 2H), 3.50 (s, 2H),
and ethyl-2-phenylacetates (16-20, 1.5g, 9.13 mmol) 2.40 (s, 6H).
were dissolved in ethanol and then hydrazine-hydrate
(99%) was added and reflux for 8-12h. Ethanol was 2-(2-chloro-4-fluorophenyl)acetohydrazide (28)
concentrated and the resultant residue was poured
White solid; Yield: 82%; M.p.: 118-119oC;
in ice cold water and stirred for 15 -20 min, the solids 1H NMR (400 MHz, CDCl3): d 7.38-7.36 (m, 1H),
that were thrown out was filtered at the pump and 7.18-7.14 (m, 1H), 7.02-6.97 9m, 1H), 6.70 (br.s,
dried to obtain the corresponding benzohydrazides 1H), 3.90 (br.s, 2H), 3.60 (s, 2H).
(21-25) and 2-phenylacetohydrazides (26-30) in 80-
82% yield.
2-(4-nitrophenyl)acetohydrazide (29)
1
Yellow solid; Yield: 88%; M.p.; 167oC; H
benzohydrazide (21)
NMR (400 MHz, CDCl3): d 8.20 (d, J = 3.0 Hz, 2H),
Pale yellow solid;Yield:80%;M.p.:125-126 7.42 (d, J = 2.6 Hz, 2H), 6.70 (br.s, 1H), 3.90 (br.s,
oC;1H NMR (DMSO-d6, 400 MHz): d 9.74 (br.s, 1H), 2H), 3.60 (s, 2H).
7.82 (d, J = 6.0 Hz, 2H), 7.52-7.44 (m, 3H), 2.28 (br.s,
2H); ESI-MS: m/z 137.0 (M+H)+.
2-(2,3-dihydrobenzofuran-5-yl)acetohydrazide
(30)
o
4-methoxybenzohydrazide (22)
White solid; Yield: 85%; M.p.: 112-113 C;
White solid;Yield:88%;M.p.:118-119 oC;1H 1H NMR (400 MHz, CDCl3): d 7.10 (s, 1H), 6.94 (d,
NMR (DMSO-d6, 400 MHz):d 9.60 (s, 1H), 7.66 (d, J J = 7.2 Hz, 1H), 6.78 (d, J = 7.2 Hz, 1H), 6.62 (br.s,
= 6.4 Hz, 2H), 6.96 (d, J = 6.4 Hz, 2H), 4.40 (s, 2H), 1H), 4.58 (t, J = 5.8 Hz, 2H), 3.84 (br.s, 2H), 3.42
3.80 (s, 3H); ESI-MS: m/z, 167.2 (M+H)+.
(s, 2H), 3.18 (t, J = 5.8 Hz, 2H).