HETEROCYCLIC CHEMISTRY: SYNTHESIS AND
BIOLOGICAL EVALUATION OF SOME AZOLE
DERIVATIVES
SUMMARY SUBMITTED TO MAHARISHI MARKANDESHWAR UNIVERSITY, MULLANA
FOR THE AWARD OF THE DEGREE OF
DOCTOR OF PHILOSOPHY IN
CHEMISTRY BY
KAMALNEET KAUR (Regn. No. 07-ECM-1158)
DEPARTMENT OF CHEMISTRY
MAHARISHI MARKANDESHWAR UNIVERSITY
MULLANA, AMBALA (HARYANA)
APRIL, 2015
i
SUMMARY
Heterocyclic compounds are an important class of organic compounds that exhibited a
wide range of biological properties. Furthermore, a large number of natural products
possess a variety of heterocyclic systems. Azoles are the five-membered heterocyclic
compounds containing two heteroatoms and atleast one of them is nitrogen. Many
azoles derivatives have been used as antibacterial, antifungal, anti-inflammatory and
anti-diabetic, antiviral, anticonvulsant and antitubercular agents. Owing to their
immense biological importance it was thought worthwhile to undertake the synthesis
of some azole derivatives, specifically pyrazoles, thiazoles and isoxazolines.
The work reported in this investigation has been presented in the form of three
Chapters (1-3), which are independent of each other.
CHAPTER-1 SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL
EVALUATION OF SOME NOVEL 3,5-DIMETHYLPYRAZOLE
DERIVATIVES
Azole derivatives have gained much more attention in the field of synthetic and
medicinal chemistry owing to their diverse biological properties. Among them,
pyrazole is a five-membered heterocyclic compound containing three carbon and two
adjacent nitrogen atoms. The general structure of pyrazole is shown in Figure 1.
N NR'
R''
R'''
R12
3 4
5
R, R', R'', R''' = H or alkyl or aryl or heteroaryl
Pyrazole
Fig.1
Pyrazole core is found in several natural products. It has been reported in literature
that substitution on pyrazole nucleus resulted in development of many medicinally
potent compounds. Pyrazole derivatives displayed broad spectrum of biological
properties such as antimicrobial, antitubercular, anticonvulsant, anti-inflammatory,
antiobesity, agricultural germicidal, insecticidal and acaricidal activities. They also act
as GABA receptor antagonists, inhibitors against DNA gyrase and topoisomerase IV
at their respective ATP binding sites, antiproliferative and anticancer agents. It has
been reported in literature that pyrazole derivatives having methyl group at position-3
ii
and/or -5 have gained much medicinal importance. A brief review regarding various
synthetic procedures and biological developments of pyrazole derivatives having
methyl group at position-3 and/or -5 is outlined in the beginning of this Chapter
(Section 1.1)
In a view of these observations it was envisaged in the present investigation to
undertake the synthesis of three series of some new 3,5-dimethyl substituted pyrazole
derivatives with an expectation to find biologically potent agents (Section 1.2A, 1.2B
and 1.2C). The structures of synthesized compounds were established with the help of
combined application of IR, NMR (1H, 13C) spectroscopy, mass spectrometry and
elemental analyses. The 2D NMR spectral techniques such as COSY, ROSEY, HSQC
and HMBC wherever required were also used in structural elucidation of some of the
synthesized compounds.
1.2A Synthesis, Characterization and Biological Evaluation of Some Novel 2-(3,5-
Dimethyl-1H-pyrazol-1-yl)-1-arylethanones
It has been found that some pyrazole derivatives having methyl group at position-3
and -5 act as potent antibacterial, antioxidant and anticancer agents I. Literature
survey also revealed that some phenacyl and napthacyl substituted pyrazole,
imidazole and triazoles exhibit a wide range of important pharmacological properties.
Keeping in view of the great biological potential and importance of 3,5-
dimethylpyrazole, phenacyl and napthacylazole, and in continuation of our ongoing
research work on the synthesis of novel pyrazole derivatives as potential biological
active agents, we planned to synthesize a series of 11 hybrid compounds having
phenacyl or napthacyl moiety at position-1 and methyl group at positions-3 and -5 of
the pyrazole nucleus.
In literature, Santhosh et al. have reported a one pot solvent mediated multicomponent
approach for the synthesis of some 2-(3,5-dimethyl-1H-pyrazol-1-yl)-1-arylethanone
derivatives (Scheme-23).
O O+ NH2NH2.H2O ArCOCH2Br
reflux271
NN
ArO
94a-d
95a-d
1' 2'
3'
4'
5'
1
2ethanol+
Scheme-23 One pot multicomponent synthesis of 2-(3,5-dimethyl-1H-pyrazol-1-yl)-
1-arylethanones by Santhosh et al.
iii
To achieve the target compounds 95a-k, we decided to perform one-pot
multicomponent approach under similar conditions as reported by Santhosh et al. with
an expectation to achieve the product in a very short period of time in a highly
regioselective manner, by the reaction of acetylacetone 71, hydrazine hydrate 2 and
differently substituted phenacyl bromides 94a-d in ethanol under reflux.
Unfortunately, in actual practice this method generated four compounds as evidenced
by appearance of four spots in TLC of the crude reaction mixture. The 1H NMR
spectrum of crude reaction mass showed a number of sharp signals at δ 2.17 (s, 3H),
2.29 (s, 3H), 2.44 (s, 9H), 5.65 (s, 2H), 5.98 (s, 1H), 6.04 (s, 1H) and many distinct
multiplets in range of δ 7.37-7.99 corresponding to 15 protons which confirmed the
formation of 95a albeit along with significant amount of side products. In view of
multicomponent reaction based results, and behavior of the reaction of different types
of 1,3-β-diketones with various hydrazines or of phenacyl bromides, it was planned to
reinvestigate and further explore this approach. To enunciate the facts,
multicomponent reaction was again carried out under similar conditions which led to
a mixture of different compounds. Thus, there was a great need to find a novel
synthetic route which not only provides the target compounds regioselectively with
excellent yields but also avoids the use of toxic solvents and prolonged reaction time.
In view of an extension of these observations, we developed a greener and
regioselective protocol to synthesize 2-(3,5-dimethyl-1H-pyrazol-1-yl)-1-
arylethanone derivatives 95a-k using one pot grind stone methodology has been
developed (Scheme-25).
In order to synthesize 95a, acetylacetone 71 (1 mole eq.) was treated with hydrazine
hydrate 2 (1.1 mole eq.) at 0 ºC and the resultant reaction mixture was ground with
phenacyl bromide 94a (0.9 mole eq.) in the presence of sodium carbonate (0.5 mole
eq.) under solvent free conditions. The desired product 95a was formed
regioselectively within 10-15 minutes in excellent yield with high purity. The
structure of crude 95a was established on the basis of a combined use of IR, 1H NMR, 13C NMR spectroscopy and mass spectrometry.
The 1H NMR spectrum of 95a displayed two sharp singlets due to six protons at δ
2.17 and 2.24 which affirm the presence of two methyl groups at positions- 3' and -5'
of the pyrazole nucleus, respectively. The CH2 protons resonated downfield as a
singlet at δ 5.46 due to its attachment with carbonyl carbon and nitrogen at position-1'
of the pyrazole ring. Another sharp singlet corresponding to one proton at δ 5.91 was
iv
observed due to 4'-H pyrazole ring, besides a multiplet centered around at δ 7.49-7.98
due to five aromatic protons. Further evidence in support of an exclusive formation of
95a came by recording its 13C NMR spectrum which showed the three characteristic
signals of pyrazole system at δ 148.29, 105.91, and 140.73 due to C-3', C-4' and C-5',
respectively. The formation of pyrazole was further supported on the basis of its mass
spectrum which showed a molecular ion peak at m/z = 214.1 (M+) in conformity with
molecular formula C13H14N2O of 95a.
Cl Br NO2 F FCH3
F FCl
a b c d e f g h i j k
Ar
For compds (94, 97)
O O
i) NH2NH2 .H2O 2, 0 oCii) ArCOCH2Br, Na2CO3, grind, 80 oC
71
NN
ArO
94a-k
95a-k
1' 2'
3'
4'
5'
1
2
One pot
Scheme-25 A highly regioselective one pot solvent free synthesis of 2-(3,5-dimethyl-
1H-pyrazol-1-yl)-1-arylethanones 95a-k
In order to assess their potential the compounds were screened for antibacterial,
anticancer potential besides study the effects of compounds on plasmid DNA under
UV irradiation. Among all, 2-(3,5-dimethyl-1H-pyrazol-1-yl)-1-(naphth-2-
yl)ethanone 95j displayed good inhibitory profile against E. coli and S. aureus which
was about 50% and 25% of the Ampicillin (standard drug), respectively. The
compounds, 95a and 95f showed relatively moderate inhibition against P. aeruginosa
and E. coli. The compounds 95c and 95d were found to be highly active and
completely degraded both forms of DNA (SC and OC), even at a very low
concentration of 1 µg (95c) under irradiation of UV light. However, 95h and 95f
resulted in complete DNA degradation at 30 µg concentration. Moreover, 95h showed
fluorescence at 15 µg concentration and increased the intensity of both bands of DNA
(SC and OC) as compared to control. On the other hand, to valorize the biological
potential, the compounds were screened for their cytotoxic activity on colon (HCT116
and HT29), prostate (DU145), ovarian (SKOV3) and lung (A549) cancer cell lines.
The compound 95j was found to be cytotoxic to all the cancer cell lines, except
SKOV3, with more selectivity towards the colon cancer cell lines (HCT116, HT29)
v
and A549 lung cancer cell line. On A549 lung cancer cell line, 95j and 95k exhibited
similar potency as carboplatin in inhibiting cell viability.
1.2B Synthesis, Characterization and Biological Evaluation of Some Novel 2-(3,5-
Dimethyl-1H-pyrazol-1-yl)-1-arylethanols
Literature revealed that alkanol derivatives bearing (1H-triazol-1-yl) group at β-
position have gained significance importance especially in the field of antifungal
research. Some potent antifungal drugs like Fluconazole, Voriconazole and
Albaconazole are alkanol derivatives having (1H-triazol-1-yl) group at β-position.
Recently, pyrazole derivatives have been reported as an excellent class of DNA-
photocleaving agents. It has been reported that pyrazole derivatives are known to
possess excellent antioxidant activity.
Keeping in view of the high antifungal potential associated with alkanol derivatives
bearing (1H-triazol-1-yl) group at β-position as well as excellent antimicrobial, DNA
photocleaving and antioxidant profile associated with pyrazole containing compounds
and in continuation to our previous work related to the synthesis of biologically
potent 2-(3,5-dimethyl-1H-pyrazol-1-yl)-1-arylethanones, it was planned to
synthesize some novel alkanol derivative having (1H-pyrazol-1-yl) group at β-
position with an expectation to find new class of antimicrobial, DNA photocleaving
and antioxidant agents.
The synthetic route adopted to synthesize 2-(3,5-dimethyl-1H-pyrazol-1-yl)-1-
arylethanols 97a-k is depicted in Scheme-27. The starting precursors 95a-k were
prepared report by performing one-pot solvent free reaction of acetyl acetone with
hydrazine hydrate and differently substituted bromides in presence of sodium
carbonate (Scheme-25). To achieve the target compounds, 2-(3,5-dimethyl-1H-
pyrazol-1-yl)-1-arylethanones 95a-k (1 mole eq.) were treated with sodium
borohydride (0.25 mole eq.) using methanol as a solvent at 5 ºC temperature. The
desired products 97a-k were formed within 10-12 minutes with high purity.
vi
NN
O
95a-k
1' 2'
3'
4'
5'
1
2
Cl Br NO2 F FCH3
F FCl
NN
OHb
97a-k
1' 2'
3'
4'
5'
1
2
Ha
Hc
Hd
Ar Ar
NaBH4, MeOH
5 oC, stir
a b c d e f g h i j k
Ar
For compds (95, 97)
Scheme-27 Synthesis of 2-(3,5-dimethyl-1H-pyrazol-1-yl)-1-arylethanols 97a-k
In IR spectral data, disappearance of carbonyl (C=O) and an appearance of hydroxyl
(OH) stretching vibrational bands at 1690 cm-1 and 3216 cm-1, respectively indicated
the formation of compound 97a. In 1H NMR spectrum, appearance of three sharp
singlets at δ 2.01, 2.24 and 5.80 due to 3'-CH3, 5'-CH3 and 4'-H protons, respectively
attached to pyrazole nucleus further provided a firm evidence in support of the
formation of 97a. A broad singlet at δ 4.80 was observed due to the presence of OHb
proton. The three doublet of doublet patterns at δ 4.01 (2JHc-Hd = 13.92 Hz and 3JHc-Ha
= 7.92 Hz), δ 4.15 (2JHd-Hc = 13.94 Hz and 3JHd-Ha = 2.76 Hz) and at δ 5.08 (3JHa-Hc =
7.72 Hz and 3JHa-Hd = 2.48 Hz) were assigned to Hc, Hd and Ha protons, respectively.
The assignment of these protons was fully supported via 1H NMR study reported by
Prakash and Claramunt et al. A multiplet center around at δ 7.27-7.56 was attributed
to five aromatic protons. Both the geminal protons (Hc and Hd) resonated at different
chemical shifts to give doublet of doublet pattern due to their diastereotopic nature.
Further evidence in support of the structure of 97a came from its recorded 13C NMR
spectrum which showed the disappearance of carbonyl carbon signal at δ 192.66 and
an appearance of a signal at δ 73.49 for C-1 carbon at more upfield value due to its
attachment with hydroxyl group.
All synthesized compounds were evaluated to assess their antimicrobial and
antioxidant potential. In addition the effect of compounds on plasmid DNA was also
studied. Among the series, compounds 97j and 97k were found to exhibit significant
inhibitory potential against C. albicans using Amphotericin-B as a standard drug.
They also exhibited moderate inhibitory potential against S. cerevisiae, which was
about 25% of standard drug. On the other hand, 97g-i were found four times less
active against both the fungal strains. The compound 97i exhibited four-fold lesser
vii
inhibitory profile against P. aeruginosa in comparison to Ciprofloxacin as a standard
drug. In the DNA photocleavage study, the compounds 97e and 97h were found to act
as potent DNA photocleaving agents at 60 µg concentration while compounds 97g,
97i and 97j exhibited moderate DNA photocleaving potential. In addition, compounds
97d and 97f protected the DNA from the effect of UV-irradiation. In the present
study, it has also been observed from DPPH method, the compounds 97d and 97e
were found to act as antioxidant agents.
1.2C Synthesis, Characterization and Biological Evaluation of Some Novel (E)-1-
Aryl-2-(3,5-dimethyl-4-(aryldiazenyl)-1H-pyrazol-1-yl)ethanones
As already discussed, pyrazole derivatives are known to possess diverse biological
properties. More specifically, 4-arylazopyrazole derivatives have gained much
importance due to a broad spectrum of their biological potential as anti-
staphylococcal, analgesic, antioxidant, cytotoxic and CDK2-cyclin E inhibiting
agents. It has already been reported that 4-arylazopyrazoles bearing 3,5-dimethyl
substituents were found to be associated with potential antibacterial and antimicrobial
activities.
Prompted from the above facts and in continuation to our ongoing interest in the
synthesis of new biologically active compounds, it was planned to synthesize some
novel arylazopyrazoles under solvent free conditions and to explore their
antimicrobial, antioxidant and UV-mediated DNA damage protecting potential with
an expectation to find new class of bioactive agents.
The synthesis of twenty-one novel (E)-1-aryl-2-(3,5-dimethyl-4-(aryldiazenyl)-1H-
pyrazol-1-yl)ethanones 101a-u has been accomplished according to Scheme-30.
viii
N N
NN
H
grind stone, 100 oC
N N
NN
R
OAr
R
CH3 Cl Br F NO2
1
2 1' 2'
3'
4'
5'
1''2''
3''4''
5''
6''
100a-c 101a-u
For compds (101) a b cR = CH3, H, F
a b c d e f g
h i j k l m n
o p q r s t u
For compds
(101)
Ar
For compds (101a-g), R = CH3(10h-n), R = H(101o-u), R = F
Na2CO3
94a-f, 94 j
Scheme-30 Solvent free synthesis of (E)-1-aryl-2-(3,5-dimethyl-4-(aryldiazenyl)-1H-
pyrazol-1-yl)ethanones 101a-u
The present methodology provides a milder and greener synthetic route to give the
products 101a-u of high purity within 10-15 minutes. In this protocol, initially 4-
methylphenylazo-3,5-dimethylpyrazole 100a was ground with phenacyl bromide 94a
in the presence of sodium carbonate at 100ºC under solvent free conditions to yield
101a. An appearance of carbonyl (C = O) stretching vibrational band at 1690 cm-1
indicated the formation of 101a. In the 1H NMR spectrum, compound 101a displayed
a singlet at δ 5.52 due to methylene (CH2) protons besides a multiplet centered
around at δ 7.50-8.00 due to five aromatic protons (H-2''' to H-6'''). The structure of
101a was further supported by its 13C NMR spectrum in which signals were appeared
at δ 191.76 and 55.57 due to carbonyl and CH2 carbon, respectively. Other signals in
the range of 128.17-134.37 were indicating the presence of aromatic carbons (C-1''' to
C-6'''). Further confirmation of 101a was supported by the mass spectral data which
showed a molecular ion peak at 332 (m/z) in conformity with molecular formula
C20H20N4O.
The present methodology provides a milder and greener synthetic route to give the
products 101a-u of high purity within 10-15 minutes. In this protocol, initially 4-
methylphenylazo-3,5-dimethylpyrazole 100a was ground with phenacyl bromide 94a
in the presence of sodium carbonate at 100ºC under solvent free conditions to yield
101a. An appearance of carbonyl (C=O) stretching vibrational band at 1690 cm-1
ix
indicated the formation of 101a. In the 1H NMR spectrum, compound 101a displayed
a singlet at δ 5.52 due to methylene (CH2) protons besides a multiplet centered
around at δ 7.50-8.00 due to five aromatic protons (H-2''' to H-6'''). The structure of
101a was further supported by its 13C NMR spectrum in which signals were appeared
at δ 191.76 and 55.57 due to carbonyl and CH2 carbon, respectively. Other signals in
the range of 128.17-134.37 were indicating the presence of aromatic carbons (C-1''' to
C-6''').
To explore biological potential, the compounds were evaluated for their antimicrobial,
antioxidant and UV mediated DNA damage protective activity. Among the series, six
compounds 101b, 101i, 101k, 101l, 101m and 101t were found to exhibit a very good
level of antibacterial activity, four compounds 101g, 101o, 101p and 101t were
emerged as an efficient class of antifungal agents in reference to the standard drugs
viz. Ciprofloxacin and Amphotericin-B, respectively. In the UV mediated DNA
damage protecting study, all compounds 101a-u (except 101d) protected the plasmid
DNA from the UV damaging effect and 101e was found to be the most potent DNA
protecting agent which avoids the transformation of the native supercoiled form into
an opencircular and linear form. In addition, the compounds 101f, 101m and 101t
were found active in antioxidant screening using DPPH assay.
CHAPTER-2 SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL
EVALUATION OF SOME NOVEL THIAZOLE DERIVATIVES
Thiazoles are the five-membered heterocyclic compounds which contain sulphur and
nitrogen at the position-1 and position-3, respectively. The general structure of
thiazole ring is shown in Figure 1.
SN
R
R'
R''
1 23
4
5
R, R', R'' =H or alkyl or aryl or heteroaryl
Thiazole
Fig. 1
Thiazole ring is found in a large number of natural products. Thiazole and its
derivatives were known to possess a wide range of biological properties. Some potent
drugs bearing thiazole nucleus include Fanetizole (anti-inflammatory agent),
Tiazofurin (antineoplastic agent), Penicillin (potent antibiotic), Sulfatiazol
x
(antimicrobial) and Abafungin (antifungal). It has been reported that substitution at
position-2 and -4 of thiazole ring leads to the development of many bioactive agents.
2,4-Disubstituted thiazoles displayed antimicrobial, anti-inflammatory, anticancer,
antimalarial, antimycobacterial, chemopreventive and antioxidant properties.
Moreover, they act as inhibitor of metastatic cancer cell migration and invasion,
ovarian cancer cell growth inhibitor, P-glycoprotein inhibitor besides corticotropin-
releasing factor 1 receptor antagonists. The most common approach used to construct
thiazole system is Hantzsch thiazole synthesis which involves the reaction of
thioureas or thioamides with α-haloketones. An update review regarding various
synthetic procedures and biological developments of 2,4-disubstituted thiazole
derivatives is outlined in the beginning of this Chapter (Section 2.1).
In a view the immense importance of 2,4-disubstitution in thiazole derivatives it was
envisaged in the present investigation to undertake the synthesis of two series of some
new 2,4-disubstituted thiazole derivatives with an expectation to find biologically
potent agents (Section 2.1A and 2.2B). The structures of synthesized compounds were
established with the help of combined application of IR, NMR (1H, 13C) spectroscopy,
mass spectrometry and elemental analyses. The 2D NMR spectral techniques such as
COSY, ROSEY, HSQC and HMBC wherever required were also used in structural
elucidation of some of the synthesized compounds.
2.2A Synthesis, Characterization and Biological Evaluation of Some Novel
Oxazolidinone-Thiazole Hybrids
Owing to diverse biological properties oxazolidinone and thiazole containing motifs
have gained a great attention of scientific community in the field of medicinal
chemistry. Oxazolidinone derivatives exhibited a wide range of applications in the
field of antimicrobial, anticancer and anti-tubercular research. Compounds bearing
oxazolidinone moiety as antimicrobial agents contributed a lot in this field. They
exhibited very high potential against Gram-positive multidrug resistant strains.
Linezolid (marketed under the trade name zyvox), a potent antimicrobial was the first
member of oxazolidinone family approved by the US Food and Drug Administration
(FDA) for the treatment of serious infection caused by Gram-positive bacteria. It
inhibits protein synthesis prior to chain initiation step by binding to the 50S ribosomal
subunit to prevent formation of 70S initiation complex. Some other biologically active
oxazolidinone pharmacores include eperezolid and posizolid, which were used as
promising antibiotics to treat bacterial infections while torezolid was used in the
xi
treatment of complicated skin infections. In addition, thiazole containing motifs have
also attracted much interest over the years due to their role in the development of
pharmacologically active compounds.
Prompted from the above facts and in continuation to our ongoing interest in the
synthesis of new biologically active compounds, it was planned to synthesize some
novel structural hybrids incorporating both the thiazole and oxazolidinone moiety.
The main objective of the study is to explore antimicrobial, antioxidant and UV-
mediated DNA damage protecting ability of the compounds with an expectation to
find new class of biologically potent agents.
The synthesis of novel oxazolidinone-thiazole hybrid compounds 87a-m has been
accomplished according to Scheme-29.
NH
O O
NH NH2
S
HaHb
ArCOCH2Br86a-m
NHO
O
NH
HaHb
S
NAr
85 87a-m
Ar =Cl BrCH3 NO2 F
FCl
O OO
O
H3C OH
1 23
54
61'
2'3'
4'
5'6'
1''2''
3''4''
5''
1'''2'''
3'''4'''
5'''6'''
2'''3'''
4'''
5'''6'''
1''' 1''' 2'''3'''
4'''
5'''6'''
1'''2'''
3'''4'''
5'''
6'''
1'''2''' 3'''
4'''
5'''6'''
1'''2'''3'''
4'''5'''6'''
1'''2'''
3'''4'''
5'''6'''
1'''2'''
3'''4'''
5'''
6'''
1''' 2'''3'''
4'''
5'''
6'''
7'''8''' 9'''
10'''
1'''2'''
3'''
4'''5'''6'''
7'''8'''
9'''
10'''
1'''2''' 3'''
4'''
5'''6'''1''''
2''''3''''
5'''' 6''''
4''''
1'''
2'''
4'''5'''6'''
3'''
1'''
2'''
3'''4'''5'''
6'''
7'''
8'''9'''
10'''
a b c d e f
g h i j k
l m
NHO
O
NH2
HaHb
84
HCl / H2O
NH4SCN, reflux1'2'
3'4'
5'
6'
1'' 2''3''
4''
5''1 2
3
45
61'
2'3'4'
5'
6'NaHCO3
EtOH, reflux
For compds (86, 87)
Scheme-29 Synthesis of oxazolidinone-thiazole hybrid compounds 87
The disappearance of two signals for NH2 protons and an appearance of a
characteristic singlet at δ 6.96 due to thiazole proton (H-5'') in the 1H NMR spectrum
confirmed the formation of 87a. In the IR spectrum, appearance of C=C, C=N and
C=O stretching vibrational bands at 1551, 1605 and 1728 cm-1, respectively further
supported the structure of 87a. In 13C NMR spectrum, observation of three
xii
characteristic signals at δ 162.92, 150.27 and 100.99 due to C-2', C-4', and C-5',
respectively provided the firm evidence in support of the formation of thiazole
nucleus.
All compounds were evaluated for their antimicrobial, antioxidant and UV mediated
DNA damage protective activity. Among the series, compound 87i was emerged as
the most potent antimicrobial agent. It exhibited equivalent inhibitory action against
one bacterial strain B. subtilis and two fungal strains namely, C. albicans and S.
cerevisiae in comparison to the respective standard drugs, Ciprofloxacin and
Amphotericin-B. The compound 87i was found to display two-fold and four-fold
lesser inhibitory potential against S. aureus as well as P. aeruginosa and E. coli,
respectively in reference to the standard drug. Other promising antimicrobial agents
include the compounds 87f-h where 87c, 87j and 87l were found to exhibit an
excellent level of antibacterial activity. In addition, all compounds 87a-m were found
to express very high DNA damage protecting ability under UV irradiation.
Furthermore, 87m was found to display a very high level of fluorescence property
among the series. The results of antioxidant study revealed that the compounds 87d
and 87j were found as the most potent antioxidants even more than ascorbic acid, a
reference compound.
2.2B Synthesis, Characterization and Biological Evaluation of Some Novel (E)-2-
(3,5-Dimethyl-4-(aryldiazenyl)-1H-pyrazol-1-yl)-4-arylthiazoles
Among azoles, thiazoles, pyrazoles and thiazole-pyrazole hybrids have attracted great
attention over the years due to their remarkable biological activities. Motifs
containing thiazole nucleus exhibited antitrypanosomal, antimicrobial, anticancer,
anti-inflammatory and antiviral properties. An extensive part of research in this field
revealed that 4-arylazo substituted pyrazole derivatives were found to act as analgesic,
cytotoxic, anti-staphylococcal, antioxidant, and CDK2-cyclin E inhibiting agents. In
literature, 3,5-dimethyl substituted 4-arylazopyrazole derivatives were also reported
to exhibit high antimicrobial and antibacterial potential. Moreover, pyrazole linked
thiazoles exhibited antibacterial, antimicrobial and ΔF508-CFTR corrector activities
besides treating cardiovascular diseases.
The literature survey revealed that compounds bearing pyrazole and thiazole nuclei
act as efficient DNA photocleaving agents.
Prompted from the above facts, it was planned to synthesize some novel 4-aryl-2-(3,5-
dimethyl-1H-pyrazol-1-yl)thiazole derivatives bearing arylazo group at position-4 of
xiii
the pyrazole moiety under solvent free conditions. The two main objectives of the
study include, to observe the influence of 4-arylazo group on the Hantzsch thiazole
approach in both the solvent free as well as solvent mediated conditions, and to
explore the biological potential of the target compound with an expectation to find a
new class of bioactive compounds.
The synthesis of novel (E)-2-(3,5-dimethyl-4-(aryldiazenyl)-1H-pyrazol-1-yl)-4-
arylthiazoles 92a-p has been accomplished via Hantzsch thiazole approach under
solvent free conditions (Scheme-31).
N N
NN
grind stone, 100 oC
N N
NN
R R
CH3ClBr F
1 2
3
4
5
1'2'
3'4'
5'
6'
NH2S
NS
Ar
1'' 2''
3''4''
5''
For compds (91) a b cR = CH3, H, F
For compds
(92)
Ar
For compds (92a-f), R = CH3(92g-l), R = H(92m-p), R = F
a b c d e f
g h i j k lm n o p
91a-c 92a-p
Na2CO3
86a, 86b, 86d-f, 86i
Scheme-31 Solvent free synthesis of (E)-2-(3,5-dimethyl-4-(aryldiazenyl)-1H-
pyrazol-1-yl)-4-arylthiazoles 92a-p
To get the product (E)-2''-(3,5-dimethyl-4-(p-tolyldiazenyl)-1H-pyrazol-1-yl)-4''-
phenylthiazole 92a, the reactant (E)-3,5-dimethyl-4-(p-tolyldiazenyl)-1H-pyrazole-1-
carbothioamide 91a was ground with phenacyl bromide 86b in the presence of
sodium carbonate at 100 ºC temperature. The product 92a of high purity was formed
within 10-15 minutes under solvent free conditions (Scheme-31). The structure of 92a
was established on the basis of a combined use of IR, NMR (1H & 13C), COSY,
ROESY, HSQC and HMBC spectroscopy.
The disappearance of N-H stretching bands at 3140 and 3387 cm-1 due to NH2 group
of carbothioamide indicated the formation of compound 92a. In the 1H NMR
xiv
spectrum, disappearance of two signals at δ 6.96 and 8.69 for NH2 protons and an
appearance of singlet at δ 7.21 due to thiazole proton (H-5'') confirmed the formation
of 92a. The structure of 92a was further supported by its 13C NMR spectrum in which
three characteristic signals of thiazole system at δ 161.67, 152.79 and 109.10 were
appeared due to C-2', C-4', and C-5', respectively.
In the present investigation, initially an attempt to perform the reaction of 91a with
86b in ethanol under reflux conditions was made which resulted in an exclusive
formation of a mixture of thiocyanatoketone 93 and cleaved pyrazole 94. The results
were supported by the appearance of a characteristic signal at δ 4.72 (s, 2H, CH2) of
93 as well as a signal at δ 2.52 (s, 6H, 3,5-CH3) and 2.34 (s, 3H, 4'-CH3) of 94 in the 1H NMR spectrum of the crude reaction mixture (Scheme-32). This observation was
consistent to the previously reported results based on the reaction of 4-unsubstituted
pyrazole-1-carbothioamide. In this study, it has been found that arylazo group present
at position-4 of the pyrazole moiety did not play any role in preventing the cleavage
of C-N bond in the reaction of differently substituted pyrazole-1-carbothioamides
with α-bromoketones.
N N N N
NH2S
NS
Ph
Z Z
+ PhCOCH2BrEtOH
reflux+ Ph
OSCN +
N NH
Z
Z = CH3NN
91a
86b
92a
93
94
Scheme-32 The reaction of (E)-3,5-dimethyl-4-(p-tolyldiazenyl)-1H-pyrazole-1-
carbothioamide 91a with phenacyl bromide 86b under solvent mediated conditions
To explore the biological potential, all the synthesized compounds were evaluated for
their antimicrobial and antioxidant potential. In addition, effect of compounds on
plasmid DNA under UV irradiation was also studied. The results of antimicrobial
study revealed that among the series, compounds 92g-l were found active selectively
against C. albicans. The compound 92l exhibited two-fold high antifungal potential in
comparison to Amphotericin-B, a standard drug against C. albicans. The compound
92k was found equipotent and 92g-j displayed half of the potential in reference to the
standard drug. In DNA based study, 92j and 92n was found as the most potent DNA
damage protecting and DNA photocleaving agent, respectively at 40 µg
xv
concentration. The compounds 92d, 92e, 92g, 92i, 92k, 92m and 92o also displayed a
significant level of DNA damage protective potential whereas 92l and 92p exhibited
appreciable DNA photocleavage activity. In the antioxidant study, all compounds
were found inactive.
CHAPTER-3 SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL
EVALUATION OF SOME NOVEL 5-HYDROXY-5-TRIFLUOROMETHYL
ISOXAZOLINE DERIVATIVES
Isoxazolines are an important class of five-membered heterocyclic compounds in
which oxygen and nitrogen heteroatoms are present at position-1 and position-2,
respectively. The general structure of isoxazoline is shown in Figure 1.
R, R', R'' = H or alkyl or aryl or heteroaryl
NO
R''
R'
R
1
2
3
4
5
Isoxazoline-2
Fig.1
Isoxazoline containing compounds were found to exhibit a wide range of bioactivities
such as anti-inflammatory, analgesic, antibacterial, anthelmimtic, anticancer and
antitubercular. Introduction of trifluoromethyl group on the isoxazoline nucleus
further resulted in development of many biologically active agents (Figure 2).
O NF3C
NR5
R6
R1
NN
N
Insecticidal
O N
F3C
Ar2
Ar1
IIAntiparasitic
O N
Ph PhSO2CF3
F3C
X
Used in Agrochemicals
NO
F3CHO
NN
R
S
Antimicrobial
IIII
IV
Fig.2
The synthetic and biological developments made in recent past of some isoxazoline
derivatives bearing trifluoromethyl group is outlined in the form of review in the
beginning of this Chapter (Section 3.1)
Also reported that halo substitution on isoxazoline moiety resulted in many potent
anticancer agents. It has been reported that azoles having arylazo group at position-4
xvi
were known as efficient antimicrobial, antibacterial, anti-staphylococcal, analgesic,
antioxidant, cytotoxic and CDK2-cyclin E inhibiting agents.
Prompted from the above facts Section 3.2 deals with the synthesis of some novel
isoxazoline derivatives having haloarylazo group at position-4 in order to explore
their biological potential with an expectation to find new class of biologically active
agents. The structures of synthesized compounds was established with the help of
combined application of IR, NMR (1H, 13C and 19F) spectroscopy, mass spectrometry
and elemental analyses.
The synthesis of some novel (E)-4-(aryldiazenyl)-3-aryl-5-(trifluoromethyl)-4,5-
dihydroisoxazol-5-ol derivatives 89 has been accomplished according to the reaction
sequence shown in Scheme-28.
Ar CF3
O O
NN
R
NH2OH.HCl / NaOAc
EtOH, reflux, 4 h
O N
N
F3CHO
N
R
Ar
87a-n, 87aa-an 89a-n, 89aa-an
For compds (87, 89) (a-g), R = I; (h-n), R = Br; (aa-ag), R = Cl; (ah-an), R = F
12
34
1''2''
3''4''
5''6''
1''2''
3''4''
5''
6''
1 2
3
45
88
OCH3Cl Br F
For compds
( 87, 89)
Ar
a b c d e f g h i j k l m n aa ab ac ad ae af agah ai aj ak al am an
��
Scheme-28 Synthesis of (E)-4-(aryldiazenyl)-3-aryl-5-(trifluoromethyl)-4,5-
dihydroisoxazol-5-ol derivatives 89 To achieve the target compound 89a, (E)-1-(4-chlorophenyl)-4,4,4-trifluoro-2-((4-
iodophenyl)diazenyl)butane-1,3-dione 87a was treated with hydroxylamine
hydrochloride 88 in the presence of sodium acetate using ethanol under reflux
conditions. The structure of 89a was established on the basis of a combined use of IR,
NMR (1H, 13C and 19F) spectroscopy and mass spectrometry. In IR spectrum, two
absorption bands due to NH and OH str. at 3292 and 3005 cm-1 were appeared. The 1H NMR spectroscopy is not a useful tool to distinguish between compounds 87 and
89. In 13C NMR spectrum of 89a, carbon-5 resonated as a quartet at δ 98.52 ppm (2JC-
xvii
F = 35.21 Hz) while C-4 and C-3 resonated as singlets at δ 131.95 and 154.60 ppm,
respectively. The carbonyl carbon peaks, C-1 at δ 189.68 and C-3 at 175.32 ppm (2JC-
F = 33.20 Hz) in the starting precursor 87a were found to be disappeared in the
product. A sharp signal in 19F NMR spectrum at δ - 78.86 ppm also provides a firm
evidence in support of the structure of isoxazoline. Further confirmation of 89a was
supported by the mass spectral data which showed a molecular ion peak at m/z =
495.9 (M+) in conformity with molecular formula C16H10ClF3IN3O2. The probable
mechanism for the formation of 89 is given in Scheme-29.
NH2OH Ar CF3
O O
R'
+Ar CF3
N
R'
OOH
N O
Ar CF3
OH
R'H87
For compound (87, 89) R' =R
NN
89
Scheme-29 The probable mechanism of formation of (87, 89)
In the study involving the effects of compounds on DNA, it has been found that some
of synthesized compounds exhibited very high DNA damage protecting effect.
EXPERIMENTAL
The Experimental part is common for all the Chapters
Chemistry
Melting points were determined by open capillary method and are uncorrected. The
FT-IR spectra of the compounds were recorded on FT-Infra-Red Spectrometer Model
RZX (Perkin Elmer) using KBr pellets. The 1H and 13C NMR spectra were recorded
on Bruker Advance II 400 NMR Spectrometer at 400 MHz and 100 MHz,
respectively; chemical shifts are expressed on δ-scale downfield from TMS as an
internal standard. Mass spectra were recorded on Waters Micromass Q-Tof Micro
Mass spectrometer equipped with electrospray ionization (ESI) and atmospheric
pressure chemical ionization sources having mass range of 4000 amu in quadruple
and 20000 amu in ToF. Thermo Scientific (FLASH 2000) CHN Elemental Analyser
was used to determine percentages of C, H and N with an accuracy of 0.3%. The
absorbance for the antioxidant activity was recorded on specord 250 analytikjena UV
spectrophotometer.
xviii
Biological Evaluation
Antibacterial Activity
Antibacterial activity of synthesized compounds 95a-k was studied by the agar well
diffusion method using N,N-dimethylformamide (DMF) solvent against various
pathogenic strains of gram positive and gram negative bacteria (Staphylococcus
aureus, Escherichia coli, Klebsiella pneumoniae, Enterococcus and Psuedomonas
aeruginosa). The tested pathogenic strains of bacteria were isolated from the patients
in Maharishi Markandeshwar Medical College, Maharishi Markandeshwar
University, Mullana, Haryana. Nutrient agar medium (25 ml) was poured into each
petri plate and agar plates were swabbed with 100 μL inocula of each test bacterium
and kept for 15 min for adsorption. Using sterile cork borer of 8 mm diameter, wells
were bored into the seeded agar plates and these were loaded with a 50 μL volume.
Solutions of the test compounds and standard were prepared in DMF at concentration
of 2000 µg/mL. From this stock solution, two-fold dilutions of the compounds (2, 4,
8….. 1024 µg/mL) were inoculated to the corresponding wells. All the plates were
incubated at 37 °C for 24 h. Antibacterial activity of each synthesized compound was
evaluated by measuring the zone of growth inhibition with zone reader (Hi Antibiotic
zone scale) and MIC was determined at the lowest concentration of the
compound tested that was able to inhibit visible growth of bacteria. DMF was used as
a negative control whereas Ampicillin was used as a reference drug.
Antimicrobial activity
Test microorganisms: On the basis of clinical importance in causing diseases in
humans, total six microbial strains were selected. These strains include two Gram-
positive bacteria viz. Staphylococcus aureus MTCC 96 and Bacillus subtilis MTCC
121, two Gram-negative bacteria viz. Escherichia coli MTCC 1652 and Pseudomonas
aeruginosa MTCC 741 and two yeasts namely Candida albicans MTCC 227 and
Saccharomyces cerevisiae MTCC 170. All the microbial cultures were purchased
from Microbial Type Culture Collection (MTCC), IMTECH, Chandigarh.
Subculturing of bacterial strains were done on Nutrient Agar (NA) while yeasts were
carried on Malt Extract Agar (MEA) plates.
Determination of zone of inhibition
The zones of inhibition of all the synthesized compounds 97a-k, 101a-u, 87a-m, 92a-
p, 89a-n and 89aa-an were measured by the agar well diffusion method. The
inoculum suspensions of the test microorganisms were prepared by using 16 h old
xix
cultures adjusted to 108 cfu/ml by referring the 0.5 McFarland standards. Total 20 ml
of agar medium (NA in case of antibacterial and MEA in case of antifungal) was
poured into each petri plate and then plates were swabbed with 100 µl inocula of the
test microorganisms and kept for 15 min for adsorption. Wells were bored into the
seeded agar plates using a sterile cork borer of diameter (8 mm) and these were
loaded with a 100 µl volume with concentration of 4.0 mg/ml of each compound
reconstituted in the dimethylsulphoxide (DMSO). The incubation of all the plates was
carried at 37 oC for 24 h. Antimicrobial activity of each compound against the
selected organisms was evaluated by measuring the zone of inhibition with zone
reader (Hi Antibiotic zone scale) Ciprofloxacin and Amphotericin-B were used as
positive control for bacterial and yeast strains, respectively. This procedure was
performed in three replicate plates for each organism.
Determination of minimum inhibitory concentration (MIC)
MIC is the lowest concentration of an antimicrobial compound that inhibits the visible
growth of the microorganisms after incubation. MIC of the various compounds
against bacterial and yeast strains was tested through a modified agar well diffusion
method. In this protocol, a two-fold serial dilution of each compound was prepared by
first reconstituting the compound in DMSO followed by dilution in sterile distilled
water to achieve a decreasing concentration range of 4 to 0.0625 mg/ml. A 100 µl
volume of each dilution was introduced into wells (in triplicate) in the agar plates
already seeded with 100µl of standardized inoculum (108 cfu/ml) of the test microbial
strain. All test plates were incubated aerobically at 37 oC for 24 h and observed for the
inhibition zones. MIC, taken as the lowest concentration of the chemical compound
that inhibited the growth of the microbes which was shown by a clear zone of
inhibition and was recorded for each test organism. Ciprofloxacin and Amphotericin-
B were used as positive controls while DMSO was used as a negative control in this
investigation.
Free radical-scavenging of the compounds using DPPH analysis
The DPPH free radical scavenging activity is based on the fact that methanolic
solution of DPPH which imparts vivid purple color and gives strong absorption band
at 515 nm, gets reduced in the presence of an antioxidant compound. Different
concentrations of the compounds 97a-k, 101a-u, 87a-m, 92a-p, 89a-n and 89aa-an
under evaluation (50-400 µg/mL) were added to 4mL of a DPPH solution (120 µM)
in methanol and incubated at 37 °C temperature for 30 min dark. The absorbance was
xx
determined at 515 nm and the percentage free radical scavenging (%) was calculated
according the following equation:
Scavenging % = [(Acontrol – Asample) / Acontrol] x 100
where, Acontrol is the absorbance of the control reaction (containing all reagents except
the test compounds), and Asample is the absorbance of the test compound. Ascorbic
acid was used as a positive control and tests were conducted in triplicate.
Effects of compounds on plasmid DNA under UV irradiation
Treatment of plasmid DNA with the samples
The stock solutions for all tested compounds were prepared by dissolving 0.005 g of
compound in 0.5 ml of DMSO. All synthesized compounds in DMSO were added
separately to volume of 2µl containing plasmid DNA in TE (Tris 10 mM, EDTA 0.01
mM, pH 8.0) buffer. The same volume of DMSO as used to make the solution of the
test compounds was added into A and control C. The reaction volumes except A were
held in caps of polyethylene microcentrifuge tubes, which were irradiated directly on
the surface of a trans-illuminator (8000 mW/cm) at 360 nm for 1 h at room
temperature. After that A, control (C) and test samples were incubated at 37 °C for
0.5 h.
Agarose gel electrophoresis
After the treatment, electrophoresis was performed according to the given procedure
mentioned.
To a 2 ml 50X tris-acetate EDTA buffer (TAE) (40 mM Tris, 20 mM acetic acid, 1
mM EDTA, pH: 8.0), added 98 ml of autoclaved water to make it 1X TAE buffer.
Agarose (0.8 g) was dissolved by boiling to the resultant mixture. When the gel
attained 55 ºC temperature, 10 mg/ml of ethidium bromide (ETBR) was added. The
treated DNA sample mixed with 6X loading dye (0.25%) bromophenol blue added
and then it was poured into gel cassette fitted with a comb. The gel was then allowed
to solidify. The comb was carefully removed and the gel was placed over
electrophoresis chamber flooded with tris-acetate EDTA buffer (40 mM Tris, 20 mM
acetic acid, 1 mM EDTA, pH: and 30% glycerol) was carefully loaded into the wells
along with control (C) and A, and electrophoresis was carried out at 5V/cm for 2.0 h
and the bands were observed under UV transilluminator.
xxi
Anticancer activity
Cell Culture
SKOV3 cell lines were grown in DMEM medium (10-013-CV, Corning), HCT116
and HT29 were maintained in McCoy’s 5A medium (166600-082, Life techonlogies),
DU145 were grown in Eagle's Minimum Essential Medium (EMEM), and A549 were
grown in RPMI medium. All the media contained 10% fetal bovine serum (FBS), 100
units/mL penicillin, and 100 mg/ml streptomycin. Cells were grown in a 37 ºC
incubator with 5% CO2.
Cell Viability assay
The effect of the compounds 95a-k on the cell viability of different cancer cell lines
was determined by performing colorimetric MTT assay as previously described, in
which the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyletetrazolium bromide) is
reduced to its insoluble crystal form formazan. Briefly, different cancer cells
(HCT116, HT29, DU145, SKOV3, and A549) were incubated in 96 well plates at
concentration of 30000 cells per mL in a 96 well plate for overnight. Further, the cells
were treated with increasing concentration of the compounds (0-50 μM) in triplicates
for 48 h and 72 h time points. MTT (M2128, Sigma) reagent (5 mg/mL) was added to
each well 3 h prior to the termination time point and plates were placed back in the
incubator at 37 ºC. After 3 h, the formazan crystals were dissolved in 100 μL DMSO.
Optical density was measured at 570 nm by using a microplate reader (Dynex
Technologies, MRX Revelation; Chantilly, VA, USA). The background reading was
measured at 630 nm, which was subtracted from 570 nm reading during the cell
viability calculation.
xxii
LIST OF PUBLICATIONS
1. Vinod Kumar, Kamalneet Kaur, Girish Kumar Gupta, Anil Kumar Sharma,
Pyrazole containing natural products: Synthetic preview and biological
significance, European Journal of Medicinal Chemistry, 2013, 69, 735-753.
2. Vinod Kumar, Kamalneet Kaur, Girish K. Gupta, Akhilesh K. Gupta, Sunil
Kumar, Developments in synthesis of the anti-inflammatory drug, celecoxib:
A review, Recent Patents on Inflammation & Allergy Drug Discovery, 2013,
7(2), 124-134.
3. Vinod Kumar, Girish Kumar Gupta, Kamalneet Kaur, Randhir Singh, 4-
Fluorophenylhydrazones as potential COX-2 inhibitors: A novel, efficient, one
solid phase synthesis, docking study and pharmacological evaluation,
Medicinal Chemistry Research, 2013, 22 (12), 5890-5900.
4. Vinod Kumar, Kamalneet Kaur, Deepkamal N. Karelia, Vikas Beniwal,
Girish Kumar Gupta, Arun K. Sharma, Akhilesh Kumar Gupta, Synthesis and
biological evaluation of some 2-(3,5-dimethyl-1H-pyrazol-1-yl)-1-
arylethanones: Antibacterial, DNA photocleavage, and anticancer activities,
European Journal of Medicinal Chemistry, 2014, 81, 267-276.
5. Kamalneet Kaur, Vinod Kumar, Anil Kumar Sharma, Girish Kumar Gupta,
Isoxazoline containing natural products as anticancer agents: A review,
European Journal of Medicinal Chemistry, 2014, 77, 121-133.
6. Girish Kumar Gupta, Kamalneet Kaur, Shikha Singh, Vinod Kumar,
Isolation of 4-hydroxythiazoline: A solid phase study in Hantzsch thiazole
reaction, Research Journal of Chemistry and Environment, 2014, 18(2), 38-34.
7. Vinod Kumar, Kamalneet Kaur, Girish Kumar Gupta, Triazole and
Oxadiazole containing Natural Products: A review, The Natural Product
Journal, 2014, 4, 115-130.
8. Girish K. Gupta, Vinod Kumar, Kamalneet Kaur, Imidazole containing
natural products as antimicrobial agents: A review, The Natural Product
Journal, 2014, 4, 73-81.
9. Kamalneet Kaur, Vinod Kumar, Vikas Beniwal, Vikas Kumar, K.R Aneja,
Vishal Sharma, Sundeep Jaglan, Synthesis, antimicrobial, antioxidant and
DNA photocleavage study of some novel 2-(3,5-dimethyl-1H-pyrazol-1-yl)-1-
arylethanols, Arabian Journal of Chemistry, 2015 (Communicated).
xxiii
10. Kamalneet Kaur, Vinod Kumar, Vikas Beniwal, Vikas Kumar, K.R Aneja,
Vishal Sharma, Sundeep Jaglan, Novel (E)-1-aryl-2-(3,5-dimethyl-4-
(aryldiazenyl)-1H-pyrazol-1-yl)ethanones: Solvent free synthesis,
antimicrobial, antioxidant and UV mediated DNA damage protective activity
studies, Medicinal Chemistry Research, 2015 (Communicated).
11. Kamalneet Kaur, Vinod Kumar, Vikas Beniwal, Vikas Kumar, K.R Aneja,
Vishal Sharma, Sundeep Jaglan, Novel (E)-1-aryl-2-(3,5-dimethyl-4-
(aryldiazenyl)-1H-pyrazol-1-yl)ethanones: Solvent free synthesis,
antimicrobial, antioxidant and UV mediated DNA damage protective activity
study, Medicinal Chemistry Research, 2015 (Communicated).
12. Vinod Kumar, Kamalneet Kaur, Fluorinated Isoxazolines and Isoxazoles:
Synthetic preview and biological significance (to be Communicated).
13. Synthesis and UV mediated DNA damage protective activity of (E)-4-
(aryldiazenyl)-3-aryl-5-(trifluoromethyl)-4,5-dihydroisoxazol-5-ols (to be
Communicated).
14. Synthesis of some novel oxazolidinone-thiazole hybrids as potential
antimicrobial, antioxidant and UV mediated DNA damage protecting agents
(to be Communicated).
PATENTS FILED
1. Process for synthesis of chalcones and uses thereof, Vinod Kumar, Kamalneet
Kaur, Duha Adnan, Girish Kumar Gupta, Vikas Beniwal, Sunil Kumar,
No.146/DEL//2014 (Application filed on dated 17/1/2014).
2. Process for Novel 2-(3,5-dimethyl-1H-pyrazol-1-yl)-1-arylethanones as DNA
photocleaving Agents, Vinod Kumar, Kamalneet Kaur, Vikas Beniwal,
Girish Kumar Gupta, Akhilesh Kumar Gupta, No.144/DEL/2014 (Application
filed on dated 17/1/2014).
3. 2-(3,5-Dimethyl-1H-pyrazol-1-yl)-1-(naphth-2-yl)ethanone as potential
anticolon cancer agent, Vinod Kumar, Kamalneet Kaur, Deepkamal N.
Karelia, Arun K. Sharma, Girish Kumar Gupta, Akhilesh Kumar Gupta,
No.145/DEL/2014 (Application filed on dated 17/1/2014).
xxiv
CONFERENCES/SEMINARS/WORKSHOPS/ SYMPOSIUM ATTENDED
1. 3rd National Conference on “Recent Advances in Chemical and Environmental
Sciences” organized by Multani Mal Modi College, Patiala on 28th Feb, 2011-
01st March, 2011.
2. National Seminar on “Recent Trends in Herbal Drug Research” organized by
Pharmaceutical Department, MMU Mullana on 20th-21st October 2011.
3. National Workshop on “Spectroscopic techniques and their applications”
organized by Chemistry Department, MMU Mullana on 12th November, 2011.
4. One day Workshop on “Analytical Techniques for Research in Pharmacy”
organized by Pharmaceutical Department, MMU Mullana on 07th December,
2012.
5. Poster presentation on the topic “A Mild Approach to 2,4-Disubstituted
Thiazoles : Solid Phase Study in Hantzsch Thiazole Synthesis” in the National
Conference on Recent Advances in Chemical and Environmental Sciences”
organized by Multani Mal Modi College, Patiala on 31st January, 2013.
6. Poster on the topic “A mild, greener and a solvent-free synthesis of 4-Aryl-2-(4-
arylazo-3,5-dimethylpyrazol-1-yl)thiazoles” to be presented in the International
Conference on the Recent Advances in Chemical Sciences (Novel Molecules for
Diagnosis and Therapeutics) organized by Arya P.G College Panipat on 24-26th
February, 2013.
7. One day seminar on “AAS instrumentation and unique patented technologies”
joinly orgainized by Perkin Elmer and M.M College of Pharmacy, Mullana on
3rd April, 2013.
8. One day seminar on “Recent Advances in Liquid Chromatography” organized
by M.M College of Pharmacy, M.M. University, Mullana-Ambala on 31st Jan,
2014.
9. Poster presentation on the topic “Greener and practical approach for synthesis of
some 2, 4-disubstituted thiazoles: A solid phase study in Hantzsch thiazole
reaction” in “Professor Ram Chand Paul National Symposium on New Visions
in Chemical Sciences” organized by Department of Chemistry & Centre of
Advanced Studies in Chemistry, Panjab University, Chandigarh on 15-16 Feb,
2014 (Won Best poster award).
xxv
10. One day Seminar, “Answering the Obesity Epidemic: Challenges and
Opportunities” organized by M.M College of Pharmacy, M.M. University,
Mullana-Ambala on 4th March, 2014.
11. 1st International Virtual Conference on “Information retrieval on scientific
literature: Emerging frontiers and challenges”, organized by M.M. University,
Mullana-Ambala on 10-11th June 2014.
12. National Seminar on “Safety in Chemistry Laboratory” organized by
Department of Chemistry, M.M. University, Mullana-Ambala on 12th Nov,
2014.
13. Poster presentation on the topic “Synthesis and antimicrobial evaluation of
some novel 2-(pyrazol-1-yl)ethanols” in the 7th National Conference on
“Recent Advances in Chemical, Biological and Environmental Sciences”
organized by Multani Mal Modi College, Patiala on 30th -31st January, 2015.