Synthesis of novel coumarin appended bis(formylpyrazole) derivatives: Studies on their antimicrobial and antioxidant activities

Article abstract of DOI:10.1016/j.bmcl.2015.11.038

A series of novel coumarin pyrazole hybrids of biological interest were synthesized from the hydrazones, carbazones and thiocarbazones via Vilsmeier Haack formylation reaction. These intermediates and formyl pyrazoles were evaluated for antimicrobial and

Full text of DOI:10.1016/j.bmcl.2015.11.038

Accepted Manuscript
Synthesis of novel coumarin appended bis(formylpyrazole) derivatives: Studies
on their antimicrobial and antioxidant activities
Renuka Nagamallu, Bharath Srinivasan, Mylarappa B Ningappa, Ajay Kumar
Kariyappa
PII:
S0960-894X(15)30247-X
http://dx.doi.org/10.1016/j.bmcl.2015.11.038
BMCL 23294
DOI:
Reference:
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
11 August 2015
5 November 2015
12 November 2015
Please cite this article as: Nagamallu, R., Srinivasan, B., Ningappa, M.B., Kariyappa, A.K., Synthesis of novel
coumarin appended bis(formylpyrazole) derivatives: Studies on their antimicrobial and antioxidant activities,
Bioorganic & Medicinal Chemistry Letters (2015), doi: http://dx.doi.org/10.1016/j.bmcl.2015.11.038
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Synthesis of novel coumarin appended bis(formylpyrazole) derivatives:
Studies on their antimicrobial and antioxidant activities
a
b
c
RENUKA NAGAMALLU , BHARATH SRINIVASAN , MYLARAPPA B NINGAPPA ,
a
AJAY KUMAR KARIYAPPA *
a
Department of Chemistry, Yuvaraja College, University of Mysore, Mysore, India.
b
Center for the Study of Systems Biology, School of Biology, Georgia Institute of Technology,
9
50, Atlantic Drive, Atlanta, Georgia 30332, USA
c
Transplant Surgery Section, Rangos Research Center, University Of Pittsburgh, PA 15201,
USA
Abstract
A series of novel coumarin pyrazole hybrids of biological interest were synthesized from
the hydrazones, carbazones and thiocarbazones via Vilsmeier Haack formylation reaction. These
intermediates and formyl pyrazoles were evaluated for antimicrobial and antioxidant activities.
Among the series, compounds 6g and 6h showed excellent antimicrobial activity against
different bacterial and fungal strains and compounds 7g, 7h were found to be potent antioxidant
agents in both DPPH and hydroxyl radical scavenging assays. Further, detailed quantitative
structure-activity relationship (QSAR) analysis indicated the molecular parameters that
contribute to increased potency of inhibition. The above findings would further encourage our
understanding in employing coumarin pyrazole hybrids as potential antibiotic agents for treating
infections caused by pathogenic microbes and fungi. Further, it also paves the way for
exploration of these compounds as potential therapeutic agents to treat conditions arising because
of excessive oxidative damage.
Keywords: Antioxidant, antimicrobial, coumarin, DPPH, hydroxyl radical, MIC, pyrazole.

An increasing interest in antioxidant activity of small molecules, particularly to prevent
the deleterious effects caused by free radicals in the human body, is attracting the attention of the
wider research community. Free radicals are believed to be associated with multiple diseases
conditions such as carcinogenesis, inflammation, mutagenesis, arthritis, cancer and genotoxicity.
These conditions arise due to the oxidative stress resulting from an imbalance between free
1
radical generation and their quenching . Despite numerous attempts to search for more effective
antioxidant agents, coumarin still remains as the scaffold of choice. It has demonstrated utility in
quenching of free radicals and, hence, has tremendous potential for exploration as candidate
molecules for drug discovery against conditions that result from oxidative damage. Coumarins
are naturally derived and synthetically taken polyphenolic substances giving a wide variety of
2
biological activities and employed as therapeutic agents for multiple diseases . A large number
of coumarin derivatives were found to affect the formation and scavenging of reactive oxygen
3
species and reactive nitrogen species displaying tissue protective antioxidant properties . Among
them, hydroxyl coumarins are effective metal chelators, free radical scavengers and powerful
chain breaking antioxidants. Many coumarin derivatives have unique ability to scavenge the
reactive oxygen species, such as hydroxyl free radicals and superoxide, to prevent free radical
injury. In addition, coumarin derivatives act as antioxidant agents with application in parasitic
4
diseases .
Coumarin derivatives, such as coumarin hydrazones, have been under investigation in
5
6
7
recent years due to their usage as pharmaceuticals , fluorescence sensors , chemoreceptors and
8
precursors for the synthesis of coumarin pyrazoles . Different coumarins are identified as
9
anticoagulants, antioxidants, antidepressants, analgesics and diagnostics . Coumarin derivatives
containing a substituted hydroxyl group at the position 7 possess antibiotic and antifungal

activities. The incorporation of another heterocyclic moiety, either as a substituent or a fused
component into coumarin, alters the properties of the parent material and the resulting
1
0
compounds generally exhibit promising or unprecedented properties .
In 1883, Knorr synthesized the first pyrazole derived compound that led to the discovery
1
1
of antipyrine and its derivatives . Since the introduction of antipyrine in 1884, the first
pyrazolone derivative, it was used in the treatment of pain, inflammation and fever. Pyrazole
derivatives possess wide spectrum of biological activities. They are extensively studied and used
1
2,13
as antimicrobial agents
. In particular, 5-chloropyrazol derivatives are reported to show
1
4
15
potential antimicrobial , analgesic and anti-inflammatory activities . Further much attention
was given to pyrazoles as antimicrobial agents after the discovery of the natural pyrazole C-
glycoside pyrazofurin; 4-hydroxy-3-β-D-ribofuranosyl-1H-pyrazole-5-carboxamide which
1
6
demonstrated a broad spectrum of antimicrobial activities . Hydrazones and semicarbazones of
ketones having an α methyl substitution prevents the formylation of pyrazoles upon treatment
1
7
18
with Vilsmeier-Haack reagent . Recently Tarik and co-workers synthesized the 4,6-bis(4-
formylpyrazol-3-yl)resorcinol from the bis-hydrazones of 4,6-diacetylresorcinol by Vilsmeier-
Haack reaction and evaluated them for their antimicrobial activity.
Prompted by the above literature survey results, we planned to study structural variation
by attaching biologically active pyrazoles to the coumarin moiety as well as hydrazono,
hydrazinecarboxamido and hydrazinecarbothioamido coumarins. These combinations were
explored in an attempt to investigate the synergetic influence of these compounds on the
antioxidant and antimicrobial activity, thus hoping to get a new lead structure for the further
study.

In continuation of our research work aiming at developing a straightforward and flexible
synthetic method towards the functionalized coumarins appended pyrazoles with remarkable
biological importance, we report the utility of 7-hydroxy-4-methyl-6,8-bis(1-(2-
phenylhydrazono)ethyl)-2H-chromen-2-one,
2,2’-((7-hydroxy-4-mrthyl-2-oxo-2H-chromene-
6
,8-diyl)bis(ethan-1-yl-1-ylidene))bis(hydrazinecarboxamide) and 2,2’-((7-hydroxy-4-methyl-2-
oxo-2H-chromene-6,8-diyl)bis(ethan-1-yl-1-ylidene))bis(hydrazinecarbothioamide) as building
blocks for the synthesis of functionalized coumarin based bis(formylpyrazole) derivatives, and
study their antimicrobial and antioxidant activity in order to get potent antimicrobial and
antioxidant agents.
The synthetic strategies adopted to obtain the target compounds are depicted in Scheme-
1
4
. The starting material 6-acetyl-7-hydroxy-4-methyl-2H-chromen-2-one 2 was prepared by 1-(2,
-dihydroxyphenyl)ethanone 1 and ethyl acetoacetate in the presence of sulfuric acid by
Pechmann reaction. The treatment of 2 with acetic anhydride to give 6-acetyl-4-methyl-2-oxo-
H-chromen-7-yl acetate 3, this on subjecting to Fries rearrangement using AlCl as a catalyst
2
3
afforded 1,1'-(7-hydroxy-4-methyl-2-oxo-2H-chromene-6,8-diyl)diethanone 4. The condensation
of the compound 4 with substituted phenylhydrazines 5(a-f), semicarbazine 5g and
thiosemicarbazine 5h in ethyl alcohol and a catalytic amount of acetic acid under reflux
conditions produced the corresponding bis-hydrazones 6(a-f), semicabazones 6g and
thiosemicarbazone 6h, which were subsequently reacted under Vilsmeier-Haack condition
furnished the target molecules 3,3'-(7-hydroxy-4-methyl-2-oxo-2H-chromene-6,8-diyl)bis(1-
aryl-1H-pyrazole-4-carbaldehyde) 7(a-f), 3,3'-(7-hydroxy-4-methyl-2-oxo-2H-chromene-6,8-
diyl)bis(4-formyl-1H-pyrazole-1-carboxamide), 7g and 3,3'-(7-hydroxy-4-methyl-2-oxo-2H-
chromene-6,8-diyl)bis(4-formyl-1H-pyrazole-1-carbothioamide), 7h in excellent yield.

1
13
All the synthesized compounds were confirmed by H NMR, C NMR, mass and CHN
1
analysis. In H NMR spectra of compound 2, the appearance of one broad singlet for only one
OH proton and the presence of one singlet for the C -proton at 5.96 ppm confirmed the
3
1
3
compound. In C NMR, the signal was observed at the region 160.24 ppm due to the presence of
C=O group, thus confirming the formation of coumarin. Compound 2 was converted to an ester
3
, which was confirmed by the disappearance of broad singlet for OH proton present in
compound 2 spectra and the presence of singlet at the region 2.26 ppm due to the presence of
1
3
CH group. Further, in the C NMR, the appearance of C=O group at the region 170.34 ppm
3
confirms the formation of ester. Fries rearrangement of compounds 3 gave hydroxy ketones 4,
which were confirmed by the appearance of broad singlet for OH proton and decrease in one
1
aromatic proton in H NMR. Further, presence of C=O group at C
7
position in compound 3
shifted to C
8
position in compound 4 at the region 196.10 ppm, confirming the formation of
ketone. Compound 4 on treatment with substituted phenylhydrazines 5(a-f), carbazine 5g and

thiocarbazine 5h gave respective hydrazones 6(a-f), carbazones 6g and thiocarbazones 6h. The
1
13
H NMR and C NMR observations reveal the appearance of two NH protons at the region 7.01-
1
7
.12 ppm in the H NMR and the presence of two C=N group at the region 167.44-168.66 ppm
1
3
in the C NMR, confirming the formation of bis hydrazones. On the other hand, bis-carbazones
and thiocarbazones were confirmed by the presence of two NH and NH group at the region
.06-8.92 ppm and 7.10-7.14 ppm in the H NMR and in the C NMR spectra, two C=N group
2
1
13
6
at the region 167.07 ppm and a C=S carbon at the region 179.22 ppm, respectively. Finally all
the compounds 6(a-h) on treatment with Vilsmeier-Haack reagent delivered the expected final
compounds 7(a-h) in good yield, which was clearly evident with the disappearance of NH and
NH groups present in the compound 6(a-h) and the formation of two CHO groups at the region
2
1
13
9
8
.80-9.93 ppm in the H NMR and 183.10-186.14 in C NMR. The peak appeared at the region
1
13
.10-8.66 ppm and 130.08-137.72 ppm in H NMR and C NMR providing the evidence for the
+
+
formation of bis-pyrazole. All the compounds gave M , MH ions as base peak and significantly
stable molecular ion peaks with a relative abundance ranging from 10-40% and showed
satisfactory CHN analysis data with the theatrically calculated values.
The antibacterial and antifungal activities of the compounds were determined by broth
1
9
dilution technique . The antibacterial tests were conducted against bacterial pathogens such as
Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus. The antifungal activity
was evaluated against different fungal strains such as Aspergillus nigar, Aspergillus flavus and
Candila albicans. The antibiotics ciprofloxacin and fluconazole were used as standard drugs
against bacteria and fungal species, respectively. Dimethyl sulfoxide was used as solvent control.
The experiments were carried out in triplicate; the results were taken as a mean ± standard
deviation (SD). The results of minimum inhibitory concentrations (MIC’s), defined as the

concentration required for 90% clearance of an organism, of the synthesized compounds against
several bacterial and fungal species are summarized in Table 1.
All the compounds exerted a wide range of modest in vitro antibacterial activity having
minimum inhibitory concentration (MIC) values ranging from 6.25-75 µg/mL. Compounds 6g
and 6h having CONH
2
and CSNH substitution in the carbazones showed excellent bacterial
2
activity by inhibiting spore germination of all the tested organisms and compounds 7g and 7h
having the same substitution in the pyrazole ring showed activity as potent as the standard.
Compounds 6d and 6b having methoxy and methyl substitution shows good activity but
compounds 7d and 7b shows less activity than the standard. Fluro, chloro and methyl
substitution in compounds 6e, 7e, 6f, 7f and 6c, 7c exhibit less activity against the organism
tested. Compound 6a, without any substitutions, resulted in moderate antibacterial and antifungal
activity against all the organisms tested and compound 7a having same substitution in pyrazole
ring exhibited poor inhibitory effect on the organisms.
All the synthesized bis-carbazones, bis-hydrazones and bis(formylpyrazole) derivatives
exerted modest antifungal activity having minimum inhibitory concentration (MIC) value 12.5-
1
00 µg/mL. CONH
antifungal activity against the organisms tested. However, 7g also having CONH
showed activity similar to that shown by the standard. 7h having CSNH group displayed higher
2
and CSNH
2
substitution in compounds 6g and 6h demonstrated excellent
2
substitution
2
potency against A. niger. Compound 6f having chloro substitution in the hydrazone showed
moderate activity while the same substitution in the pyrazole ring (compound 7f ) retard the
activity against the fungal strains. However compound 6d having methoxy group showed
activity against A. niger and the compound 7d showed activity similar to that shown by the
standard. Methyl substitution present in the compound 6b exhibits good activity with A. flavus

and C. albicans. Remaining compounds 6e, 7e having fluro; 6c, 7c having methyl at meta
position; 7b having methyl at ortho position and 6a, 7a having no substitution exhibit lesser
activity against all the organisms tested.
In an attempt to interpret and correlate the molecular parameters of the small molecules
with the potency of inhibition against the various microorganisms, detailed quantitative
structure-activity relationship (QSAR) analysis was carried out. Physicochemical parameters for
2
0
the small molecules were computed and both pair-wise and multivariate analysis was carried
2
1,22
out as specified in the literature
and elaborated in the supplementary material. As shown in
Fig S1-S7 summarizes the pair-wise correlation analysis. Examination of the figures suggest that
parameters like hydrogen-bonding acceptors/donors, polar surface area and presence of double
bonds are positively correlated with the ability of compounds 6a-h and compounds 7a-h against
the various microbes tested. Further, parameters like LogP, aromatic bond content, molecular
weight, number of atoms and bonds were negatively correlated with inhibition potency.
Further, multivariate analysis using genetic algorithm for compounds 6a-h yielded good
models for E. coli, A. niger and C. albicans. The model for S. aureus was poor most probably
due to limiting data and lack of pairwise correlation with good p-values (Fig S1A-I). Likewise,
when modeling for compounds 7a-h, the multivariate model for E. coli and C. albicans were
very poor and hence were not considered.
Analysis of the results indicate that the small-molecule features that likely contribute to
increased potency of inhibition vary across different microorganisms in spite of overall similarity
in the pair-wise correlation profiles (Fig S1-S7). This is an encouraging observation since
specific variation of a particular molecular feature would lead to increased specificity towards a
particular kind of microorganism. Further, this analysis also points out to the parameters that can

be modulated to increase the potency of these compounds in general across the different
microorganisms employed. However, care must be exercised in interpreting these results given
the small sample size that was employed across compounds 6a-h and 7a-h (8 compounds each)
and the fact that MIC, instead of IC-50, was considered as the dependent variable.
Table 1: MIC’s of the test compounds 6(a-h) and 7(a-h) against bacterial and fungal species
Compound
Minimum inhibitory concentration (MIC’s) in µg/mL*
Staphylococcus Escherichia Pseudomonas Aspergillus Aspergillus Candida
aureus
coli
aeruginosa
niger
flavus
albicans
6
a
50±0.11
25±0.40
25±0.45
50±0.50
50±0.4
50±0.56
6
b
25±0.17
50±0.35
25±0.45
75±0.65
50±0.40
25±0.20
25±0.51
50±0.50
75±0.28
75±0.79
50±0.61
75±0.65
50±0.50
50±0.17
25±0.41
25±0.3
50±0.28
12.5±0.25
50±0.45
50±0.45
12.5±0.45
12.5±0.50
50±0.52
50±0.70
50±0.41
50±0.55
75±0.28
25±0.65
12.5±0.81
25±0.41
25±0.15
25±0.25
12.5±0.56
50±0.40
25±0.35
12.5±0.30
6.25±0.76
50±0.36
25±0.40
25±0.9
50±0.66
75±0.61
12.5±0.62
50±0.51
25±0.55
12.5±0.46
12.5±0.30
50±0.36
50±0.36
75±0.55
25±0.56
75±0.25
50±0.3
25±0.70
50±0.75
25±0.94
75±0.25
50±0.40
25±0.60
12.5±0.45
75±0.5
50±0.70
50±0.66
50±0.61
75±0.23
50±0.15
25±0.97
25±0.85
50±0.42
50±0.79
50±0.60
50±0.17
100±0.36
100±0.21
50±0.46
50±0.29
6
c
6
d
6
e
6
f
6
g
6
h
7
a
7
b
75±0.45
75±0.4
7
c
7
d
12.5±0.45
50±0.60
25±0.15
25±0.70
12.5±0.37
50±0.3
7
e
75±0.45
50±0.61
25±0.21
25±0.3
7
f
7
g
25±0.41
12.5±0.45
7
h

a
cipro
25±0.75
----
25±0.70
----
12.5±0.45
----
----
----
----
b
fluc
25±0.25
25±0.21
50±0.96
*
Values are mean ± SD of three replicates
ciproafloxacin was used as a positive control against bacteria species
fluconazole was used as a positive control against fungi species
a
b
Further, various assays were performed to assess the antioxidant activities of the
compounds. Radical scavenging potency of all the compounds 6(a-h) and 7(a-h) was assessed in
2
3
24
vitro by the DPPH , and hydroxyl radical scavenging assay . The experiments were performed
in triplicate; the results were taken as a mean ± standard deviation (SD) and are presented in
Table 2 and Table 3.
The capacity to scavenge the stable free radical 2, 2-diphenyl-1-picrylhydrazyl (DPPH)
2
3
was monitored according to the Blois method . A freshly prepared DPPH solution shows a deep
purple color with an absorption maximum at 517 nm. When the purple color changes to yellow,
it leads to decreased absorbance. This is because of the antioxidant molecule reducing the DPPH
free radical through donation of hydrogen atom. Instantaneously or concomitant decrease in
absorbance would be indicative of potent antioxidant activity by the compound. Based on the
experimental results, we found out those compounds 7g and 7h having CONH
the pyrazole ring showed antioxidant activity better than the standard ascorbic acid. Compounds
g, 6h also having the same substituent in the carbazones showed better activity than the
2
and CSNH in
2
6
standard, but less activity compared to 7g and 7h. Compounds 6a, 7a, 6d, and 7d having no
substitution and methoxy group showed moderate activity. Compounds 7b and 7f having methyl
and chloro substitution showed antioxidant properties closer to the standard but the compounds
6
b and 7f ,having the same substitution, showed less activity compared to standard. Remaining

compounds 6c, 7c having methyl at meta position and fluro substitution in the compounds 6e, 7e
showed less activity compared with the standard ascorbic acid.
Table 2: Antioxidant activity of the compounds 6(a-h) and 7(a-h) in DPPH method.
Test samples
% Radical Scavenging activity*
2
5 (µg/mL)
50 (µg/mL)
16.96±0.42
75 (µg/mL)
19.35±0.57
100 (µg/mL)
22.22±0.19
6
a
15.03±0.27
14.29±0.44
10.92±0.45
14.57±0.34
8.49±0.42
6
b
16.65±0.55
11.80±0.26
17.17±0.45
11.69±0.59
14.75±0.76
17.84±0.46
17.86±0.54
17.34±0.73
17.28±0.14
16.40±0.84
17.87±0.60
14.93±0.39
17.55±0.60
23.36±0.84
26.93±0.45
16.87±0.89
19.43±0.43
13.97±0.23
19.70±0.69
14.01±0.66
17.41±0.17
21.89±0.74
22.24±0.37
20.08±0.59
20.75±0.26
18.78±0.66
21.14±0.34
17.69±0.39
20.63±0.46
25.70±0.58
29.81±0.54
21.98±0.31
22.45±0.66
17.29±0.51
22.40±0.42
17.45±0.12
20.62±1.09
24.09±0.52
26.13±0.37
23.60±0.46
24.56±0.74
24.02±0.52
24.59±0.45
19.44±0.73
23.61±0.32
29.26±0.55
36.15±0.34
24.25±0.22
6
c
6
d
6
e
6
f
10.73±0.43
14.65±0.84
15.46±0.50
15.10±0.46
16.00±0.27
13.24±0.70
14.2±0.55
6
g
6
h
7
a
7
b
7
c
7
d
7
e
11.62±0.77
15.58±0.52
18.98±0.39
23.93±0.25
15.08±0.83
7
f
7
g
7
h
a
aa
*
Values are mean ± SD of three replicates
a
ascorbic acid was used as a standard antioxidant

The hydroxyl radical is a highly reactive free radical formed in biological systems and it
2
5
is capable of damaging biomolecule found in living cells . The hydroxyl radical has the ability
to break DNA and cause strand breakage, which contributes to carcinogenesis, mutagenesis and
cytotoxicity. In this method, compounds 6(a-h) and 7(a-h) were found to be possess stronger to
weak hydroxyl radical scavenging activity. Among the compounds studied, CONH
2
and CSNH
2
substitution in compounds 7g and 7h exhibited remarkable capacity for scavenging hydroxyl
radical, significantly higher than that of the standard BHA, whereas the same substitution present
in compounds 6g and 6h also showed good activity against the radical. Compound 7d having
methoxy substitution in the pyrazole ring shows excellent activity while the compound 6d
having the same group showed moderate scavenging activity. However compounds 7a, 7b and 7f
having no substitution, methyl and chloro group present in the pyrazole ring exhibit moderate
activity but the same group present in compounds 6a, 6b and 6f showed least activity against this
radical. Methyl group at meta substitution and fluro substitution present in the compounds 6c, 7c
and 6e, 7e exhibits weak radical scavenging activity.
Table 3: Antioxidant activity of the compounds 6(a-h) and 7(a-h) in Hydroxyl radical
method.
Test samples
% Radical Scavenging activity
2
5 (µg/mL)
50 (µg/mL)
12.49±0.81
75 (µg/mL)
24.36±0.32
100 (µg/mL)
29.65±0.39
6
a
9.31±0.37
9.60±0.28
8.40±0.36
11.82±0.37
6.60±0.46
6
b
13.92±0.31
13.56±0.65
18.23±0.22
11.44±0.18
25.54±0.26
24.22±0.38
26.36±0.67
17.33±0.34
30.52±0.38
30.78±0.31
33.01±0.40
26.6±0.27
6c
6
d
6e

6
f
10.1±0.68
14.12±0.44
14.21±0.31
10.20±0.50
10.85±0.28
10.58±011
14.08±0.46
8.99±0.39
15.56±0.39
19.01±0.65
21.06±0.86
17.77±0.41
19.34±0.47
18.15±0.24
21.57±0.25
15.30±0.52
16.63±0.50
24.41±0.16
27.83±0.40
17.95±0.12
23.49±0.79
26.72±0.45
27.78±0.32
25.9±0.33
30.75±0.22
33.92±0.67
34.24±0.18
30.04±0.36
31.48±0.17
30.1±0.73
6
g
6
h
7
a
7
b
27.07±0.37
26.49±0.35
29.40±0.47
21.27±0.26
24.77±0.91
32.33±0.34
35.40±0.25
25.58±0.20
7c
7
d
35.13±0.76
29.47±0.30
32.07±0.27
36.80±0.33
40.84±0.44
32.03±0.32
7e
7f
10.46±0.66
17.55±0.66
19.56±0.62
12.02±0.05
7
g
7
h
a
BHA
*
Values are mean ± SD of three replicates
a
butylated hydroxyanisole was used as a positive control
In summary, in order to develop antimicrobial and antioxidant molecules, we have
synthesized new bioactive coumarin based bis hydrazones, biscarbazones and bis formyl
pyrazole analogues and evaluated them for antimicrobial and antioxidant activities. Compounds
6
7
g and 6h exhibited potent antimicrobial activity among the series synthesised. Compounds 7g,
h and 7d showed potent antioxidant properties in DPPH and hydroxyl radical scavenging assay.
From these biological results, the pyrazole derivatives 7(a-h) displayed much higher antioxidant
activity than those of the carbazones and hydrazone derivatives 6(a-h), whereas 6(a-h) shows
higher antimicrobial activity than the pyrazole derivatives 7(a-h). Further, detailed QSAR
analysis paves the way for design of potent and specific inhibitors for the various microbes
assessed in this study. Looking at the results, compounds 6g, 6h and 7g, 7h could be considered

as potent antimicrobial and antioxidant drugs for further detailed studies. Efforts have been made
for developing new methodologies to increase the structural complexity while decreasing the
number of synthetic steps to facilitate the construction of new coumarin based
bis(formylpyrazole) derivatives.
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