Synthesis, antioxidant, antifungal, molecular docking and ADMET studies of some thiazolyl hydrazones

Article abstract of DOI:10.1016/j.bmcl.2017.06.043

Some thiazolyl hydrazones were synthesized by one pot reaction of thiophene-2-carbaldehyde or 2, 4-dichlorobenzaldehyde, thiosemicarbazide and various phenacyl bromides which were preliminarily screened for in vitro antioxidant and antifungal activities.

Full text of DOI:10.1016/j.bmcl.2017.06.043

Accepted Manuscript
Synthesis, antioxidant, antifungal, molecular docking and ADMET studies of
some thiazolyl hydrazones
Sushama Kauthale, Sunil Tekale, Manoj Damale, Jaiprakash Sangshetti,
Rajendra Pawar
PII:
S0960-894X(17)30645-5
DOI:
http://dx.doi.org/10.1016/j.bmcl.2017.06.043
BMCL 25077
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
8 May 2017
29 May 2017
15 June 2017
Please cite this article as: Kauthale, S., Tekale, S., Damale, M., Sangshetti, J., Pawar, R., Synthesis, antioxidant,
antifungal, molecular docking and ADMET studies of some thiazolyl hydrazones, Bioorganic & Medicinal
Chemistry Letters (2017), doi: http://dx.doi.org/10.1016/j.bmcl.2017.06.043
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Graphical Abstract
Synthesis, antioxidant, antifungal, molecular
docking and ADMET Studies of Some
thiazolyl hydrazones
Leave this area blank for abstract info.
Sushama Kauthalea, Sunil Tekaleb, Manoj Damalec, Jaiprakash Sangshettid and Rajendra Pawara*
Some thiazolyl hydrazones were synthesized by one pot reaction of thiophene-2-carbaldehyde or 2, 4-dichlorobenzaldehyde, thiosemicarbazide
and various phenacyl bromides which were preliminarily screened for in vitro antioxidant and antifungal activities. Excellent DPPH and H2O2
radical scavenged antioxidant activities were observed with almost all the tested compounds. Compounds 4a, 4b, 4c, 4e, 4f and 4i showed
comparable DPPH scavenged antioxidant potential (90.26 to 96.56%) whereas H2O2 scavenged antioxidant activity (90.98 to 92.08%) was
noticeable in case of 4a and 4f; showing significant antioxidant potential comparable with the standard ascorbic acid (95.3%). In vitro antifungal
activity of synthesized compounds against fungal species Candida Albicance, Aspergillus Niger and Aspergillus Flavus was found to be
moderate to good as compared with the standard fluconazole and MIC values were in the range of 3.12 to 25 µg/mL. Molecular docking studies
revealed that the compounds 4a, 4b and 4c have a potential to become lead molecules in drug discovery process. In silico ADMET study was
also performed for predicting pharmacokinetic and toxicity profile of the synthesized antioxidants which expressed good oral drug like behaviour
and non-toxic nature.
100
95
R2
4a-DPPH
90
4f-H2O2
AA
N
85
R1
N
S
N
H
80
20
40
60
80 100
Excellent Antioxidants-IC50
Good antifungal activity - MIC
Conc. (µg/ mL)
1

Bioorganic & Medicinal Chemistry Letters
journal homepage: www.els evier.com
Synthesis, antioxidant, antifungal, molecular docking and ADMET studies of
some thiazolyl hydrazones
Sushama Kauthalea, Sunil Tekaleb, Manoj Damalec, Jaiprakash Sangshettid and Rajendra Pawara*
aDepartment of Chemistry, Deogiri College, Station Road, Aurangabad (MS) 431 005 India.
bDepartment of Chemistry, Shri Muktanand College, Gangapur (MS) 431 109 India.
cDepartment of Pharmaceutical Chemistry, Shri. Bhagwan College of Pharmacy, Aurangabad (MS) 431003 India.
dY.B. Chavan College of Pharmacy, Dr. Rafiq Zakaria Campus, Aurangabad (MS) 431001 India.
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
Some thiazolyl hydrazones were synthesized by one pot reaction of thiophene-2-
carbaldehyde or 2, 4-dichlorobenzaldehyde, thiosemicarbazide and various phenacyl
bromides which were preliminarily screened for in vitro antioxidant and antifungal
activities. Excellent DPPH and H2O2 radical scavenged antioxidant activities were
observed with almost all the tested compounds. Compounds 4a, 4b, 4c, 4e, 4f and 4i
showed comparable DPPH scavenged antioxidant potential (90.26 to 96.56%) whereas
H2O2 scavenged antioxidant activity (90.98 to 92.08%) was noticeable in case of 4a and 4f;
showing significant antioxidant potential comparable with the standard ascorbic acid
(95.3%). In vitro antifungal activity of synthesized compounds against fungal species
Candida Albicance, Aspergillus Niger and Aspergillus Flavus was found to be moderate to
good as compared with the standard fluconazole and MIC values were found in the range
of 3.12 to 25 µg/mL. Molecular docking studies revealed that the compounds 4a, 4b and 4c
have a potential to become lead molecules in drug discovery process. In silico ADMET
study was also performed for predicting pharmacokinetic and toxicity profile of the
synthesized antioxidants which expressed good oral drug like behaviour and non-toxic
nature.
Keywords:
Thiazolyl hydrazones
Antioxidant
Antifungal
Molecular Docking
ADMET
2009 Elsevier Ltd. All rights reserved
.
Designing and development of heterocyclic compounds with
multiple biological activities is a significantly considerable new
facet of chemistry. One pot multi-component reactions are highly
desirable in modern synthetic organic chemistry and drug
discovery due to economic, time saving, cost effective and high
atom efficiency benefits. Such reactions assist in creating
libraries of drug like molecules and reduce environmental
pollution by obeying the principles of sustainable and green
chemistry 1.
Thiazole (a); a five membered heterocyclic compound bearing
sulfur and nitrogen in the ring constitutes a vital role in medicinal
and pharmaceutical chemistry due to wide spectrum of
biological activities such as antitumor2, anti-inflammatory3,
enzyme inhibitors4, antioxidant5 etc. Besides this, thiazole ring
containing heterocyclic compounds are also used as multitasking
agents in Alzheimer’s disease6 as well as effective antimicrobial
agents7. Consequently, thiophene core structured compounds
play a crucial role in the context of medicinal and pharmaceutical
chemistry8-9. During the past decade, more efforts are directed
towards the structure-activity modification of thiazole and
thiophene based heterocyclic compounds as new potent drug like
molecules10-11. Dichlorophenyl ring contributes significantly to
various biological activities12-13. Thus from literature survey and
biological screening studies, thiophene and 2, 4-dichlorophenyl
ring bearing scaffolds are useful for the creation of diverse
chemical libraries of “drug-like” molecules.
Oxidation reactions occurring in various metabolic processes
and food products generate free radicals which may damage cell
membranes, DNA, cellular proteins and lipids through chain
reactions leading to heart, liver, kidney related chronic diseases
such as cancer, arthritis and Alzheimer’s disease14. In various
clinical studies it has been seen that inflammatory diseases are
caused due to excessive generation of free radicals and thus the
search for non-steroidal anti-inflammatory agents becomes
essential.
An antioxidant, a molecule inhibiting the oxidation of other
molecules; terminates chain reactions thereby preventing
oxidation and thus beneficial for body tissues and health effects.
Antioxidant potential of a compound is usually determined
spectrophotometrically in terms of 2, 2-diphenyl-1-
picrylhydrazyl (DPPH) radical scavenging ability. DPPH radical
model is the most widely used method for quick evaluation of
free radical scavenging activity of organic compounds. It is an

easy, economic and rapid method to determine the antioxidant
potential of non-enzymatic compounds.
Antioxidant activity of the synthesized compounds was
evaluated using reported method17. Almost all the compounds
exhibited promising DPPH and H2O2 radical scavenged
antioxidant activity (Table 2). Compounds 4a (95.5%), 4b
(94.4%) and 4e (94.3%) at the lowest concentration of 20 µg/ mL
showed better antioxidant activities as compared to the standard
ascorbic acid (93.4%). DPPH scavenged antioxidant activity was
Fungi may act as pathogens and parasites. Many fungi
existing in nature are parasites and affect human health, plant
kingdom as well as the environment. To overcome the resistance
shown by fungi through genetic changes to the existing
antifungal compounds; the development of novel antifungal
agents becomes inevitable15.
more with Ar
= 2-thienyl ring as compared to 2, 4-
In continuation of our successful attempts in search of
biologically active heterocyclic compounds16; in present study we
report synthesis, characterization, antioxidant and antifungal
screening of some thiazole based hydrazones bearing thiophene
and 2, 4-dichlorophenyl rings (Scheme 1). Molecular docking
study was performed to predict the possible binding modes and to
rationalize the observed biological activity. In silico ADMET
(Absorption, Distribution, Metabolism, and Excretion - Toxicity)
study was also performed to predict the pharmacokinetic and
toxicity profile of the synthesized compounds.
dichlorophenyl moiety. The presence of halogen on either the
aldehyde or phenacyl bromide had a remarkable effect on
enhancing the antioxidant activity. Compounds 4a, 4b, 4c, 4e, 4f
and 4i showed comparable DPPH scavenged antioxidant
potential (average % DPPH inhibition from 90.26 to 96.56)
whereas H2O2 scavenged antioxidant potential was excellently
observed in case of 4a and 4f (90.98-92.08% inhibition). Thus
the compounds 4a and 4f showed significant antioxidant
potential in both the assays comparable with the standard
ascorbic acid (average % inhibition = 95.3). IC50 values of the
samples were obtained from linear regression analysis of dose-
response curve by plotting % inhibition against concentration18
and summarized in Table 2. The results of antioxidant activities
are graphically expressed in Figure 2.
X
O
Br
N
S
X
H
(3)
Conc. HCl
NH2
N
S
S
Ar
N
N
ArCHO H2N
N
Ar
N
EtOH, Reflux, 5h
EtOH, reflux, 3 h
H
(4a-k)
H
NH2
(2)
Figure 3 shows the graphical representation of variation of
antioxidant activity for the compounds 4a (% DPPH inhibition)
and 4f (% H2O2 inhibition) as a function of concentration and
comparison with the standard. Compound 4a (96.56% DPPH
inhibition) was found to be the most prolific and even more
potent than the standard ascorbic acid (95.3% inhibition) having
highest antioxidant potential in terms of % DPPH inhibition at 60
µg/mL concentration whereas H2O2 scavenged antioxidant
activity of 4f was directly proportional to concentration and
highest activity was observed at 100 µg/mL as in case of the
standard.
Antifungal activity of the synthesized compounds against
Candida Albicance, Aspergillus Niger and Aspergillus flavus
fungal strains was studied at different concentrations i. e. 25, 50
and 100 µL using well diffusion method19-20 and the results were
expressed in terms of zones of inhibition and Minimum
Inhibitory Concentrations (MICs) as shown in Table 3, 4.
MIC value of an antimicrobial compound is its lowest
concentration that prevents visible growth of the microorganism.
It is a measure of effective ability of the antimicrobial against the
concerned microbe. MIC values of compounds (4a-4k) as
determined by serial dilution technique are expressed in Table 4.
Compounds with thiophene ring were found to be effective
antifungal agents against C. Albicance. Compounds 4a, 4b and
4k showed good antifungal activity against Candida albicance
and Aspergillus Niger whereas the compounds 4g and 4h were
effective against all the three fungal strains. Compound 4d
showed good antifungal results against C. Albicance and A.
Niger. In general, almost all the synthesized compounds
exhibited excellent antioxidant activities and moderate to good
antifungal activity but less potent than the standard fluconazole.
In order to explore binding affinity, binding mode and
molecular interactions of synthesized compounds; molecular
docking study was carried out against COX-2; an isoform of
cycloxygenase or prostaglandin endoperoxidase synthease
(PGHS). COX-1 is the first isoform of PGHS mostly responsible
for maintaining gastric functions. It provides integrity and
vascular homeostasis in case of gastric protective layer i.e. gastric
mucosa. COX-2 expresses inflammatory response so it acts as
strong target for non- steroidal anti-inflammatory and antioxidant
agents21-23. The reference standard NSAIDs like Diclofenac and
DPPH standard ascorbic acid which have strong radical
scavengers were used to compare antioxidant activity of the
synthesized 1, 3-thiazole derivatives.
(1)
(Scheme 1)
Ar = 2-Thienyl, 2,4-dhichlorophenyl
X = H, 4-Cl, 4-F, 4-Me, 4-OMe etc
Figure 1: Scheme for the synthesis of thiazolyl hydrazones
The synthesis of thiazolyl hydrazones (4a-k) was achieved by
one pot approach. Initially, thiophene-2-carbaldehyde or 2, 4-
dichlorobenzaldehyde was refluxed at 80oC for 3 h in ethanol in
the presence of concentrated HCl. To this mixture, appropriate
phenacyl bromide was added and the contents were subsequently
refluxed for further 5 hr. After completion of reaction as
monitored by TLC, the reaction mass was concentrated under
reduced pressure and poured onto ice cold water. The resultant
precipitated solid was collected by filtration, washed several
times with ice cold water to remove the traces of concentrated
HCl and finally purified by recrystallization from ethanol to
afford the corresponding thiazolyl hydrazones in highly pure
form. The reactions proceeded smoothly in almost all cases.
Good yield of thiazolyl hydrazones were obtained in both the
cases
of
thiophene-2-carbaldehyde
and
2,4-
dichlorobenzaldehyde. However comparatively low yields of the
corresponding products (4c, 4i and 4j) were obtained in case of
phenacyl bromides with electron donating groups- 4-Me or 4-
OMe (Table 1, Entries 3, 9, 10) whereas good yields were
obtained in case of phenacyl bromides with X = H, Cl and F.
Structures of the products were confirmed by analysis of
spectroscopic data 1H, 13NMR, IR and mass [Supplementary
information].
1
In H NMR spectra; the hydrogen of =CH imine C appeared
as a singlet in the range of 8.23-8.34 δ ppm, hydrogen of –NH
was observed as a broad singlet around 12.5 δ ppm and H of
thiazole ring appeared as a singlet from 7.18-7.7 δ ppm value. In
13C NMR the most deshielded C (C between N and S) of thiazole
ring appeared around 167 δ ppm. The C of thiazole ring adjacent
to S atom was observed to be the most shielded C among the
aromatic region between 102.66-104. In IR spectra; the
characteristic peak around 3150-3400 cm-1 appeared due to the N-
H stretch and peaks in the range of 1550-1800 and 1450-1560
cm-1 were observed for C=N and C=C stretch respectively.
Finally the structures were confirmed from mass analyses by
(M+1)+ peaks at appropriate values.
3

Table 1: Yield and melting points of thiazolyl hydrazones 4a-k
Entry Ar
X
Product Yield (%)@
Melting point (oC)
1
2
3
4
5
6
7
8
2-Thienyl
2-Thienyl
2-Thienyl
2-Thienyl
2-Thienyl
2,4-Dichlorophenyl 4-F
2,4-Dichlorophenyl
2,4-Dichlorophenyl 4-Cl
H
4-Cl
4-Me
4-F
4a
4b
4c
4d
4e
4f
4g
4h
4i
84
90
76
89
91
88
87
90
80
85
83
160-162
228-230
192-194
156-158
164-166
208-210
193-195
201-203
190-192
225-227
196-198
3-COOMe, 4-OCH2Ph
H
9
10
11
2,4-Dichlorophenyl 4-Me
2,4-Dichlorophenyl 4-OMe
2,4-Dichlorophenyl 3-COOCH2Ph, 4-OH
4j
4k
@ Isolated yields on the reaction of aldehyde (3 mmol), thiosemicarbazide (3 mmol) and phenacyl bromide (3 mmol).
Table 2: Antioxidant activities of 4a-4k
Compound / Conc. DPPH % Inhibition
A*
IC50 (µg/mL)
H2O2 % Inhibition
A*
IC50 (µg/mL)
µg/ mL
20
40
60
80
100
20
40
60
80
100
4a
4b
4c
4d
4e
4f
4g
4h
95.5
94.4
90.9
92.4
94.3
90.7
76.6
73.9
86.0
65.5
19.2
93.4
95.8
96.0
97.0
93.3
94.9
93.3
90.2
85.9
86.2
69.5
37.2
94.6
97.6
96.1
97.6
94.6
95.5
94.6
92.8
88.9
93.3
86.9
41.9
95.5
97.1
96.6
97.8
66.3
96.0
95.5
92.6
92.3
90.7
90.6
45.5
96.0
96.8
97.0
98.1
97.0
96.3
96.0
95.8
92.4
95.1
93.3
56.1
97.0
96.56
96.02
96.28
88.72
95.4
26.008
26.335
29.837
44.12
28.131
27.139
29.307
32.224
30.791
34.966
88.844
26.771
87.5
82.8
79.6
84.2
79.6
88.4
78.1
76.0
76.2
78.1
58.9
93.4
90.0
83.2
82.8
87.5
82.8
90.0
78.9
76.2
80.4
79.7
63.5
94.6
91.0
85.2
84.4
90.3
84.4
92.4
80.4
80.4
83.2
82.8
66.3
95.5
92.4
86.0
88.4
91.9
87.6
94.0
83.1
83.1
84.2
84.2
71.8
96.0
94.0
87.1
91.0
92.4
92.4
95.6
87.4
84.4
85.3
87.5
75.0
97.0
90.98
84.86
85.24
89.26
85.36
92.08
81.58
80.02
81.86
82.46
67.1
31.03
39.58
35.933
35.206
29.212
35.539
43.712
43.537
40.004
40.405
57.873
26.771
94.02
89.6
86.68
90.26
81.16
39.98
95.3
4i
4j
4k
Ascorbic acid
95.3
A* = Average percentage inhibition for concentrations 20, 40, 60, 80 and 100 µg/mL recorded after 15 minutes of incubation.
DPPH % Inhibition
H2O2 % Inhibition
100
80
60
40
20
0
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
AA
Compound
Figure 2: Graphical representation of antioxidant activity of 4a-4k
4a-DPPH
4f-H2O2
AA
Table 3: Antifungal activity of 4a-4k against different fungi
Zone of Inhibition (mm)
100
Candida
Albicance
Aspergillus
Niger
Aspergillus
Flavus
95
90
85
80
Comp/ Conc
(µg/ mL)
100
50
25
100
50
25 100
50
25
4a
4b
4c
4d
4e
4f
4g
4h
12
18
15
15
10
13
15
18
8
10
14
14
14
8
11
14
15
6
06
11
13
12
6
10
12
10
6
10
8
8
6
6
6
6
6
6
15
20
6
12
17
6
8
8
6
6
6
6
6
13
6
10
6
6
6
6
6
6
6
6
8
12
25
16
16
6
10
15
15
10
6
8
11
17
6
10
13
6
12
12
6
6
6
20
40
60
80
100
12
6
Concentration (µg/ mL)
4i
4j
4k
7
13
28
6
10
22
6
12
15
6
6
6
6
6
6
14
6
Figure 3: Concentration dependent antioxidant activity of
4a, 4f and ascorbic acid.
Fluconazole
25
20
14
20
18
15

Table 4: MIC values of thiazolyl hydrazones (4a-4k)
most active among all the synthesized derivatives. When the
most active derivative 4b was compared with reference co-
crystallised ligand Diclofenac and Ascorbic acid; it has a strong
potential to inhibit COX-2 and produces both radical scavenging
and anti-inflammatory activity. Compounds 4e, 4f and 4i had
potential to act as anti-inflammatory and antioxidant agents
which is indicated by intermediate total docking score (3.3 to 3.0)
given in Table 5. The thiazolyl hydrazones 4b (4.3072), 4a
(4.1500) and 4c (3.9574) showed efficient binding mode and
penetrating active site cavity by forming hydrogen bond
interactions (conventional/pi donor) and π interactions with
active site residues. The most active 4b (4.3072) derivative
interacts with active site of amino acid residue ASN375 and
GLY533 forms by conventional hydrogen bond and Carbon-
Hydrogen bond interactions with phenyl ring para substituted (-
Cl) of distance 3.19 and 4.41 Å respectively. The amino acid
TYR385 and SER530 showed pi-donor hydrogen bond
interactions with distance of 2.23 and 2.73 Å respectively with
thiazole ring. The amino acid ALA527, TYR385, VAL349,
PHE205, LEU534, PHE209 and ILE377 various pi interactions
with thiophene, thiazole, phenyl ring and chlorine atom which
includes pi-sigma, alkyl, pi-pi T shaped and pi-sulfur shown in
Figure 4. The second most active thiazolyl derivative 4a (4.1500)
forming hydrogen bond interactions (Conventional/Pi-Donor)
with amino acids VAL523 and TYR355 with hydrogen atom of
nitrogen and phenyl ring of thiazole of distance 2.801 and 3.88 Å
respectively. The amino acid PHE381, PHE518, GLY526,
ALA527, VAL349 and LEU359 forms pi-sulfur, pi-pi T shaped
and amide- pi-stacked and pi-alkyl interactions with thiophene,
thiazole, phenyl ring (Figure 5).
FAF Drug2 tool was used for in silico ADMET predictions. In
particular, we calculated the compliance of synthesized
compounds to the Lipinski’s rule of five which is widely used as
a filter for lead molecules that would likely be further developed
for drug design programs. We have assessed parameters like
%ABS, MW, logP, N-ROTB and H/C. The values obtained are
summarized in Table 6. Topological polar surface area (TPSA)
i.e. surface belonging to polar atoms and molecular weight
are the descriptors which correlate with passive molecular
transport through membranes that allows prediction of route
of transport of drugs through the barrier membranes the intestine
and blood-brain barrier (BBB). The percentage of absorption (%
ABS) was calculated using TPSA by using formula %ABS=109-
(0.345xTPSA)31.The values of partition coefficient, number of
rotatable bonds, number of rigid bonds and ratio of H/C
determine the absorption performance through the lipophilic
phospholipid membranes and toxicity. Moreover, none of the
synthesized compounds violated Lipinski’s rule of five and it’s
varients. Thus all the thiazolyl hydrazones have the potential to
be developed as an orally active drug like candidates and may be
potentially active anti-inflammatory and antioxidants drug
candidates against COX-2.
Entry Compound
MIC (µg/mL)
CA
A N
25
NT
NT
25
AF
NT
12.5
NT
NT
1
2
3
4
5
6
4a
4b
4c
4d
4e
4f
12.5
6.25
6.25
6.25
25
NT
NT
6.25
3.12
3.12
25
NT
12.5
< 3.12
6.25
25
7
8
9
4g
4h
4i
12.5
6.12
NT
10
11
12
4j
4k
25
6.25
NT
NT
< 3.12
NT
NT
< 3.12
Fluconazole < 3.12
MIC = Minimum Inhibitory Concentration, NT = Not tested
CA- Candida Albicance, AN - Aspergillus Niger, AF- Aspergillus flavus
Molecular docking has given brief insight about strength of
molecular complexes, suggesting that the synthesized derivatives
have a strong potential to inhibit the prostaglandin precursor
COX-2. Physicochemical properties prediction (ADMET) has
highlighted that these compounds have potential of acting as
orally active anti-inflammatory agents. In silico study was
performed to evaluate pharmacokinetic and safety potential of
synthesized 1,3-thiazole derivatives 4a-k, standard Diclofenac
and Ascorbic acid using ADMET predictor FAF Drugs2 which
runs on Linux OS24-25. In particular, we calculated the compliance
of synthesized compounds to the Lipinski’s rule of five26-27
.
To identify the possible identical poses of synthesized 1, 3-
thiazole derivatives they were docked into active site of protein
and further ranked based on total docking score and interactions.
To perform molecular docking three dimensional X-ray crystal
structure of COX-2 (PDB ID: 1PXX Resolution 2.90 Å)
complex with Diclofenac was used28. The complex 1PXX is
advantageous over other COX-2 complexes as COX-2 protein
present in complex Diclofenac and Diclofenac which have a
number of activities including antimicrobial, ulcerogenic,
analgesic, anti-inflammatory, lipid peroxidation, antitumor and
inhibitor formation of transthyretin amyloid so it will provide
important clue in understanding of details inhibition at molecular
level29. Docking study was carried out using Surflex-Dock
module of Sybyl 2.1.1 package following standard procedure30.
To represent the details of docking score, the following terms
were used: a) Total score as total docking score b) Crash score as
degree of inappropriate penetration by the ligand into the protein
and interpenetration between ligand atoms that are separated by
rotatable bonds of compounds. c) Polar score giving an idea
about the contribution of polar non-hydrogen bonding
interactions to the total score are shown in Table 5.
Table 5: % Inhibition (DPPH Assay) and Molecular Docking
details.
Compound
% DPPH
Molecular Docking Score
Inhibition@
Polar Score
Total Score
(-log Ki)
4.15
4.3072
3.9574
3.327
Crash Score
In summary, different thiazolyl hydrazones were synthesized
by one pot reaction of thiophene-2-carbaldehyde or 2, 4-
dichlorobenzaldehyde, thiosemicarbazide and various phenacyl
bromides. The synthesis is simple, facile and high yielding to
afford the corresponding products in high yields. In vitro
antioxidant and antifungal activities revealed that compounds 4a,
4b, 4c, 4e, 4f and 4i exhibited excellent DPPH scavenged
antioxidant potential which was comparable at 20 µg/mL as the
lowest concentration. H2O2 scavenged antioxidant activities of 4a
and 4f were comparable with the standard ascorbic acid at 40 µg/
mL concentration.
4a
4b
4c
4e
4f
4i
95.5
94.4
90.9
94.3
90.7
86
-1.3255
-0.9746
-0.4864
-0.6737
-0.8576
-0.7686
-1.8105
-0.7739
0.7188
0.8591
0
0.5479
0.0028
1.0846
1.4606
0.0009
3.0994
3.2562
3.4402
3.5259
Diclofenac
AA
97.14
93.4
@ % Inhibition at 20 µg/mL concentration.
The analysis of binding affinity (-logki) values and molecular
interactions of thiazolyl hydrazone derivatives such as 4b
(4.3072), 4a (4.1500) and 4c (3.9574) suggested that they are the
5

Figure 4. Binding pose and molecular interactions of 4b into the active site of COX-2
Figure 5. Binding pose and molecular interactions of 4a into the active site of COX-2
Table 6: In silico drug like (physicochemical) properties of 4a-k, diclofenac and ascorbic acid
Comp.
MW
(<500Da)
%ABS
(100%)
LogP
(<5.6)
PSA
(<140Å)
RotatableB
(<10)
HBD
(<5)
HBA
(<10)
Rings
(3-5)
Ratio H/C
(<1)
Toxicity
4a
285.3872
319.8323
299.41
76.6528
76.6528
73.46845
76.6528
60.59995
86.3956
86.3956
86.3956
86.3956
83.21125
70.34275
92.095
4.3906
93.76
93.76
102.99
93.76
140.29
65.52
65.52
65.52
65.52
74.75
112.05
49
4
4
5
4
6
4
4
4
4
5
6
4
2
1
1
1
1
2
1
1
1
1
1
2
1
4
4
4
5
4
7
3
3
3
3
4
6
2
6
3
3
3
3
3
3
3
3
3
3
3
2
1
0.357
0.428
0.4
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
4b
5.044
4c
4.3992
4.5297
3.8828
5.775
4d
303.3777
449.55
0.428
0.5
4e
4f
366.2401
348.2496
382.6947
362.2762
378.2756
512.41
0.437
0.375
0.437
0.352
0.411
0.5
4g
5.6359
6.2893
5.9443
5.6445
5.1281
3.1024
NA
4h
4i
4j
4k
Diclofenac
AA
295.1407
176.12
0.357
0.32
72.0091
107.22
(Percent absorption, MW: molecular weight, LogP: logarithm of partition coefficient of compound between n-octanol and water, PSA: Polar surface area, n-
RotBond: number of rotatable bonds, n-RigBond: number of rigid bonds, HBA: hydrogen bond acceptors and HBD: hydrogen bond donor); NT = Non Toxic.
Thus the compounds 4a and 4f were found as the most
promising antioxidants exhibiting potential comparable with the
standard ascorbic acid. Invitro antifungal activity of the
synthesized compounds revealed that most of them exhibited
good antifungal activity against C. Albicans with MIC values in
the concentration range of range of 3.12 to 25 µg/mL.
Compounds 4a, 4b, 4d and 4k showed good antifungal activity
against Candida albicance and Aspergillus Niger whereas,
compounds 4g and 4h were found as broad spectrum antifungal
agents effective against all the three fungal strains. In general, all
the synthesized compounds exhibited excellent antioxidant
activities; percentage radical scavenging activity of 4a and 4f
being comparable with the standard even at 20 and 40 µg/mL
concentrations respectively. Some of the compounds showed
6

26. Sangshetti J, Khan F, Chouthe R, et al. Chem Lett. 2014;25:1033-
1038.
27. Lipinski C, Lombardo F, Dominy B. Adv Drug Deliv Rev. 2001;
46:3-26.
28. Kurumbail RG, Stevens AM, Gierse JK, et al. Nature.
1996;384:644-648.
29. El-Henawy AA. Chem Mat Res. 2013;3:75-89.
30. Huang Y, Hickey RP, Yeh JL, et al. Faseb J.2004;18:1138-1140.
31. Ertl P, Rohde B, Selzer P J Med Chem. 2000;43:3714-3747.
moderate to good antifungal activity but less potent than the
standard fluconazole. Computational molecular docking study
highlights and supports the experimental results for the observed
antioxidant activity and demonstrated that 4a, 4b and 4c are the
most active forms having potential to act as strong antioxidant
and anti-inflammatory agents. Prediction of pharmacokinetics
parameter suggests that the synthesized compounds have
potential of high oral drug bio-availability. Thus, thiazolyl
hydrazone skeleton has broad spectrum activities as potential
antioxidants, anti-inflammatory and good antifungal agents and
there exist new opportunities for the possible modification as per
pharmaceutical requirement in future.
Acknowledgements
Authors are thankful to the Director SAIF, Panjab University,
Chandigarh for providing spectral data and to the Director, Scan
Research Laboratories, Bhopal (MP) India for providing the
results of biological activity.
Supplementary data Spectroscopic data and full experimental
details associated this article are available in the supplementary
information.
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