Synthesis of thiazole-based substituted piperidinone oximes: Profiling of antioxidant and antimicrobial activity

Article abstract of DOI:10.1134/S1068162017020042

The synthesis of novel thiazole-based piperidinone oximes and screening of their antioxidant and antimicrobial activity are described. The obtained results revealed that the electronic effects of active substituents at C-4 terminals of phenyl rings on either side of piperidinone skeleton, as well as at 2-hydrazinyl thiazole, played a major role in development of antioxidant and antimicrobial activity. Antioxidant activity seems to be based also on radical dissipating ability of the thiazole ring. The nucleophilic character of sulfur in thiazole and lipophilic nature of piperidinone skeleton substantially influenced the observed antimicrobial activity of thiazole-based piperidinone oximes. Among the synthesized compounds, 2,6-bis(4-hydroxy-3-methoxyphenyl)-1-methylpiperidin-4-one O-(2-(2-(4-hydroxy-3-methoxybenzylidene)hydrazinyl)thiazol-4-yl) oxime exhibited excellent antioxidant activity whereas compound 2,6-bis(4-chloro phenyl)-1-methylpiperidin-4-one O-(2-(2-(4-nitrobenzylidene)hydrazinyl)thiazol-4-yl)oxime emerged as an outstanding antimicrobial agent.

Full text of DOI:10.1134/S1068162017020042

ISSN 1068-1620, Russian Journal of Bioorganic Chemistry, 2017, Vol. 43, No. 2, pp. 186–196. © Pleiades Publishing, Ltd., 2017.
Synthesis of Thiazole-Based Substituted Piperidinone Oximes:
Profiling of Antioxidant and Antimicrobial Activity1
Salakatte Thammaiah Harinia, 2, Honnaiah Vijay Kumarb, Javarappa Rangaswamya, and Nagaraja Naika, 2
aDepartment of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore, Karnataka, 570006 India
bDepartment of Chemistry, University of Minnesota, Minneapolis, MN, 55455 USA
Received May 10, 2016; in final form, October 22, 2016
Abstract—The synthesis of novel thiazole-based piperidinone oximes and screening of their antioxidant and
antimicrobial activity are described. The obtained results revealed that the electronic effects of active substit-
uents at C-4 terminals of phenyl rings on either side of piperidinone skeleton, as well as at 2-hydrazinyl thi-
azole, played a major role in development of antioxidant and antimicrobial activity. Antioxidant activity
seems to be based also on radical dissipating ability of the thiazole ring. The nucleophilic character of sulfur
in thiazole and lipophilic nature of piperidinone skeleton substantially influenced the observed antimicrobial
activity of thiazole-based piperidinone oximes. Among the synthesized compounds, 2,6-bis(4-hydroxy-3-
methoxyphenyl)-1-methylpiperidin-4-one O-(2-(2-(4-hydroxy-3-methoxybenzylidene)hydrazinyl)thiazol-
4-yl) oxime exhibited excellent antioxidant activity whereas compound 2,6-bis(4-chloro phenyl)-1-meth-
ylpiperidin-4-one O-(2-(2-(4-nitrobenzylidene)hydrazinyl)thiazol-4-yl)oxime emerged as an outstanding
antimicrobial agent.
Keywords: hydrazinyl thiazoles, piperidinone oximes, antioxidant activity, antibacterial activity, antifungal
activity
DOI: 10.1134/S1068162017020042
INTRODUCTION
group have been proven to exert better microbiological
activities than their corresponding ketones [4]. In view
of interest to the development of simpler and more
convenient synthetic routes for achieving the biologi-
cally active thiazole-nucleated piperdinone analogues
and in continuation of our research interest in func-
tionalization of new tricyclic and heterocyclic com-
pounds [5–7], we synthesized a series of novel thiazole
based piperidinone oximes (VIII–XXVII) to explore
their antioxidant and antimicrobial potential. The
general structure and the proposed plan for substitu-
tion pattern of the thiazole-nucleated moieties is
depicted in Figs. 1 and 2.
The thiazole ring system is found in a diverse range
of natural products and functional materials. It plays a
central role in the biochemistry of life; the thiazole
ring present in vitamin B1 serves as an electron sink
and its coenzyme form is important for the decarbox-
ylation of α-keto acids [1]. Besides, thiazoles are also
synthetic intermediates and common substructures in
numerous biologically active compounds. Thus, the
thiazole nucleus was much studied in the field of
organic and medicinal chemistry. Owing to its inter-
esting biological and pharmaceutical properties and
synthetic utility, substantial interest has been demon-
strated towards piperidin-4-one as another bioactive
compound [2]; the compounds containing this sub-
structure are widely prevalent in numerous natural
alkaloids and synthetically derived compounds of bio-
logical importance. Specifically, piperidinone-based
chemical entities with aryl substituents at C-2 and C-6 of
the piperidinone ring were potent antioxidant and
antimicrobial agents [3]. Moreover, thiosemicarba-
zones, oximes, or sulfur and nitrogen-containing het-
erocycles obtained by exploring the reactivity of keto
The installation of several active groups in thi-
azole nucleated moiety plays a preponderant role for
the enhancement of antioxidant and antimicrobial
activity.
RESULTS AND DISCUSSION
In the present investigation, synthesis of thiazole-
based library of compounds was aimed. Initially, 2-
(substituted benzylidene)hydrazinecarbothioamides
(IIa–d) were furnished by refluxing substituted benz-
aldehyde and thiosemicarbazide with catalytic
amount of concentrated sulfuric acid [8]. The cyclisa-
tion of (IIa–d) with chloroacetyl chloride in ethanol
(Scheme 1) affords key scaffolds of 4-chloro-2-(2-
1
2
The article is published in the original.
Corresponding author: phone: +91-9482959088; fax:
+91-821-2412191; e-mail: drnaikchem@gmail.com; st.hari-
ni988@gmail.com.
186

SYNTHESIS OF THIAZOLE-BASED PIPERIDINONE OXIMES
187
Electron donation,
radical dissipation
by thiazole ring
R1
Electronic effects
R3
R4
R2
S
N
C
H
N
H
O
N
N
N
Me
Lipophilic nature
R3
R4
Fig. 1. Structural requirements for the thiazole-nucleated piperidinone oximes.
(substituted benzylidene)hydrazinyl)thiazoles (IIIa– scaffolds (IIIa–d). The scaffolds 2,6-bis(substituted
d). IR spectrum showed the absence of NH2 bands at
phenyl)-1-methylpiperidin-4-one oximes (VIIa–e)
were accomplished via three-step reactions involv-
ing Mannich reaction of substituted benzaldehydes
(IVa–e), acetone, and ammonium acetate to obtain
2,6-bis(substituted phenyl)-piperidin-4-one (Va–e)
followed by N-methylation and oximation
3417.57 cm–1 and the presence of a sharp band at
1
3430.57–3435.0 cm–1 due to NH. The H NMR
spectrum also revealed the absence of primary amine
signals at δ (ppm) 8.40–8.52 (s, 2H, NH2) and the
presence of H-signal of the thiazole ring at δ (ppm)
7.0 (s, 1H, thiazole H) confirms the formation of key (Scheme 2) [3].
CHO
H
C
H
N
NH2
R2
R1
S
Conc · H2SO4, MeOH
reflux, 5 h
N
H2N
+
N
H
NH2
S
R2
R1
(Ia−d)
(IIa−d)
(Ia) (R1 = NO2, R2 = H)
(Ib) (R1 = OCH3, R2 = H)
(Ic) (R1 = OH, R2 = H)
C2H2Cl2O, MeOH
reflux, 4 h
(Id) (R1 = OH, R2 = OCH3)
Cl
N
HN
S
HC
N
R2
(IIIa−d)
R1
Scheme 1. Reaction protocol for the synthesis of 4-chloro-2-(2-(substituted benzylidene)hydrazinyl) thiazole (IIIa–d).
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188
SALAKATTE THAMMAIAH HARINI et al.
O
O
H3C
CH3
O
O
R3
R4
R3
R4
R3
R4
R3
R4
Absolute EtOH, HCl
N
H
H
H
+
30°C
NH4OAc
MeI, K CO3,
2
(IVa−e)
(IVa) (R3 = H, R4 = Cl)
reflux, 4 h
Me2CO
(IVb) (R3 = H, R4 = NO2)
(IVc) (R3 = H, R4= OCH 3)
(IVd) (R3 = H, R4 = OH)
(IVe) (R3 = OCH3, R4 = OH)
HO
N
O
N
NH2OH ⋅ HCl, EtOH
R3
R4
R3
R4
R3
R4
R3
R4
N
Me
NaOAc ⋅ 3H2O, reflux, 2 h
Me
(VIIa−e)
(VIa−e)
Scheme 2. Reaction protocol for the synthesis of 2,6-bis(substituted phenyl)-1-methylpiperidin-4-one oxime (VIIa–e).
R1
R3
R4
HO
R2
S
Cl
N
S
N
N
C
HN
HC N
N
H
H
O
N
N
R3
R4
R3
R4
N
TEA
N
Me
Me
R2
+
CH2Cl2, reflux, 6 h
R1
R3
(IIIa−d)
(VIIa−e)
R4
(VIII−XXVII)
(VIIa) (R3 = H, R4 = Cl)
(VIIb) (R3 = H, R4 = NO2)
(VIIc) (R3 = H, R4 = OCH3)
(VIId) (R3 = H, R4 = OH)
(VIIe) (R3 = OCH3, R4 = OH)
(IIIa) (R1 = NO2, R2 = H)
(IIIb) (R1 = OCH3, R2 = H)
(IIIc) (R1 = OH, R2 = H)
(IIId) (R1 = OH, R2 = OCH3)
Scheme 3. Synthesis of thiazole-based piperidinone oximes (VIII–XXVII).
Finally, 2,6-bis(substituted phenyl)-1-meth-
The results of the antioxidant assays revealed that
ylpiperidin-4-one oximes (VIIa–e) were incorporated majority of the synthesized compounds exerted a wide
with key scaffolds (IIIa–d) in the presence of triethyl- range of modest antioxidant activity [9]. Fifty percent
amine to obtain thiazole-based piperidinone oximes inhibitory concentration (IC50) values are depicted in
(VIII–XXVII) in good yields (Scheme 3). The
Table 1. Initially, key scaffolds (IIIa–d) exhibited cer-
1H NMR spectrum showed the absence of oxime pro- tain degree of antioxidant activity. Here, the thiazole
ton (N–OH) resonating at δ (ppm) 2.10–2.15 (s, 1H, nucleus itself acts as a reactive center towards the rad-
NOH), which confirms the formation of target com- ical species and this reactivity may attribute to its high
pounds (VIII–XXVII).
resonance stability and very low energy barrier towards
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SYNTHESIS OF THIAZOLE-BASED PIPERIDINONE OXIMES
189
H3CO
OH
N
HO
N
Me
(IVe)
OH
HO
N
H3CO
N
N
N
OH
R2
HO
(XX−XXIII)
R1
Cl
Me
(IVa)
Cl
Me
(IVd)
OH
(VIII−XI)
CH
N
NH
S
O2N
N
N
OH
Cl
OCH3
N
(IIIa−d)
Me
(IVb)
N
HO
N
Me
NO2
(IVc)
OCH3
Fig. 2. Pathway rationale of target compounds.
radical reactions. In addition, the radical dissipation (DPPH) free radical scavengers. Among the synthe-
sized molecules, compounds (XIX), (XXII), (XXIII),
(XXVI), and (XXVII) demonstrated significant radical
scavenging activity (RSA) up to 13–15-fold higher
than the key scaffolds (IIIa–d), which were more
active than standard butylated hydroxy anisole (BHA).
This may be due to the plenty electron donating
hydroxyl and methoxy groups in the phenyl ring pres-
ent on the either side of the piperidinone skeleton, as
well as on phenyl ring attached to 2-hydrazinyl thi-
azole. Thus, free radical scavenging capacity primarily
attributed to the high reactivity of hydroxyl substitu-
ents [10]. Compounds (XXI), (XXIV), (XXV), and
(XVIII) also showed appreciable RSA, bearing 8–
inside the thiazole system would be mandatory for the
observed antioxidant activity [1]. Further, to explore the
better antioxidant motifs, the key scaffolds (IIIa–d) were
coupled with 2,6-bis(substituted phenyl)-1-meth-
ylpiperidin-4-one oximes (VIIa–e). Inclusion of
piperidinone oximes into the key scaffolds played a
vital role for significant enhancement of antioxidant
activity. The electronic effects of substituents on C-4
terminals of phenyl ring attached to piperidin-4-one
skeleton may also play an important role for enhanced
antioxidant activity.
Nearly all the tested compounds, except (VIII–
XV), acted as effective 2,2'-diphenyl-1-picrylhydrazyl 9 folds more activity than initial scaffolds (IIIa–d),
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190
SALAKATTE THAMMAIAH HARINI et al.
Table 1. Concentration required for 50% inhibition (IC50) of
DPPH and LPO radicals by the compounds (IIIa–d) and
(VIII–XXVII) and the standard antioxidant compound BHA
The tested compounds (VIII–XXVII) exhibited vary-
ing range of antioxidant potency. Indeed, compounds
(XXII), (XXIII), (XXVI), (XXVII), and (XIX) revealed
potent LPO radical scavenger properties. Probably,
this result is associated with the presence of hydroxyl
groups at para-position of the phenyl rings and the
unique geometry of the compounds. The next promis-
ing lipid peroxidation inhibitors are (XXI), (XXIV),
(XXV), and (XVIII). On the other hand, compounds
(VIII), (IX), (X), (XI), (XII), and (XIII) having elec-
tron-withdrawing chloro/nitro groups had apprecia-
ble antioxidant activity. The increasing order of LPO
activity is as follows (XXVII) > (XXIII) > (XIX) >
(XXVI) > (XXII) > BHA > (XVIII) > (XXV) > (XXI) >
(XXIV) > (XX) > (XVI) > (XVIII) > (XV) > (XIV) >
(XI) > (X) > (XIII) > (IX) > (XII) > (VIII) > (IIId) >
(IIIc) > (IIIb) > (IIIa). The results of this assay
revealed that most of the synthesized compounds
exerted a wide range of modest antioxidant activity.
Scavenging activity*
Compounds
DPPH•
LPO•
(IIIa)
(IIIb)
(IIIc)
(IIId)
(VIII)
(IX)
(X)
(XI)
(XII)
(XIII)
(XIV)
(XV)
(XVI)
(XVII)
(XVIII)
(XIX)
(XX)
(XXI)
(XXII)
(XXIII)
(XXIV)
(XXV)
(XXVI)
(XXVII)
BHA
162.1 0.9
158.0 0.5
151.0 0.7
140.0 0.8
132.0 0.1
119.0 0.1
102.0 0.6
98.0 0.3
129.0 0.1
112.0 0.4
96.0 0.7
79.0 0.1
51.0 0.2
38.0 0.0
12.1 0.3
9.2 0.1
32 0.3
19 0.1
10.2 0.4
8.9 0.2
26 0.6
15.2 0.2
9.8 0.5
8.2 0.4
112.0 0.1
105.0 0.1
98.0 0.2
89.0 0.1
82.1 0.4
77.2 0.1
68.3 0.1
62.3 0.4
78.2 0.9
72.1 0.1
62.0 0.5
59.5 0.1
32.6 0.8
36.1 0.2
5.8 0.1
The potentiality of the synthesized compounds as
antimicrobials was appraised for their antibacterial
studies against different strains of human pathogens,
namely, Escherichia coli ATCC 25922 (gram-nega-
tive), Staphylococcus aureus ATCC 25923 (gram-posi-
tive), and Pseudomonas aeruginosa ATCC 27853
(gram-negative) by well plate method [12]. The results
were obtained as zone of inhibition (mm). The major-
ity of the synthesized compounds showed varying
degree of inhibition against tested bacterial strains
(Table 2). The reason would be the presence of sulfur in
thiazole nucleus resulting. The nucleophilic character of
sulfur might help in penetrating through the microbial
cell wall easily, thereby arresting cell growth [13]. Among
the synthesized derivatives, compounds (VIII) and
(XII) exhibited enhanced antibacterial activity, which
was also higher than that of standard streptomycin.
The lipophilic nature of piperidinone core [14], along
with the presence of electron withdrawing groups, like
chloro/nitro groups at para position of all the phenyl
rings, may contribute to the enhanced antibacterial
activity. Halogens like chlorine, are very useful to
modulate the electronic effects in phenyl rings. Chlo-
rine has strong inductive electron-attracting effects,
moreover these atoms may also influence the steric
characteristics and the hydrophilic–hydrophobic bal-
ance of the molecules [15]. It is indicative that lipo-
philic and steric parameters are the prerequisites for
these molecules to act as potent antimicrobial agents.
The replacement of the nitro group by electron donat-
ing methoxy/hydroxyl functions as C-4 substituent in
phenyl ring attached to 2-hydrazinyl thiazole in com-
pounds (IX), (X), (XIII), and (XIV) resulted in slightly
reduced activity compared to (VIII) and (XII). Substi-
tution of methoxy and hydroxyl groups in phenyl ring
attached to piperidinone skeleton in (XVI) and (XX)
resulted in appreciable activity against E. coli and
P. aeruginosa strains. Compounds (XI), (XV), (XXI),
(XXIV), (XXV), (XVII), and (XVIII) showed moderate
4.8 0.1
28.2 0.4
12.0 0.5
5.2 0.7
4.5 0.3
23.4 0.7
7.2 0.3
5.0 0.8
4.8 0.2
5.3 0.2
12.0 0.1
* The values are expressed as μM concentration; lower IC val-
50
ues indicate higher radical scavenging activity.
but slightly less than the reference compound. Mean-
while, derivatives (XX), (XIV), (XV), and (XVII)
exhibited enhanced activity with 5–6 fold higher than
that of (IIIa–d) because of the presence of electron-
donating hydroxyl and methoxy groups on the piper-
idinone phenyl moiety and electron-withdrawing
chloro/nitro group as C-4 substituent on phenyl ring
attached to 2-hydrazinyl thiazole moiety. Compounds
(X) and (XI) demonstrated marked decrease in RSA
compared to standard. On the other hand, compounds
(VIII) and (XII) showed least antioxidant activity.
This could be due to the presence of chloro/nitro
function at para-position of the phenyl rings.
The arrays of compounds having abilities to scav-
enge free radicals were further confirmed by inhibition
of lipid peroxidation (LPO) assay in a liposome model
system [11]. IC50 values of LPO inhibition for the
newly synthesized analogues are depicted in Table 1. activity. Compounds (XIX), (XXII), (XXIII), (XXVI),
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SYNTHESIS OF THIAZOLE-BASED PIPERIDINONE OXIMES
191
Table 2. Inhibitory zone (diameter, mm) of the synthesized compounds (IIIa–d) and (VIII–XXVII) against tested bacterial
strains by well plate method
Escherichia coli
Staphylococcus aureus
Pseudomonas aeruginosa
Compounds
1000
500
1000
500
1000
500
Concentration, μg/mL
(IIIa)
(IIIb)
(IIIc)
(IIId)
(VIII)
(IX)
(X)
(XI)
(XII)
(XIII)
(XIV)
(XV)
(XVI)
(XVII)
(XVIII)
(XIX)
(XX)
(XXI)
(XXII)
(XXIII)
(XXIV)
(XXV)
(XXVI)
(XXVII)
Streptomycin
5.0 0.1
4.1 0.2
3.0 0.2
3.4 0.1
20.1 0.1
15.4 0.2
13.1 0.2
12.2 0.2
18.8 0.3
12.6 0.1
8.4 0.1
11.6 0.1
13.4 0.1
10.2 0.1
9.7 0.2
4.7 0.1
11.0 0.2
8.3 0.1
6.5 0.1
4.3 0.2
7.7 0.1
7.1 0.1
4.0 0.2
10.2 0.1
18.3 0.1
4.2 0.2
3.1 0.1
3.5 0.3
2.8 0.1
13.2 0.1
12.0 0.1
11.5 0.2
10.5 0.1
10.1 0.2
8.3 0.1
7.3 0.1
8.2 0.1
9.7 0.1
7.5 0.2
5.1 0.1
3.4 0.1
8.3 0.1
6.4 0.1
4.0 0.2
3.8 0.2
5.2 0.2
5.8 0.2
3.1 0.2
7.5 0.2
10.2 0.1
4.4 0.2
3.5 0.1
2.6 0.1
2.4 0.2
18.8 0.1
13.4 0.1
14.7 0.2
11.0 0.1
16.8 0.1
9.1 0.2
9.8 0.1
9.3 0.2
10.9 0.2
8.7 0.1
7.9 0.2
5.1 0.2
9.7 0.1
8.2 0.2
5.2 0.1
4.4 0.1
8.9 0.2
7.5 0.1
5.4 0.1
8.7 0.1
15.0 0.2
3.1 0.1
2.3 0.2
1.2 0.1
1.4 0.2
12.3 0.1
9.2 0.1
8.2 0.2
8.0 0.2
10.5 0.2
8.4 0.2
7.7 0.1
6.3 0.1
8.6 0.1
6.3 0.1
5.4 0.2
3.8 0.1
7.5 0.1
6.7 0.2
3.2 0.1
2.3 0.1
6.7 0.2
5.4 0.1
2.1 0.1
6.3 0.1
10.5 0.1
6.3 0.1
5.5 0.1
3.4 0.2
3.3 0.2
23.7 0.1
18.0 0.1
17.5 0.2
14.3 0.2
20.8 0.2
10.3 0.1
12.2 0.1
12.5 0.2
17.3 0.1
11.7 0.2
10.3 0.2
8.4 0.1
14.5 0.1
10.5 0.2
9.1 0.1
4.2 0.2
2.3 0.1
2.4 0.2
1.5 0.1
14.6 0.1
10.3 0.2
9.3 0.2
8.4 0.1
12.4 0.2
8.1 0.1
8.2 0.1
6.3 0.1
9.3 0.1
7.2 0.1
6.6 0.1
4.5 0.1
7.2 0.2
7.5 0.2
3.7 0.2
3.3 0.1
8.8 0.1
6.7 0.1
2.5 0.2
7.2 0.1
125 0.2
7.3 0.1
12.4 0.2
8.3 0.1
7.5 0.1
11.7 0.2
18.2 0.1
and (XXVII), holding electron-donating methoxy and pounds (IX) and (XIII) made them the next potent anti-
hydroxyl substituents in phenyl rings, demonstrated
least antibacterial activity compared to other ana-
logues.
fungal agents. Meanwhile, the presence of hydroxyl sub-
stituent at C-4 atom in phenyl ring of 2-hydrazinyl thi-
azole, along with chloro group (compound (X)) and
nitro group (compound (XI)) at para-position of phe-
nyl rings attached to piperidinone skeleton resulted in
moderate activity. However, compounds (XI), (XV),
(XVII), (XX), and (XXIV) showed appreciable activity
against the C. keratinophilum strain whereas its activity
against C. albicans and A. flavus was diminished.
Notable decrease in antifungal activity was observed
for compounds (XXIII) and (XXVII) with electron-
withdrawing nitro/chloro group replaced by
hydroxyl/methoxy substituents. It is tempting to spec-
ulate that the results of the antimicrobial activity of the
different derivatives appear to be related to the nature
In vitro antifungal activity was evaluated against
three pathogenic fungal species, namely Aspergillus
flavus MTCC 3306, Candida albicans MTCC 3017,
and Chrysosporium keratinophilum MTCC 2827 by
well plate method [16]. Compounds (XIX), (XXII),
(XXIII), (XXVI), and (XXVII) possessing electron
donating methoxy and hydroxyl substituents failed to
show good antifungal activity even at higher concen-
trations (Table 3). Compounds (VIII) and (XII) pos-
sessing chloro/nitro substituent at para-position of
piperidinone phenyl rings emerged as active antifungal
agents against all tested fungal strains compared with
standard fluconazole. The introduction of methoxy
function instead of nitro group at para-position on
phenyl ring attached to 2-hydrazinyl thiazole in com- of substituent on the para-position of the phenyl rings.
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SALAKATTE THAMMAIAH HARINI et al.
Table 3. Inhibitory zone (diameter, mm) of the synthesized compounds (IIIa–d) and (VIII–XXVII) against tested fungal
strains by well plate method
Aspergillus flavus
Chrysosporium keratinophilum
Candida albicans
Compounds
1000
500
1000
500
1000
500
Concentration, μg/mL
(IIIa)
(IIIb)
(IIIc)
(IIId)
(VIII)
(IX)
(X)
(XI)
(XII)
(XIII)
(XIV)
(XV)
(XVI)
(XVII)
(XVIII)
(XIX)
(XX)
(XXI)
(XXII)
(XXIII)
(XXIV)
(XXV)
(XXVI)
(XXVII)
Fluconazole
5.2 0.1
4.1 0.2
2.4 0.2
2.7 0.1
15.5 0.2
12.7 0.2
9.8 0.2
8.4 0.2
13.4 0.3
10.8 0.1
8.3 0.1
6.4 0.1
11.8 0.1
7.4 0.1
4.1 0.2
3.8 0.1
6.4 0.2
6.3 0.1
3.2 0.1
3.1 0.3
5.6 0.1
5.9 0.1
3.0 0.2
2.3 0.1
13.2 0.1
4.2 0.2
3.3 0.2
2.2 0.1
2.3 0.2
12.2 0.1
9.5 0.1
7.1 0.2
6.2 0.1
10.5 0.2
8.4 0.1
5.4 0.1
5.2 0.1
9.3 0.1
4.7 0.2
3.3 0.1
2.5 0.2
5.8 0.1
5.6 0.1
2.5 0.2
2.6 0.1
3.6 0.2
4.6 0.2
3.7 0.2
1.4 0.1
12.3 0.2
6.5 0.1
4.7 0.2
3.1 0.2
3.4 0.1
19.3 0.2
16.4 0.1
15.6 0.2
14.3 0.2
17.6 0.1
10.3 0.2
9.3 0.1
13.6 0.2
15.8 0.2
9.5 0.1
7.5 0.2
5.7 0.1
16.8 0.1
8.6 0.2
6.4 0.1
4.2 0.2
11.5 0.2
6.9 0.1
6.5 0.1
3.4 0.1
17.7 0.2
5.1 0.2
2.4 0.1
2.3 0.2
1.9 0.1
17.2 0.1
13.5 0.1
12.4 0.2
11.8 0.2
15.4 0.2
9.7 0.2
8.3 0.1
10.6 0.1
14.6 0.1
8.6 0.1
6.4 0.2
4.5 0.1
12.4 0.1
7.7 0.2
5.5 0.1
2.7 0.1
10.2 0.2
5.5 0.1
4.7 0.1
2.3 0.1
16.2 0.1
8.3 0.1
6.4 0.2
4.7 0.2
4.0 0.1
23.4 0.1
18.2 0.1
17.3 0.2
13.9 0.2
20.7 0.2
12.8 0.2
12.2 0.1
12.3 0.2
17.3 0.1
11.2 0.2
10.1 0.2
9.2 0.1
16.4 0.1
10.1 0.2
9.3 0.1
5.1 0.1
5.2 0.1
4.3 0.1
2.1 0.2
1.8 0.1
22.3 0.2
17.7 0.2
16.3 0.2
10.9 0.1
21.4 0.2
10.9 0.1
10.4 0.1
9.5 0.1
19.3 0.1
10.6 0.1
9.3 0.1
8.3 0.1
14.8 0.2
11.2 0.2
8.5 0.2
3.1 0.1
12.9 0.1
7.6 0.1
6.3 0.2
4.3 0.1
20.4 0.2
13.7 0.2
8.5 0.1
9.8 0.1
5.4 0.1
22.3 0.2
EXPERIMENTAL
mass spectra were recorded with a Waters-Q-TOF
Ultima spectrometer.
All the reagents used were purchased from Merck
(Darmstadt, Germany); chemicals were of AR grade
and were used without further purification. Melting
points were determined by using an open capillary
method and are uncorrected. Thin layer chromatogra-
phy (TLC) was performed with aluminum sheets–Sil-
ica gel 60 F254 purchased from Merck. The synthe-
sized compounds were purified using column chroma-
tography with silica gel (60–120 mesh) in hexane–
ethylacetate (8 : 2) as eluent. IR spectra (ν, cm–1) were
recorded with a Nicolet 5700 FT-IR spectrophotome-
ter using KBr Wafer technique. 1H NMR and
13C NMR spectra were recorded at 400 and 100 MHz,
respectively, in a Bruker spectrometer using DMSO-d6
as a solvent for all the compounds. Micro analytical
Preparation of 2,6-bis(Substituted phenyl)-1-Meth-
ylpiperidin-4-one O-2-(2-(4-Chloroben-
zylidene)hydrazinyl)thiazol-4-yl Oximes (VIII–XXVII)
An equimolar mixture of 4-chloro-2-(2-(substituted
benzylidene)hydrazinyl)thiazoles (IIIa–d) (1 mmol),
2,6-bis(substituted phenyl)-1-methylpiperidin-4-one
oximes (VIIa–e) (1 mmol), and triethylamine
(1 mmol) was refluxed for 6 h in dichloromethane
(10 mL). Then, the product was poured into ice-cold
water. The precipitate was collected by filtration and
recrystallized with methanol to obtain products
(VIII–XXVII) in good yields.
2,6-Bis(4-chlorophenyl)-1-methylpiperidin-4-one
O-(2-(2-(4-nitrobenzylidene)hydrazinyl)thiazol-4-yl)
data were obtained by Elemental-Vario EL-III and oxime (VIII). White solid; yield 82%; mp 120–123°C.
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SYNTHESIS OF THIAZOLE-BASED PIPERIDINONE OXIMES
193
Anal. calcd. for C28H24Cl2N6O3S (594.16): C, 56.47; HC=N), 7.11 (s, 1H, thiazole carbon), 4.00 (s, 1H,
NH), 3.90–3.86 (m, 2H, CH), 3.29–3.14 (m, 4H,
H, 4.06; N, 14.11; found: C, 56.44; H, 4.02; N,
14.08%. IR: 3417.57 (N–H), 3051–2956 (Ar-CH), CH2), 1.92 (s, 3H, N–CH3). 13C NMR: 172.44,
1
1628 (C=N). H NMR: 8.03 (s, 1H, HC=N), 7.68– 158.23, 144.82, 139, 128, 136.56, 134.53, 132.05,
6.97 (m, 13H, Ar-H), 4.01 (s, 1H, NH), 3.90–3.86 (t, 131.82, 130.54, 128.17, 67.72, 66.47, 41.11, 37.58, 34.29.
2H, CH), 3.11–2.71 (m, 4H, CH2), 1.92 (s, 3H, N–
1-Methyl-2,6-bis(4-nitrophenyl)piperidin-4-one
O-2-(2-(4-methoxybenzylidene)hydrazinyl)thiazol-4-
CH3). 13C NMR: 172.0, 170.35, 160.0, 158.1, 156.41,
143.82, 139.1, 134.0, 133.3, 132.41, 131.8, 129.69,
127.77, 110.1, 67.78, 66.0, 42.0, 41.43, 37.38, 36.29.
yl oxime (XIII). Yellow solid; yield; 88%; mp 160–
162°C. Anal. calcd. for C29H27N7O6S (601.17) C,
57.23; H, 4.29; N, 16.69 found: C, 57.24; H, 4.25; N,
16.61%. IR: 3421.57 (N–H), 3068–2967 (Ar-CH),
2,6-Bis(4-chlorophenyl)-1-methylpiperidin-4-one
O-2-(2-(4-methoxybenzylidene) hydrazinyl)thiazol-4-
yl oxime (IX). Yellow solid; yield 87%; mp 160–162°C.
Anal. calcd. for C29H27Cl2N5O2S (579.15): C, 60.00;
H, 4.69; N, 12.06; found: C, 60.12; H, 4.72; N,
12.51%. IR: 3407.87 (N–H), 3058–2967 (Ar-CH),
1
1629 (C=N). H NMR: 7.93 (s, 1H, HC=N), 7.73–
7.07 (m, 13H, Ar-H), 7.05 (s, 1H, thiazole carbon),
4.03 (s, 1H, NH), 3.88–3.84 (m, 2H, CH), 3.80 (s,
3H, OCH3), 3.21–3.10 (m, 4H, CH2), 1.92 (s, 3H, N–
CH3). 13C NMR: 171.05, 155.11, 143.52, 138.41,
126.45, 135.36, 133.43, 132.62, 130.73, 128.69, 127.41,
67.69, 65.58, 41.52, 37.38, 36.52.
1
1627 (C=N). H NMR: 8.07 (s, 1H, HC=N), 7.89–
7.27 (m, 13H, Ar-H), 7.12 (s, 1H, thiazole carbon),
4.40 (s, 1H, NH), 3.90–3.86 (m, 2H, CH), 3.82 (s,
3H, OCH3), 3.29–3.14 (m, 4H, CH2), 1.92 (s, 3H,
1-Methyl-2,6-bis(4-nitrophenyl)piperidin-4-one O-
2-(2-(4-hydroxybenzylidene)hydrazinyl)thiazol-4-yl oxime
(XIV). Pale yellow solid; yield 94%; mp 156–158°C.
Anal. calcd. for C28H25N7O6S (587.19): C, 57.23; H,
4.29; N, 16.69; found: C, 57.24; H, 4.25; N, 16.61%.
IR: 3417.17 (N–H), 3067–2953 (Ar-CH), 1630
(C=N). 1H NMR 7.93 (s, 1H, HC=N), 7.73–7.07 (m,
13H, Ar-H), 7.05 (s, 1H, thiazole carbon), 5.35 (s, 1H,
OH), 4.03 (s, 1H, NH), 3.88–3.84 (m, 2H, CH),
3.21–3.10 (m, 4H, CH2), 1.92 (s, 3H, N–CH3).
N–CH3). 13C NMR: 170.35, 156.41, 143.82, 139, 127,
134, 133.3, 132.41, 131.8, 129.69, 127.77, 67.78, 65.38,
41.43, 37.38, 36.29.
2,6-Bis(4-chlorophenyl)-1-methylpiperidin-4-one
O-2-(2-(4-hydroxybenzylidene)hydrazinyl) thiazol-4-
yl oxime (X). White solid; yield 92%; mp 134–136°C.
Anal. calcd. for C28H25Cl2N5O2S (565.13): C, 59.36;
H, 4.45; N, 12.36; found: C, 59.34; H, 4.41; N,
12.38%. IR: 3419.57 (N–H), 3072–2941 (Ar-CH),
1625 (C=N). 1H NMR: 8.14–7.72 (m, 13H, Ar-
H),8.01 (s, 1H, HC=N), 7.10 (s, 1H, thiazole carbon),
5.30 (s, 1H, OH), 4.10 (s, 1H, NH), 3.86–3.78 (m,
2H, CH), 3.21–3.14 (m, 4H, CH2), 1.76 (s, 3H, N–
13C NMR 171.05, 155.11, 143.52, 138.41, 126.45,
135.36, 133.43, 132.62, 130.73, 128.69, 127.41, 67.69,
65.58, 41.52, 37.38, 36.52.
1-Methyl-2,6-bis(4-nitrophenyl)piperidin-4-one
O-(2-(2-(4-hydroxy-3-methoxybenzylidene)hydrazinyl)-
thiazol-4-yl) oxime (XV). Brown solid; yield 92%; mp
147–149°C. Anal. calcd. for C29H27N7O7S (617.13) C,
56.39; H, 4.41; N, 15.87; found: C, 56.35; H, 4.46; N,
15.88%. IR: 3417.97 (N–H), 3045–2956 (Ar-CH),
CH3). 13C NMR: 170.35, 156.41, 143.82, 139, 127, 134,
133.3, 132.41, 131.8, 129.69, 127.77, 67.78, 65.38,
41.43, 37.38, 36.29.
2,6-Bis(4-chlorophenyl)-1-methylpiperidin-4-one
O-(2-(2-(4-hydroxy-3-methoxy benzylidene)hydraz-
inyl)thiazol-4-yl) oxime (XI). Yellow solid; yield 88%;
mp 167–169°C. Anal. calcd. for C29H27Cl2N5O3S
(595.19): C, 58.39; H, 4.56; N, 11.74; found: C, 58.31;
H, 4.53; N, 11.71%. IR: 3416.57 (N–H), 3047–2958
(Ar-CH), 1629 (C=N). 1H NMR: 8.03 (s, 1H,
HC=N), 8.01–7.57 (m, 12H, Ar-H), 7.04 (s, 1H, thi-
azole carbon), 5.34 (s, 1H, OH), 3.96 (s, 1H, NH),
3.89–3.85 (m, 2H, CH), 3.81 (s, 3H, OCH3), 3.29–
1
1624 (C=N). H NMR: 7.78 (s, 1H, HC=N), 7.72–
7.35 (m, 12H, Ar-H), 7.11 (s, 1H, thiazole carbon),
5.30 (s, 1H, OH), 4.00 (s, 1H, NH), 3.90–3.86 (m,
2H, CH), 3.29–3.14 (m, 4H, CH2), 1.92 (s, 3H, N–
CH3). 13C NMR: 170.55, 156.62, 143.83, 138.52,
126.63, 134.15, 133.31, 130.41, 130.58, 129.19, 127.72,
69.78, 65.35, 55.41, 41.53, 37.52, 36.51.
2,6-Bis(4-methoxyphenyl)-1-methylpiperidin-4-one
O-(2-(2-(4-nitrobenzylidene)hydrazinyl)thiazol-4-yl)
oxime (XVI). Off white solid; yield 81%; mp 146–
148°C. Anal. calcd. for C30H30N6O5S (586.17): C,
61.42; H, 5.15; N, 14.33; found: C, 61.45; H, 5.14; N,
14.31%. IR: 3417.17 (N–H), 3025–2948 (Ar-CH),
3.14 (m, 4H, CH2), 1.84 (s, 3H, N–CH3). 13C NMR:
169.25, 155.81, 142.82, 138, 129, 134.52, 133.55,
131.41, 130.08, 129.19, 126.77, 66.78, 64.58, 55.62,
42.53, 38.38, 36.89.
1-Methyl-2,6-bis(4-nitrophenyl)piperidin-4-one O-
2-(2-(4-nitrobenzylidene)hydrazinyl)thiazol-4-yl oxime
(XII). Yellow solid; yield; 79%; mp 117–119°C. Anal.
calcd. for C28H24N8O7S (616.16): C, 54.54; H, 3.92;
N, 18.17; found: C, 54.52 H, 3.90; N, 18.16%. IR:
1
1631 (C=N). H NMR: 8.30–6.59 (m, 13H, Ar-H),
8.03 (s, 1H, HC=N), 7.09 (s, 1H, thiazole carbon),
4.20 (s, 1H, NH), 3.90–3.86 (m, 2H, CH), 3.84 (s,
3H, OCH3), 3.82 (s, 3H, OCH3), 3.25–3.16 (m, 4H,
3417.67 (N–H), 3058–2959 (Ar-CH), 1624 (C=N). CH2), 1.78 (s, 3H, N–CH3). 13C NMR: 172.35,
1H NMR: 8.29–6.92 (m, 13H, Ar-H), 8.03 (s, 1H, 155.31, 144.82, 139.45, 129.52, 134.59, 133.56, 132.51,
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SALAKATTE THAMMAIAH HARINI et al.
131.58, 128.69, 127.14, 67.68, 65.28, 41.53, 36.38, 144.82, 138.25, 129.24, 135.48, 134.71.3, 132.41, 131.8,
35.59.
2,6-Bis(4-methoxyphenyl)-1-methylpiperidin-4-one
129.71, 126.81, 68.78, 65.53, 40.43, 38.28, 36.29.
2,6-Bis(4-hydroxyphenyl)-1-methylpiperidin-4-one
O-(2-(2-(4-methoxybenzylidene)hydrazinyl)thiazol-4-
yl) oxime (XXI). Brown solid; yield 78%; mp 158–
160°C. Anal. calcd. for C29H29N5O4S (543.14): C,
64.07; H, 5.38; N, 12.88; found: C, 64.05; H, 5.36; N,
12.85%. IR: 3417.43 (N–H), 3064-2953 (Ar-CH),
O-(2-(2-(4-methoxybenzylidene)hydrazinyl)thiazol-4-
yl) oxime (XVII). Brown solid; yield 76%; mp 150–
152°C. Anal. calcd. for C31H33N5O4S (571.21) C,
65.13; H, 5.82; N, 12.25; found: C, 65.13; H, 5.82; N,
12.25%. IR: 3417.27 (N–H), 3029–2956, (Ar-CH),
1
1
1625 (C=N). H NMR: 8.07–6.75 (m, 13H, Ar-H),
1628 (C=N). H NMR: 8.13 (s, 1H, HC=N), 7.64–
8.03 (s, 1H, HC=N), 7.03 (s, 1H, thiazole carbon),
4.00 (s, 1H, NH), 3.93–3.87 (m, 2H, CH), 3.85 (s,
3H, OCH3), 3.83 (s, 3H, OCH3), 3.78 (s, 3H, OCH3),
3.16–3.01 (m, 4H, CH2), 1.68 (s, 3H, N–CH3).
7.27 (m, 13H, Ar-H), 7.10 (s, 1H, thiazole carbon),
6.28 (s, 1H, OH), 6.26 (s, 1H, OH), 4.08 (s, 1H, NH),
3.81 (s, 3H, OCH3), 3.78–3.69 (m, 2H, CH), 3.29–
3.14 (m, 4H, CH2), 1.92 (s, 3H, N–CH3). 13C NMR:
170.54, 156.01, 143.80, 138.45, 128.47, 134.47, 133.45,
132.89, 131.63, 129.79, 128.33, 67.15, 65.19, 55.52,
41.52, 37.26, 35.69.
13C NMR: 171.52, 155.21, 142.82, 138.58, 126.75,
134.51, 133.59, 132.21, 130.56, 129.99, 126.57, 67.78,
66.38, 55.65, 55.21, 42.53, 37.68, 36.19.
2,6-Bis(4-methoxyphenyl)-1-methylpiperidin-4-one
O-(2-(2-(4-hydroxybenzylidene)hydrazinylthiazol-4-
yl) oxime (XVIII). Off white solid; yield 91%; mp 148–
150°C. Anal. calcd. for C30H31N5O4S (557.21): C,
64.61; H, 5.60; N, 12.56; found: C, 64.64; H, 5.62; N,
12.58%. IR: 3414.57 (N–H), 3064–3029 (Ar-CH),
2,6-Bis(4-hydroxyphenyl)-1-methylpiperidin-4-one
O-(2-(2-(4-hydroxybenzylidene)hydrazinyl)thiazol-4-
yl) oxime (XXII). White solid; yield 89%; mp 131–
133°C. Anal. calcd. for C28H27N5O4S (529.15): C,
63.50; H, 5.14; N, 13.22; found: C, 63.52; H, 5.12; N,
13.20%. IR: 3417.87 (N–H), 3057–2972 (Ar-CH),
1
1
1631 (C=N); H NMR: 8.25–7.65 (m, 13H, Ar-H),
1628 (C=N). H NMR 8.03 (s, 1H, HC=N), 7.89–
8.03 (s, 1H, HC=N), 7.05 (s, 1H, thiazole carbon),
5.29 (s, 1H, OH), 4.00 (s, 1H, NH), 3.98 (s, 3H,
OCH3), 3.96 (s, 3H, OCH3), 3.90–3.86 (m, 2H, CH),
3.29–3.14 (m, 4H, CH2), 1.92 (s, 3H, N–CH3).
7.32 (m, 13H, Ar-H), 7.01 (s, 1H, thiazole carbon),
6.35 (s, 1H, OH), 6.33 (s, 2H, OH), 4.04 (s, 1H, NH),
3.86–3.75 (m, 2H, CH), 3.29–3.14 (m, 4H, CH2),
1.94 (s, 3H, N–CH3). 13C NMR: 168.78, 156.65,
142.82, 139.58, 127.61, 134.41, 132.45, 131.41, 130.25,
129.32, 128.77, 67.88, 65.36, 41.44, 37.32, 34.85.
13C NMR: 170.41, 157.41, 143.86, 138.26, 128.63,
135.54, 134.51, 130.41, 129.86, 128.69, 127.27, 69.78,
66.38, 55.89, 42.03, 37.18, 36.59.
2,6-Bis(4-hydroxyphenyl)-1-methylpiperidin-4-one
O-(2-(2-(4-hydroxy-3-methoxybenzylidene)hydraz-
inyl)thiazol-4-yl) oxime (XXIII). Yellow solid; yield
93%; mp 164–166°C. Anal. calcd. for C29H29N5O5S
(559.15): C, 62.24; H, 5.22; N, 12.51; found: C, 62.22;
H, 5.20; N, 12.53%. IR: 3418.57 (N–H), 3057–2983
(Ar-CH), 1628 (C=N). 1H NMR: 7.82 (s, 1H,
HC=N), 7.76–7.35 (m, 12H, Ar-H), 7.04 (s, 1H, thi-
azole carbon), 6.55 (s, 1H, OH), 6.53 (s, 1H, OH),
5.83 (s, 1H, OH), 4.05 (s, 1H, NH), 3.86–3.90 (m,
2H, CH), 3.82 (s, 3H, OCH3), 3.27–3.14 (m, 4H,
2,6-Bis(4-methoxyphenyl)-1-methylpiperidin-4-one
O-(2-(2-(4-hydroxy-3-methoxybenzylidene)hydraz-
inyl)thiazol-4-yl) oxime (XIX). Yellow solid; yield 94%;
mp 155–157°C. Anal. calcd. for C31H33N5O5S
(587.24) C, 63.36; H, 5.66; N, 11.92; found: C, 63.32;
H, 5.61; N, 11.90%. IR: 3417.67 (N–H), 3032–2986
(Ar-CH), 1628 (C=N). 1H NMR: 7.81 (s, 1H,
HC=N), 7.52–6.95 (m, 12H, Ar-H), 7.11 (s, 1H, thi-
azole carbon), 5.29 (s, 1H, OH), 4.04 (s, 1H, NH),
3.84 (s, 3H, OCH3), 3.83–3.80 (m, 2H, CH), 3.82 (s,
3H, OCH3), 3.73 (s, 3H, OCH3), 3.34–3.14 (m, 4H,
CH2), 1.92 (s, 3H, N–CH3). 13C NMR: 172.35,
155.42, 145.72, 139.41, 128.31, 134.12, 133.78, 132.45,
131.44, 129.69, 125.17, 67.75, 64.18, 41.42, 36.51,
35.29.
2,6-Bis(4-hydroxy-3-methoxyphenyl)-1-methylpiperi-
din-4-one O-2-(2-(4-nitro benzyli-dene)hydraz-
inyl)thiazol-4-yl oxime (XXIV). Yellow solid; yield
CH2), 1.71 (s, 3H, N–CH3). 13C NMR: 172.35,
157.28, 144.82, 138.54, 129.51, 135.25, 133.45, 132.10,
131.15, 129.68, 127.12, 68.78, 66.38, 55.78, 42.03,
37.30, 35.20.
2,6-Bis(4-hydroxyphenyl)-1-methylpiperidin-4-one
O-(2-(2-(4-nitrobenzylidene)hydrazinyl)thiazol-4-yl)
oxime (XX). Off white solid. yield 84%; mp 165– 76%; mp 134–136°C. Anal. calcd. for C30H30N6O7S
168°C. Anal. calcd. for C28H26N6O5S (558.12): C,
60.20; H, 4.69; N, 15.04 found: C, 60.21; H, 4.65; N, H, 4.82; N, 13.51%. IR: 3416.57 (N–H), 3067–2958
(618.20): C, 58.24; H, 4.89; N, 13.58; found: C, 58.28;
1
15.03%. IR: 3417.49 (N–H), 3081–2954 (Ar-CH),
(Ar-CH), 1624 (C=N). H NMR: 8.30–6.69 (m,
1
1625 (C=N). H NMR: 8.33–6.89 (m, 13H, Ar-H), 10H, Ar-H), 7.96 (s, 1H, HC=N), 7.10 (s, 1H, thi-
8.01 (s, 1H, HC=N), 7.08 (s, 1H, thiazole carbon), azole carbon), 6.33 (s, 1H, OH), 6.29 (s, 1H, OH),
6.10 (s, 1H, OH), 6.13 (s, 1H, OH), 4.12 (s, 1H, NH), 4.08 (s, 1H, NH), 3.77–3.68 (m, 2H, CH), 3.86 (s,
3.90–3.86 (m, 2H, CH), 3.29–3.14 (m, 4H, CH2), 3H, OCH3), 3.88 (s, 3H, OCH3), 3.34–2.18 (m, 4H,
1.94 (s, 3H, N–CH3). 13C NMR: 168.35, 158.41, CH2), 1.88 (s, 3H, N–CH3). 13C NMR: 168.35,
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SYNTHESIS OF THIAZOLE-BASED PIPERIDINONE OXIMES
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156.41, 143.12, 138.41, 127.23, 133.58, 133.01, 132.41, was prepared without the compounds and ethanol was
131.16, 129.29, 127.77, 66.54, 65.38, 55.62, 54.23, used for the baseline correction. Changes (decrease)
41.23, 37.21, 35.29.
in the absorbance at 517 nm were measured using a
UV-visible spectrophotometer and the remaining
DPPH was calculated. The percent decrease in the
absorbance was recorded for each concentration and
percent quenching of DPPH was calculated on the
basis of the observed decrease in absorbance of the
radical. The radical scavenging activity was expressed
as the inhibition percentage.
2,6-Bis(4-hydroxy-3-methoxyphenyl)-1-methylpiper-
idin-4-one
O-2-(2-(4-methoxybenzylidene)hydraz-
inyl)thiazol-4-yl oxime (XXV). Brown solid; yield 75%;
mp 172–174°C. Anal. calcd. for C31H33N5O6S
(603.20): C, 61.68; H, 5.51; N, 11.60; found: C, 61.65;
H, 5.49; N, 11.58%. IR: 3417.14 (N–H), 3045–2967
(Ar-CH), 1628 (C=N). 1H NMR: 7.98 (s, 1H,
HC=N), 7.70–6.57 (m, 11H, Ar-H) 7.03 (s, 1H, thi-
azole carbon), 5.50 (s, 1H, OH), 5.47 (s, 1H, OH),
4.06 (s, 1H, NH), 3.82 (s, 3H, OCH3), 3.80 (s, 3H,
OCH3), 3.69 (s, 3H, OCH3), 3.51–3.41 (m, 2H, CH),
3.18–2.04 (m, 4H, CH2), 1.87 (s, 3H, N–CH3).
In the inhibition of microsomal lipid peroxidation assay,
liver excised from adult male Wistar rat, was homogenized
in 0.02 M Tris buffer, pH 7.4 (20 g/100 mL liquid). Mic-
rosomes were isolated by the calcium aggregation
method. In the assay, 100 μL of liver microsomal sus-
13C NMR: 169.52, 155.41, 146.81, 139.46, 128.47, pension (0.5 mg protein) was incubated with
134.54, 133.74, 132.21, 131.98, 129.22, 127.77, 67.72, 1 mmol/L each of FeSO4 and ascorbic acid with or
64.38, 55.58, 54.23, 42.13, 36.68, 36.21.
without compounds in a total volume of 1 mL in
0.1 mol/L phosphate buffer (pH 7.4). After incubation
at 37°C for 60 min, the reaction mixture was boiled
with thiobarbituric acid (TBA) (0.67 g/100 mL water)
for 15 min. Formation of TBA reactive substances
(TBARS) was calculated from the absorbance at
535 nm. BHA was used as the positive control.
2,6-Bis(4-hydroxy-3-methoxyphenyl)-1-methylpiper-
idin-4-one
O-2-(2-(4-hydroxybenzylidene)hydraz-
inyl)thiazol-4-yl oxime (XXVI). Off white solid; yield
84%; mp 125–127°C. Anal. calcd. for C30H31N5O6S
(589.23): C, 61.11; H, 5.30; N, 11.88; found: C, 61.14;
H, 5.32; N, 11.86%. IR: 3417.67 (N–H), 3067–2938
(Ar-CH), 1628 (C=N). 1H NMR: 7.93 (s, 1H,
HC=N), 7.69–6.67 (m, 11H, Ar-H) 7.01 (s, 1H, thi-
azole carbon), 5.50 (s, 1H, OH), 5.48 (s, 1H, OH),
5.40 (s, 1H, OH), 4.06 (s, 1H, NH), 3.82 (s, 3H,
OCH3), 3.80 (s, 3H, OCH3), 3.47–3.41 (m, 2H, CH),
3.18–2.04 (m, 4H, CH2), 1.87 (s, 3H, N–CH3).
The antibacterial activity assay was carried out
against 24-h cultures of various bacterial strains. The
test compounds were dissolved in dimethyl sulfoxide
(DMSO) at concentrations of 1000 and 500 μg/mL.
Twenty milliliter of sterilized agar media was poured
into each pre-sterilized Petri dish. Excess of suspen-
sion was decanted and plates were dried by placing in
an incubator at 37°C for an hour. About 60 mL of 24-h
culture suspension were poured and neatly swabbed
with the pre-sterilized cotton swabs. Six millimeter
diameter wells were then punched carefully using a
sterile cork borer and 30 μL of test solutions of differ-
ent concentrations were added into each labeled well.
The plates were incubated for 24 h at 37°C. The inhi-
bition zone that appeared after 24 h around the well in
each plate was measured as zone of inhibition in mm.
Experiments were carried out in triplicates and stan-
dard deviation was calculated.
13C NMR: 172.45, 157.41, 142.82, 137.41, 128.29,
134.11, 133.35, 131.41, 130.38, 129.09, 127.70, 67.71,
65.26, 56.15, 55.46, 40.58, 37.22, 35.29.
2,6-Bis(4-hydroxy-3-methoxyphenyl)-1-methylpiper-
idin-4-one O-(2-(2-(4-hydroxy-3-methoxy ben-
zylidene)hydrazinyl)thiazol-4-yl) oxime (XXVII). Off
white solid; yield 89%; mp 157–159°C. Anal. calcd.
for C31H33N5O7S (619.42) C, 60.08; H, 5.37; N, 11.30;
found: C, 60.04; H, 5.32; N, 11.33%. IR: 3417.77 (N–
1
H), 3089–2951 (Ar-CH), 1628 (C=N). H NMR:
7.78 (s, 1H, HC=N), 7.72–6.67 (m, 10H, Ar-H), 7.01
(s, 1H, thiazole carbon), 6.53 (s, 1H, OH), 6.52 (s,
1H, OH), 6.50 (s, 1H, OH), 4.06 (s, 1H, NH), 3.90–
3.87 (m, 2H, CH), 3.85 (s, 3H, OCH3), 3.83 (s, 3H,
OCH3) 3.80 (s, 3H, OCH3), 3.29–3.14 (m, 4H, CH2),
Antifungal studies were carried out using Sab-
ouraud agar media. Normal saline was used to make a
suspension of spore of fungal strains for inoculation. A
loopful of particular fungal strain was transferred into
3 mL of saline to get a suspension of corresponding
species. Twenty milliliter of agar media was poured
into each Petri dish. Excess of suspension was
decanted and plates were dried by placing in the incu-
bator at 37°C for 1 h. Carefully punched wells were
placed on these seeded agar plates and 30 μL of test
solution of different concentrations in DMSO were
added into each labeled well. A control was also pre-
1.90 (s, 3H, N–CH3). 13C NMR: 171.10, 154.41,
145.82, 140.45, 134.52, 133.49, 132.43, 131.28, 129.56,
127.67, 127.23, 67.78, 65.38, 55.52, 54.23, 54.02,
40.83, 37.35, 36.21.
In DPPH radical scavenging assay, solutions of differ-
ent concentrations (10, 25, 50, 100, 200, and 500 μM) of
the synthesized compounds (VIII–XXVII) were pre-
pared in distilled ethanol. To 1 mL of each compound
solution, 4 mL of 0.1 mM ethanol solution of DPPH
was added, and the tube was shaken vigorously. Then, pared for the plates in the same way using DMSO as a
they were incubated in the dark room at RT for 20 min. solvent. The Petri dishes were prepared in triplicate
BHA was used as internal standard. A DPPH blank and maintained at 25°C for 72 h. Antifungal activity
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196
SALAKATTE THAMMAIAH HARINI et al.
8. Jaishree, V., Ramdas, V.N., Sachin, J., and Ramesh, B.,
was determined by measuring the diameter of the inhi-
bition zone.
J. Saudi Chem. Soc., 2012, vol. 16, pp. 371–376.
9. Blois, M.S., Nature, 1958, vol. 181, p. 1199.
10. Heim, K.E., Tagliaferro, A.R., and Bobilya, D.J.,
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