Design, synthesis and antimicrobial properties of novel 3,3a,4,5,6,7-hexahydroindazole and arylthiazolylpyrazoline derivatives

Article abstract of DOI:10.2174/157340613804488422

A remarkable diastereoselective synthesis of some novel arylthiazolyl pyrazoline derivatives 3(a-l) is displayed which were evaluated for their in vitro antimicrobial activities. In particular, compounds 3e, 3g & 3l (MIC 12.5 μg /ml) showed good activity against S. aureus and compounds 3b & 3j (MIC 12.5 μg / ml) against B. subtilis. Compounds 3g, 3i, 3j (MIC 12.5 μg/ ml) and 3l (MIC 6.25 μg / ml) also displayed excellent antifungal activity against C. albicans. Of all the synthesized compounds, 3g and 3e exerted a wide range of antibacterial activities against entire tested gram positive (S. aureus and B. subtilis) and gram negative (E. coli and P. aeruginosa) bacterial strain except P. aeruginosa.

Full text of DOI:10.2174/157340613804488422

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Medicinal Chemistry, 2013, 9, 45-52
45
Design, Synthesis and Antimicrobial Properties of Novel 3,3a,4,5,6,7-
Hexahydroindazole and Arylthiazolylpyrazoline Derivatives
Abha Bishnoi1,*, Suruchi Singh1, Anil K. Tiwari1, Arun Sethi1 and Chandrakant Mani Tripathi2
1Department of Chemistry, Lucknow University, University Road, Lucknow-226007, India
2Fermentation Division, Central Drug Research Institute, Lucknow-226001, India
Abstract: A remarkable diastereoselective synthesis of some novel arylthiazolyl pyrazoline derivatives 3(a-l) is displayed
which were evaluated for their in vitro antimicrobial activities. In particular, compounds 3e, 3g & 3l (MIC 12.5 ꢀg /ml)
showed good activity against S. aureus and compounds 3b & 3j (MIC 12.5 ꢀg / ml) against B. subtilis. Compounds 3g, 3i,
3j (MIC 12.5 ꢀg/ ml) and 3l (MIC 6.25 ꢀg / ml) also displayed excellent antifungal activity against C. albicans. Of all the
synthesized compounds, 3g and 3e exerted a wide range of antibacterial activities against entire tested gram positive (S.
aureus and B. subtilis) and gram negative (E. coli and P. aeruginosa) bacterial strain except P. aeruginosa.
Keywords: Antibacterial Activity, Antifungal Activity, Arylthiazolylpyrazoline, Cyclization, Diastereoselectivity,
Heterocycles.
1. INTRODUCTION
Heterocyclic molecules can act as highly functionalized
scaffolds and are known pharmacophores of a number of
biologically active and medicinally useful molecules [5,6].
Electron-rich nitrogen heterocyclics play an important role in
diverse biological activities. The pyrazoles, pyrazolones and
alkylpyrazoles are heterocyclic compounds having wide
range of pharmacological applications [7-14]. A second ni-
trogen in the five-membered ring also influences the antibac-
terial or pharmacokinetic properties [15-17]. 2-Pyrazoline
derivatives have also been reported in the literature to exhibit
various pharmacological activities such as antimicrobial [18-
23], anti-inflammatory/ antioxidant [24] and antihyperten-
sive [25]. Synthesis of aryl pyrazoles is also of major interest
because the ring system is present in numerous compounds
of therapeutic importance. eg- Celecoxib or Deracoxib (Fig.
1). Thiazole nucleus is also a very important pharmacophore
in drug discovery, and its derivatives constitute an important
class of bioactive molecules used in the field of drugs and
pharmaceuticals [26-30].
The increasing resistance of human pathogens to existing
antimicrobial agents is a serious medical problem. During
the 20th century, vaccines for bacterial toxins and many
other common acute viral infections were developed and
made widely available. There are currently thirty vaccines
that are mainly given prophylactically to prevent or mini-
mize diseases by agents infectious to human. These have
changed the face of viral disease as much as antibiotics have
affected the course of bacterial disease. The World Health
Organization (WHO) estimates that sixty percent of hospital-
acquired (nosocomial) infections are drug-resistant [1-4].
Fungal infections are being recognized with increasing
frequency as an important cause of both morbidity and mor-
tality. Fortunately, out of 250,000 species, only around 200
species of fungi are pathogenic to mammals. Many of the
drugs currently available have undesirable side effects and
might be toxic to varying extent from being highly toxic to
mild. Considering the fact that the available antifungal
agents originate from a limited number of sources, and that
most of them have similar modes of activity, it is very im-
portant to explore additional sources for substances with
potential antifungal activity, which could possibly have dif-
ferent modes of activity or affect different sites in the fungal
cells.
In view of the above mentioned findings, to identify new
candidates that may be valued in designing new, potent, se-
lective and less toxic antimicrobial agents, we report here the
synthesis of some new arylthiazolylpyrazoline derivatives
starting from cyclohexanone and various aromatic alde-
hydes.
In view of wide spread of resistant strains of microorgan-
ism there is an urgent need for the development of new an-
timicrobial agents to treat the patients infected with
multidrug-resistant bacteria and fungi.
Giving attention to the possible biological effects of both
pyrazole and thiazole moieties present in an aromatic nu-
cleus, it was thought worthwhile to synthesize a new series
of arylthiazolylpyrazoline derivatives and to evaluate them
as antimicrobial agents.
2. CHEMISTRY
*Address correspondence to this author at the Department of Chemistry,
Lucknow University, University Road, Lucknow-226 007, India; Tels: +91-
9415028822, +91-0522-2662777; E-mails: abhabishnoi5@gmail.com,
dr.abhabishnoi@gmail.com
Our initial attempt to obtain thiosemi/semicarbazones 4
by reaction of ketone with thiosemi/semi carbazide under
1875-6638/13 $58.00+.00
© 2013 Bentham Science Publishers

46 Medicinal Chemistry, 2013, Vol. 9, No. 1
Bishnoi et al.
F
F
F
F
F
N
N
N
N
O
F
S
O
S
NH2
O
O
O
H2N
Deracoxib
Celecoxib
Fig. (1).
acidic conditions failed and instead 2-pyrazolines were iso-
lated in good yields.
appears to overlap with the multiplet of the aromatic hydro-
gens. The downfield shift is due to anisotropic deshielding of
the non-bonded electron pairs on N-1 [33]. Secondly, the
condensed and partly saturated six membered ring can exist
in two preferred conformations. These chair and boat like
forms with out of plane C-5 and C-7a atoms are both dis-
torted approaching the sofa arrangement with coplanar C-7a.
It is to be noted that the inversion of six membered ring
hardly influence the envelop form of the pyrazoline ring
(with an out of plane C-3 atom) bearing the phenyl/ substi-
tuted phenyl group in quasi-equatorial position [34]. The
cyclo condensation reaction of (2a-f) with substituted aceto-
phenones in presence of iodine gave the corresponding 2-(4-
aryl-2-thiazoyl)-7-benzylidene-3,3a,4,5,6,7-hexahydro-3
phenyl-2H-indazole compounds (3a-l). The characterization
data of the novel compounds are displayed in Table 1.
The disappearance of C=O IR peak in 2 suggests the
C=O band is probably replaced by a C=N. The C=N vibra-
tion band in IR spectra of 2 afford the possibility of distin-
guishing between 1 and 2- pyrazolines, as the C=N peak is
reported at ~1600- 1687 cm-1 in 2-pyrazolines whereas in 1-
pyrazoline the same peak is shown to be much lower at
~1500 cm-1. The absence of NN-H proton peak showed that
the product obtained was not compound 4. The evidence for
formation of the pyrazoline was established with the help of
3a proton NMR peak at ꢀ 3.52-3.95 in 2(a-f). This peak
would have been of two protons, instead of one proton, in
case 4 was formed. The 3a-H showed vicinal coupling with
3-H with a J-value of nearly 10-11 Hz revealing the confor-
mation to be cis. The 3a-C is also shown to be tetrahedral,
13C-NMR peak at 49.5-55.6, instead of trigonal. The forma-
tion of thiazole ring in 3(a-l) was evidenced by the peak at ꢀ
2.98-3.76.
3. EXPERIMENTAL SECTION
All melting points are uncorrected. IR spectra were re-
corded on a Perkin- Elmer 1430 spectrophotometer using
KBr pellets. Mass spectra were recorded on a Va 70-70H
The synthetic route of the proposed compounds is illus-
trated in Scheme 1. The requisite starting material 2,6-
bis(aryl methylidene)cyclohexanones 1(a-d) were prepared
by the Claisen condensation of cyclohexanone with different
aldehydes according to the known procedure. Reaction of 1
with substituted hydrazines under acidic conditions yielded
7-benzylidene – 3, 3a, 4,5, 6, 7 hexahydro-3-phenyl-2-
thiocarbamoyl-2H-indazoles 2(a-f). The formation of two
diastereoisomers (cis and trans for 3-H and 3a-H) is reported
in the literature [31, 32]. The cyclization performed with
thiosemicarbazide under acidic conditions yielded only one
diastereoisomer of the 2(a-d) i.e. 3H, 3a-H cis. The reaction
with semicarbazide for 2e and 2f afforded a mixture of cis
(62% major) and trans (15% minor) isomers, which have
been separated through column chromatography. The cycli-
zation step leading to the formation of Thiazole 3(a-l) was
carried out from the major isolable portion (2a-f, cis). The
structure and relative configuration of the compounds have
been determined by spectroscopic techniques (1H and 13C
NMR). It was thought necessary to consider the two aspects
1
spectrophotometer at 70 eV. H and 13C spectra were re-
corded in CDCl3 using TMS as an internal standard on a
Bruker F 400 MHz NMR spectrophotometer respectively.
Elemental analyses were carried out on Carlo Erba EA- 1108
element analyzer. Starting material 1(a-d) were prepared as
per the literature procedure [35-39].
1a[a]: %Yield= 75, M.p.= 118o C. Recrystallization sol-
vent= Acetone. IR(KBr)cm-1: 1731 (C=O), 1595 (C=C).
1HNMR (CDCl3)ꢀ: 1.6-1.72 (q, 2H, 4-CH2), 2.85-2.90 (t,
4H, 3-CH2 & 5-CH2), 7.08-7.62 (m, 12 H, Ar-H). 13CNMR
(CDCl3) ꢀ: 190.4 (C-1), 137.4 (C-2, C-6), 26.1(C-3, C-5),
25.6(C-5), 127.9-135.6 (Ar-H).
1b[a]:%Yield= 73, M.p.= 253oC . Recrystallization sol-
vent= Acetone. IR(KBr)cm-1: 1729 (C=O), 1593 (C=C).
1HNMR (CDCl3)ꢀ: 1.33-1.56 (q, 2H, 4-CH2), 1.80-1.82 (t,
4H, 3-CH2& 5-CH2), 6.91-7.62 (m, 10 H, Ar-H). 13CNMR
(CDCl3) ꢀ: 191.1 (C-1), 138 (C-2, C-6), 26.8(C-3, C-5),
26.2(C-5), 125.8-133.9 (Ar-H).
1
of stereo structures on the basis of results of H and 13C –
1c[a]:%Yield = 69.5, M.p.= 175oC. Recrystallization sol-
vent= Ethanol. IR(KBr)cm-1: 1736 (C=O), 1591 (C=C).
1HNMR (CDCl3)ꢀ: 1.49-1.61 (q, 2H, 4-CH2), 1.73-1.76 (t,
4H, 3-CH2& 5-CH2), 6.51-7.51 (m, 10 H, Ar-H). 13CNMR
(CDCl3) ꢀ: 190.7 (C-1), 137.2 (C-2, C-6), 26.4(C-3, C-5),
25.5(C-5), 127-136.2 (Ar-H).
NMR, that is, geometrical isomerism of the benzylidene
moiety and the conformation of partly saturated condensed
ring. The formation of Z isomer (S- cis Ar and N-1) is pre-
vented due to unfavourable steric structure. The S-cis (to N-
1) position of the hydrogen in the exocyclic =CH- group
1
reveals a high downfield shift of its H NMR signal, which

Arylthiazolylpyrazoline Derivatives as Antimicrobials
Medicinal Chemistry, 2013, Vol. 9, No. 1 47
O
O
H
Ar
2
NaOH, EtOH
NNHCXNH2
Ar
NH2NHCNH2 , AcOH
X
O
1(a-d)
8
Ar
Ar
Ar
[X= S, O]
4
, AcOH
NH2NHCNH2
X
[X= S, O]
Ar
6
1
N
7
7a
NH2
X
2
N
3a
3
5
H
4
Ar
2(a-f)
O
R
, I2, Glacial AcOH
CH3
R
Ar
N
N
N
X
H
Ar
3(a-l)
Scheme 1.
1d: %Yield= 75.3, M.p.= 150oC. Recrystallization sol-
vent= Ethanol. IR(KBr)cm-1: 1745 (C=O), 1589 (C=C).
1HNMR (CDCl3)ꢀ: 1.09-1.36 (q, 2H, 4-CH2), 1.21-1.30 (t,
4H, 3-CH2 & 5-CH2), 6.28-7.69 (m, 8 H, Ar-H). 13CNMR
(CDCl3) ꢀ: 190.9 (C-1), 138.3 (C-2, C-6), 26.9(C-3, C-5),
26.7(C-5), 128.6-132.2 (Ar-H).
2a[a]:%Yield= 49, M.p.= 165-167oC. Recrystallization
solvent= Acetone. IR(KBr)cm-1: 3415 (N-H), 1633 (C=N),
1
1580 (C=C), 1319 (C=S). HNMR (CDCl3)ꢀ: 1.21-3.34 (m,
6H, CH2 of cyclohexanone), 3.45 (m,1H, 3a-H), 5.81 (d, 1H,
3-H, J= 11.5 Hz), 7.30-7.71 (br s, 2H, NH2), 7.40-8.15 (m,
11 H, Ar-H). 13CNMR (CDCl3) ꢀ: 67.2 (C-3), 49.5 (C-3a),
28.0 (C-4), 23.8 (C-5), 25.1 (C-6), 137.6 (C-7), 159.4 (C-7a),
177 (thiocarbomyl carbon). Mass (m/Z): M+ 347(3.9),
273(100), 217(25.3), 91(36.5), 76(42.4).
General procedure for the preparation of 7-(4-substituted
benzylidene)-3,3a,4,5,6,7-hexahydro-3-(4-substituted
phenyl)-2-thiocarbamoyl/ carbamoyl-2H-indazoles 2(a-f).
2b: %Yield= 52, M.p.= 169oC. Recrystallization solvent=
A mixture of thiosemicarbazide or semicarbazide (0.02
mol) and 2,6-bis-benzylidene cyclohexanones (1a-d) (0.01
mol) in ethanol (30 ml) and glacial acetic acid (2 ml) was
refluxed until the disappearance of the starting unsaturated
ketone (in 2-6 hrs). The reaction mixture was concentrated,
made alkaline and poured into water. The precipitate thus
obtained was filtered, washed with cold dilute ethanol and
recrystallized from an appropriate solvent.
Ethanol. IR(KBr)cm-1: 3384 (N-H), 1527 (C=N), 1511
1
(C=C), 1284 (C=S). HNMR (CDCl3)ꢀ: 1.05-3.09 (m, 6H,
CH2 of cyclohexanone), 3.21 (dt,1H, 3a-H), 5.65 (d, 1H, 3-
H, J= 11.8 Hz), 6.16 (br s, 2H, NH2), 6.24-7.60 (m, 9 H, Ar-
H). 13CNMR (CDCl3) ꢀ: 65.3 (C-3), 48.7 (C-3a), 27.1 (C-4),
22.9 (C-5), 23.9 (C-6), 135.3 (C-7), 156.2 (C-7a), 171 (thio-
carbomyl carbon).
2c: %Yield= 54, M.p.= 156oC. Recrystallization solvent=
The cis stereoisomers, obtained by reaction with semi-
carbazide hydrochloride were separated as the major isolable
product by column chromatography and were then purified
with suitable solvent.
Ethanol. IR(KBr)cm-1: 3330 (N-H), 1643 (C=N), 1529
1
(C=C), 1295 (C=S), 726 (C-Cl). HNMR (CDCl3)ꢀ: 1.19-
3.27 (m, 6H, CH2 of cyclohexanone), 3.37 (dt,1H, 3a-H),

48 Medicinal Chemistry, 2013, Vol. 9, No. 1
Bishnoi et al.
5.72 (d, 1H, 3-H, J= 11.9 Hz), 7.29 (br s, 2H, NH2), 7.41-
8.24 (m, 9 H, Ar-H). 13CNMR (CDCl3) ꢀ: 64.2 (C-3), 48.9
(C-3a), 28.1 (C-4), 22.6 (C-5), 24.7 (C-6), 136.5 (C-7), 156.4
(C-7a), 176.2 (thiocarbomyl carbon). Mass (m/Z): M+
417(4.6), 419(1.4), 344(97), 346(39.2), 91(27.6).
zole). Mass (m/Z): M+ 496(2.7), 361(30.9), 175(100),
133(40.5).
3c: %Yield= 65, M.p.= 112-114oC. Recrystallization sol-
vent= Ethanol. IR(KBr)cm-1: 1678 (C=N), 1460 (C=C), 1065
1
(C-S), 721 (C-Cl). HNMR (CDCl3)ꢀ: 1.05-2.89 (m, 6H,
2d: %Yield= 57, M.p.= 180oC. Recrystallization solvent=
CH2 of cyclohexanone), 2.74 (m, 1H, 3a-H), 3.15 (s, 1H,
=CH of thiazole), 4.92 (d, 1H, 3-H, J= 10.8 Hz), 7.25-8.8 (m,
15 H, Ar-H). 13CNMR (CDCl3) ꢀ: 66.9 (C-3), 49.5 (C-3a),
27.7 (C-4), 23.2 (C-5), 25 (C-6), 135.3 (C-7), 160.8 (C-7a),
177.2 (thiocarbomyl carbon), 151.4 (C-N thiazole), 105 (C-S
thiazole). Mass (m/Z): M+ 516(3.2), 518(1.0), 480(2.9),
344(30.4), 346(10.9), 175(100), 133(47.8), 91(43.9).
Ethanol. IR(KBr)cm-1: 3516 (O-H), 3347 (N-H), 1619
1
(C=N), 1572 (C=C), 1296 (C=S). HNMR (CDCl3)ꢀ: 1.03-
3.15 (m, 6H, CH2 of cyclohexanone), 3.19 (dt,1H, 3a-H),
5.68 (d, 1H, 3-H, J= 11.6 Hz), 6.24 (br s, 2H, NH2), 7.16-
8.07 (m, 9 H, Ar-H). 13CNMR (CDCl3) ꢀ: 65.7 (C-3), 50.7
(C-3a), 27.8 (C-4), 22.4 (C-5), 25 (C-6), 136.2 (C-7), 161.5
(C-7a), 175.9 (thiocarbomyl carbon).
3d: %Yeild= 63, M.p.= 122oC. Recrystallization solvent=
2e[a]: %Yield= 50, M.p.=144-145oC. Recrystallization
Ethanol. IR(KBr)cm-1: 3113 (O-H), 1673 (C=N), 1454
solvent= Methanol. IR(KBr)cm-1: 3362 (N-H), 1584 (C=N),
(C=C), 1052 (C-S). HNMR (CDCl3)ꢀ: 0.4-3.0 (m, 6H, CH2
1
1
1727 (C=O), 1557 (C=C). HNMR (CDCl3)ꢀ: 0.5-2.56 (m,
of cyclohexanone), 3.19 (s, 1H, =CH of thiazole), 3.42 (m,
1H, 3a-H), 5.3 (d, 1H, 3-H, J= 10.9 Hz), 6.9-7.49 (m, 15 H,
Ar-H). 13CNMR (CDCl3) ꢀ: 66.3 (C-3), 48.2 (C-3a), 29.1 (C-
4), 22.7 (C-5), 24.3 (C-6), 134.6 (C-7), 157.2 (C-7a), 178.3
(thiocarbomyl carbon), 150.6 (C-N thiazole), 106.3 (C-S
thiazole). Mass (m/Z): M+ 539(2.7), 319(31.5), 175(100),
133(47.2).
6H, CH2 of cyclohexanone), 3.18 (dt,1H, 3a-H), 4.82 (d, 1H,
3-H, J= 11.7 Hz), 5.21-5.55 (br s, 2H, NH2), 6.85-7.79 (m,
11 H, Ar-H). 13CNMR (CDCl3) ꢀ: 66.7 (C-3), 43.4 (C-3a),
24.8 (C-4), 25.5 (C-5), 27.8 (C-6), 130.9 (C-7), 156.5 (C-7a),
155.3 (carbomyl carbon). Mass (m/Z): M+ 347(4.2),
273(100), 91(46.5), 76(42.9).
2f: %Yield= 46, M.p.= 129-130oC. Recrystallization sol-
3e: %Yield= 50, M.p.= 135oC. Recrystallization solvent=
vent= Methanol. IR(KBr)cm-1: 3358 (N-H), 1561 (C=N),
Ethanol. IR(KBr)cm-1: 3293 (N-H), 1686 (C=N), 1470
1
1
1719 (C=O), 1525 (C=C), 714 (C-Cl). HNMR (CDCl3)ꢀ:
(C=C), 1063 (C-S). HNMR (CDCl3)ꢀ: 1.21-3.32 (m, 6H,
1.15-3.24 (m, 6H, CH2 of cyclohexanone), 2.93 (dt,1H, 3a-
H), 4.69 (d, 1H, 3-H, J= 11.2 Hz), 7.25 (br s, 2H, NH2),
7.36-8.13 (m, 9 H, Ar-H). 13CNMR (CDCl3) ꢀ: 66 (C-3),
42.3 (C-3a), 24.1(C-4), 24.9(C-5), 26.6 (C-6), 131.1 (C-7),
155 (C-7a), 153.2 (carbomyl carbon). Mass (m/Z): M+
401(3.7), 403(1.3), 344(100), 346(30.7), 91(29.4).
CH2 of cyclohexanone), 3.70 (m, 1H, 3a-H), 5.60 (d, 1H, 3-
H, J= 11.2 Hz), 6.99 (s, 2H, p-NH2,D2O exchangeable),
7.49-7.70 (m, 10 H, Ar-H). 13CNMR (CDCl3) ꢀ: 67.7 (C-3),
49.8 (C-3a), 28.3 (C-4), 23.6 (C-5), 25.7 (C-6), 135.5 (C-7),
161.5 (C-7a), 176.9 (thiocarbomyl carbon), 152.3 (C-N thia-
zole), 105.5 (C-S thiazole). Mass (m/Z): M+ 462(3.2),
273(32.6), 189(100), 147(54.8).
General procedure for the preparation of cis-2-(4-aryl-2-
thiazolyl/
oxazolyl)-7-(4-substituted
benzylidene)-
phenyl)-2H-
3f: %Yield= 68, M.p.= 142-144oC. Recrystallization sol-
3,3a,4,5,6,7-hexahydro-3-(4-substituted
indazoles 3(a-l).
vent= Ethanol. IR(KBr)cm-1: 3291 (N-H), 1677 (C=N), 1458
1
(C=C), 1058 (C-S). HNMR (CDCl3)ꢀ: 1.08-3.45 (m, 6H,
CH2 of cyclohexanone), 2.61-2.84 (m, 1H, 3a-H), 3.23 (s,
1H, =CH of thiazole), 5.98 (d, 1H, 3-H, J= 10.9 Hz), 6.67 (s,
2H, p-NH2, D2O exchangeable), 6.81-7.96 (m, 10 H, Ar-H).
13CNMR (CDCl3) ꢀ: 66.7 (C-3), 48.9 (C-3a), 28.3 (C-4),
23.8 (C-5), 24.6 (C-6), 136 (C-7), 158.3 (C-7a), 175.8 (thio-
carbomyl carbon), 150.4 (C-N thiazole), 106.6 (C-S thia-
zole). Mass (m/Z): M+ 510(3.7), 361(33.1), 189(98.7),
147(56.3).
A mixture of compound (2a-f) (0.01 mol), substituted
acetophenones (0.01 mol) and iodine (1.3 gm) in absolute
alchohol (25 ml) was refluxed for 6-11 hrs. On cooling, the
solid separated was filtered, dried and recrystallized from an
appropriate solvent.
3a[a]:%Yield= 68, M.p.= 116oC. Recrystallization sol-
vent= Methanol. IR(KBr)cm-1: 1689 (C=N), 1474 (C=C),
1
1067 (C-S). HNMR (CDCl3)ꢀ: 1.01-3.39 (m, 6H, CH2 of
3g: %Yield= 66, M.p.= 92oC. Recrystallization solvent=
cyclohexanone), 3.61 (s, 1H, =CH of thiazole), 3.82-4.24 (m,
1H, 3a-H), 5.65 (d, 1H, 3-H, J= 10.5 Hz), 7.20-7.95 (m, 17
H, Ar-H). 13CNMR (CDCl3) ꢀ: 67.6 (C-3), 49.9 (C-3a), 28.2
(C-4), 23.9 (C-5), 25.4 (C-6), 135.7 (C-7), 163 (C-7a), 176.4
(thiocarbomyl carbon), 152.8 (C-N thiazole), 105.8 (C-S
thiazole). Mass (m/Z): M+ 447(2.9), 273(27.9), 175(100),
133(51.5).
Methanol. IR(KBr)cm-1: 3288 (N-H), 1674 (C=N), 1453
1
(C=C), 1059 (C-S), 719 (C-Cl). HNMR (CDCl3)ꢀ: 1.12-
2.97 (m, 6H, CH2 of cyclohexanone), 2.86-3.05 (m, 1H, 3a-
H), 3.2 (s, 1H, =CH of thiazole), 5.06 (d, 1H, 3-H, J= 11.3
Hz), 6.86 (s, 2H, p-NH2, D2O exchangeable), 7.39-8.99 (m,
10 H, Ar-H). 13CNMR (CDCl3) ꢀ: 67.5 (C-3), 49.3 (C-3a),
27.8 (C-4), 23.4 (C-5), 25.2 (C-6), 135.4 (C-7), 160 (C-7a),
177.4 (thiocarbomyl carbon), 151.9 (C-N thiazole), 104.7
(C-S thiazole). Mass (m/Z): M+ 530(3.5), 532(1.3), 494(3.3),
344(36.2), 346(12.1), 189(99.1), 147(53.9), 91(46.8).
3b: %Yield= 61, M.p.= 108oC. Recrystallization solvent=
Ethanol. IR(KBr)cm-1: 1679 (C=N), 1463 (C=C), 1061 (C-
1
S). HNMR (CDCl3)ꢀ: 1.04-3.09 (m, 6H, CH2 of cyclohex-
anone), 2.58-2.80 (m, 1H, 3a-H), 2.98 (s, 1H, =CH of thia-
zole), 5.7 (d, 1H, 3-H, J= 10.7 Hz), 6.63-7.82 (m, 15 H, Ar-
H). 13CNMR (CDCl3) ꢀ: 66.5 (C-3), 48.8 (C-3a), 28.3 (C-4),
23.6 (C-5), 24.7 (C-6), 137.3 (C-7), 158 (C-7a), 175.9 (thio-
carbomyl carbon), 150.9 (C-N thiazole), 106.4 (C-S thia-
3h: %Yield= 67, M.p.= 118-120oC. Recrystallization
solvent= Ethanol. IR(KBr)cm-1: 3272 (N-H), 3100 (O-H),
1
1669 (C=N), 1451 (C=C), 1051 (C-S). HNMR (CDCl3)ꢀ:
0.95-2.92 (m, 6H, CH2 of cyclohexanone), 1.85 (s, 3H, p-
OCH3), 3.29 (s, 1H, =CH of thiazole), 3.80-3.95 (m, 1H, 3a-

Arylthiazolylpyrazoline Derivatives as Antimicrobials
Medicinal Chemistry, 2013, Vol. 9, No. 1 49
Table 1. Characterization Table
% C
Obs(Calc.)
%H
Obs(Calc.)
%N
Obs(Calc.)
Compd
Ar
X
R
Mol.Formula
[a]1a
[a]1b
[a]1c
1d
Phenyl
4-N(Me)2 phenyl
4-Cl phenyl
-
-
-
C20H18O
C24H30N2O
88.03(87.59)
77.98(79.56)
70.12(69.77)
70.53(71.74)
72.05(72.62)
68.91(69.28)
61.47(60.72)
60.95(62.87)
75.48(76.13)
64.06(63.16)
77.11(77.85)
72.87(74.3)
66.67(67.57
70.18(69.02
74.69(75.32)
70.99(72.26)
63.80(65.66)
65.76(67.15)
80.23(80.74)
67.34(69.74)
76.51(78.03)
65.79(67.70)
6.49(6.57)
8.55(8.28)
4.84(5.23)
6.09(6.52)
5.67(6.05)
6.79(7.16)
4.62(4.58)
4.73(5.09)
6.64(6.34)
4.18(4.76)
5.45(5.59)
6.83(6.57)
3.87(4.47)
4.75(5.38)
5.12(5.63)
5.99(6.56)
4.27(4.53)
5.91(5.42)
4.93(5.80)
4.09(4.61)
6.04(5.83)
4.54(4.67)
-
-
7.42(7.73)
-
-
-
-
C20H18Cl2O
C22H24O5
4-OH,3-OCH3 phenyl
Phenyl
-
-
[a]2a
2b
S
S
S
S
O
O
S
S
S
S
S
S
S
S
O
O
O
O
-
C21H21N3S
11.90(12.10)
16.38(16.17)
9.98(10.12)
9.59(9.57)
12.85(12.69)
9.73(10.53)
9.08(9.40)
12.86(13.13)
7.64(8.16)
8.06(7.79)
11.91(12.12)
15.50(15.33)
9.80(10.57)
10.67(10.11)
10.06(9.74)
8.19(8.42)
12.73(12.56)
11.45(10.89)
4-N(Me)2 phenyl
4-Cl phenyl
-
C25H31N5S
2c
-
C21H19N3SCl2
C23H25N3SO4
C21H21N3O
C21H19N3OCl2
C29H25N3S
2d
4-OH,3-OCH3 phenyl
Phenyl
-
[a]2e
2f
-
4-Cl phenyl
-
[a]3a
3b
Phenyl
H
4-N(Me)2 phenyl
4-Cl phenyl
H
C33H35N5S
3c
H
C29H23N3SCl2
C31H30N4S04
C29H26N4S
3d
4-OH,3-OCH3 phenyl
Phenyl
H
3e
NH2
NH2
NH2
NH2
H
3f
4-N(Me)2 phenyl
4-Cl phenyl
C33H36N6S
3g
C29H24N4SCl2
C31H34N4SO4
C29H25N3O
C30H25N4O2Cl2
C29H26N4O
C29H24N4OCl2
3h
4-OH,3-OCH3 phenyl
Phenyl
3i
3j
4-Cl phenyl
H
3k
Phenyl
NH2
NH2
3l
4-Cl phenyl
[a] Compounds are already known in literature.
H), 4.92 (d, 1H, 3-H, J= 10.6 Hz), 6.53 (s, 2H, p- NH2, D 2O
exchangeable), 6.96-8.23 (m, 14 H, Ar-H). 13CNMR (CDCl3)
ꢀ: 64.7 (C-3), 47.9 (C-3a), 29.2 (C-4), 22.9 (C-5), 24.1 (C-6),
134.9 (C-7), 157.7 (C-7a), 177.9 (thiocarbomyl carbon),
150.2 (C-N thiazole), 106.1 (C-S thiazole). Mass (m/Z): M+
554(3.6), 319(35.8), 189(100), 147(56.1).
thiazole), 4.87 (d, 1H, 3-H, J= 10.8 Hz), 6.93-8.15 (m, 10 H,
Ar-H). 13CNMR (CDCl3) ꢀ: 67 (C-3), 49.4 (C-3a), 28.4 (C-
4), 23.1 (C-5), 24.9 (C-6), 132 (C-7), 155.4 (C-7a), 151.4
(carbomyl carbon), 140.5 (C-N oxazole), 139.1 (C-O oxa-
zole). Mass (m/Z): M+ 500(4.4), 502(1.5), 464(4.9),
344(30.4), 346(9.9), 159(99.1), 117(52.6), 91(42.6).
3i: %Yield= 69, M.p.= 139oC. Recrystallization solvent=
Methanol. IR(KBr)cm-1: 1690 (C=N), 1470 (C=C), 1254 (C-
O). 1HNMR (CDCl3)ꢀ: 0.6-2.9 (m, 6H, CH2 of cyclohex-
anone), 3.40 (s, 1H, =CH of thiazole), 3.48 (m, 1H, 3a-H),
5.20 (d, 1H, 3-H, J= 11.1 Hz), 6.70-7.50 (m, 14 H, Ar-H).
13CNMR (CDCl3) ꢀ: 67.5 (C-3), 49.7 (C-3a), 28.3 (C-4),
23.5 (C-5), 25.5 (C-6), 131.6 (C-7), 155.9 (C-7a), 150.6
(carbomyl carbon), 140.9 (C-N oxazole), 139.9 (C-O oxa-
zole). Mass (m/Z): M+ 431(3.9), 273(29.5), 159(99.3),
117(53.7).
3j: %Yield= 56, M.p.= 128oC. Recrystallization solvent=
Ethanol. IR(KBr)cm-1: 1686 (C=N), 1468 (C=C), 1252 (C-
O), 718 (C-Cl). 1HNMR (CDCl3)ꢀ: 0.81-3.06 (m, 6H, CH2 of
cyclohexanone), 2.69 (m, 1H, 3a-H), 3.12 (s, 1H, =CH of
3k: %Yield= 49, M.p.= 126-127oC. Recrystallization
solvent= Ethanol. IR(KBr)cm-1: 3284 (N-H), 1684 (C=N),
1
1464 (C=C), 1249 (C-O). HNMR (CDCl3)ꢀ: 0.72-3.02 (m,
6H, CH2 of cyclohexanone), 3.51 (m, 1H, 3a-H), 3.45 (s, 1H,
=CH of thiazole), 5.18 (d, 1H, 3-H, J= 11.6 Hz), 6.97 (s, 2H,
p-NH2, D2O exchangeable), 7.3-8.29 (m, 10 H, Ar-H).
13CNMR (CDCl3) ꢀ: 67.4 (C-3), 49.2 (C-3a), 28.7 (C-4),
23.7 (C-5), 25.5 (C-6), 131.8 (C-7), 156.1 (C-7a), 150.3
(carbomyl carbon), 140.8 (C-N oxazole), 139.8 (C-O oxa-
zole). Mass (m/Z): M+ 446(4.7), 273(29.9), 174(98.7),
132(53.8).
3l: %Yield= 55, M.p.= 102oC. Recrystallization solvent=
Methanol. IR(KBr)cm-1: 3275 (N-H), 1672 (C=N), 1459
1
(C=C), 1241 (C-O), 714 (C-Cl). HNMR (CDCl3)ꢀ: 0.93-

50 Medicinal Chemistry, 2013, Vol. 9, No. 1
Bishnoi et al.
Table 2. Antimicrobial Activity of test Compounds Against Various Strains (Zone of Inhibition in mm)
S.
aureus
Compound
B. subtilis
P. aeruginosa
E. coli
C. albicans
3a
3b
10
17
11
15
40
18
31
8
6
6
6
6
6
6
10
20
10
10
10
32
36
13
36
34
11
42
6
3c
6
7
6
3d
6
6
6
3e
6
7
6
3f
14
21
6
9
10
22
6
3g
18
6
3h
3i
24
22
18
40
8
9
9
8
3j
21
19
6
6
6
3k
9
9
3l
6
6
Control
6
6
6
Table 3. Antimicrobial Activity of Test Compounds Against
Various Strains (MIC (ꢀg/ ml)
phenones in presence of iodine to arylthiazolylpyrazoline
derivatives. The new series of arylthiazolyl pyrazoline de-
rivatives was evaluated for antimicrobial activity towards the
gram positive and gram negative bacterial species and a fun-
gal strain which are Staphylococcus aureus (ATCC9144),
Bacillus subtilis (ATCC6633), Pseudomonas aeruginosa
(ATCC25619), Escherichia coli (MTCC739) and Candida
albicans (ATCC24433) respectively. Antimicrobial activities
were evaluated by measuring the diameter of zone of inhibi-
tion against test organisms and Minimal inhibition concen-
tration [40, 41] (MIC), the values of which are illustrated in
Tables 2 and 3 respectively. Erythromycin and Ampicillin
were used as standard antibaterials and Fluconazole as stan-
dard antifungal drug and their MIC values were also evalu-
ated along with the test compounds.
Compound
S. aureus
B. subtilis
C. albicans
3b
3e
3f
3g
3i
50
12.5
25
12.5
25
>100
>100
50
25
12.5
50
>100
>100
12.5
>100
2.87
-
12.5
12.5
12.5
6.25
-
3j
25
3l
12.5
-
It was found that the newly synthesized novel heterocy-
cles exhibited promising antimicrobial activity against S.
aureus, B. subtilis and C. albicans. Among the arylthiazolyl
pyrazolines synthesized, compounds 3j, 3g and 3l possess
pronounced antimicrobial activity against S. aureus, B. sub-
tilis (both gram positive) and C. albicans in comparison with
the other compounds. Interestingly all the three compounds
bear a 4-chlorophenyl group. Compound 3g showed signifi-
cant growth inhibitory action against all tested strains. The
above observations indicate that the presence of 4-
chlorophenyl group enhances the antimicrobial activity. On
the other hand, compounds with 4-N,N-dimethyl phenyl
group and 3-hydroxy,4-methoxyphenyl groups in heterocyc-
lic pyrazoline ring exhibited weak antimicrobial activity.
Compounds 3e, 3g and 3l were most active against S. aureus
with an MIC of 12.5 ꢃg/ml which is quite close to the stan-
dard drug Ampicillin. Compounds 3b and 3j showed good
activity against B.subtilis with a MIC value of 12.5 ꢃg/ml
but none of them could compete with that of the standard
drug Erythromycin. Generally, most of the compounds have
Erythromycin
Ampicillin
6.25
-
-
Fluconazole
-
6.25
3.26 (m, 6H, CH2 of cyclohexanone), 2.68-2.76 (m, 1H, 3a-
H), 3.21 (s, 1H, =CH of thiazole), 4.87 (d, 1H, 3-H, J= 11.0
Hz), 6.82 (s, 2H, p-NH2, D2O exchangeable), 7.18-8.53 (m,
10 H, Ar-H). 13CNMR (CDCl3) ꢀ: 64.2 (C-3), 49.3 (C-3a),
22.8 (C-4), 23.8 (C-5), 24.6 (C-6), 132.7 (C-7), 155.8 (C-7a),
151.2 (carbomyl carbon), 140.3 (C-N oxazole), 139.4 (C-O
oxazole). Mass (m/Z): M+ 514(4.2), 516(3.1), 478(4.5),
344(29.1), 346(9.6), 174(99.5), 132(55.6), 91(42.6).
4. RESULT AND DISCUSSION
During the present study a series of 2-pyrazolines was
prepared by reaction of ꢁ, ꢂ-unsaturated ketones with cyclo-
hexanone which were then cyclized with substituted aceto-

Arylthiazolylpyrazoline Derivatives as Antimicrobials
Medicinal Chemistry, 2013, Vol. 9, No. 1 51
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shown poor or no activity against Gram-negative bacteria
(Pseudomonas aeruginosa and Escherichia coli) with the
exception of compound 3g which showed a slight potency,
although without any significant MIC value. Compounds 3g,
3i, 3j (MIC 12.5 ꢄg/ml) and 3l (MIC 6.25 ꢄg/ml) of this se-
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[12]
[13]
[14]
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5. CONCLUSION
The results obtained make the novel arylthiazolylpyra-
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thetic and biological evaluation. It can be concluded that this
class of compounds certainly holds great promise towards
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the preliminary results and mode of action studies are re-
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CONFLICT OF INTEREST
None of the authors of the above manuscript has declared
any conflict of interest which may arise from being named as
an author on the manuscript.
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The authors express their sincere thanks to the Head, De-
partment of Chemistry, Lucknow University, Lucknow, for
providing laboratory facilities. They are also thankful to the
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[33]
[34]
[40]
[41]
[35]
Recieved: August 08, 2011
Revised: May 09, 2012
Accepted: May 20, 2012