Arabian Journal of Chemistry (2014) 7, 553596

King Saud University

Arabian Journal of Chemistry

www.ksu.edu.sa
www.sciencedirect.com

REVIEW
1st Heterocyclic Update
Synthetic and biological studies of pyrazolines
and related heterocyclic compounds
Mohamad Yusuf *, Payal Jain

Department of Chemistry, Punjabi University, Patiala 147002, Punjab, India

Received 5 May 2011; accepted 10 September 2011

Available online 1 October 2011

KEYWORDS Abstract This review provides a comprehensive survey relating to the synthesis and biological
Pyrazole; applications of pyrazolines and related heterocycles in the last ve years (20072011). These com-
Bispyrazoline; pounds are usually prepared from the cyclization of chalcones with hydrazine and its derivatives
Chalcones; under the alcoholic conditions. The major incentive behind the synthesis of these compounds
Bischalcone; was the immense biological activities associated to these heterocyclic derivatives. The aim of this
Cyclocondensation review is to nd out different methods for the synthesis of pyrazoline derivatives.
2011 Production and hosting by Elsevier B.V. on behalf of King Saud University.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 553
2. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 554
Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 594
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 594

1. Introduction

The development of a clean procedure for the preparation of

* Corresponding author. Tel.: +91 175 2287607; fax: +91 175
heterocyclic compounds is a major challenge in modern het-
2283073. erocyclic chemistry in view of the environmental, practical
E-mail address: yusuf_sah04@yahoo.co.in (M. Yusuf).
and economic issues. Pyrazolines are an important class of het-
Peer review under responsibility of King Saud University.
erocyclic compounds containing two nitrogen atoms in the ve
membered ring. The substituted 2-pyrazolines have found
application as activators for polymerization (Bauer and
Production and hosting by Elsevier Piatert, 1981), dyes for wool, nylon (Evans and Waters,

http://dx.doi.org/10.1016/j.arabjc.2011.09.013
1878-5352 2011 Production and hosting by Elsevier B.V. on behalf of King Saud University.
554
1978), as electro photographic conductors (Murayama and
Mater, 1981) and as wavelength shifters in liquid and
polymer scintillation (Poduzhailo et al., 1979). Pyrazoline
derivatives are the electron rich nitrogen heterocycles which
play an important role in the diverse biological activities.
These heterocyclic compounds widely occur in nature in the
form of alkaloids, vitamins, pigments and as constituents of
plant and animal cell. Considerable attention has been
focused on the pyrazolines and substituted pyrazolines due
to their interesting biological activities. These compounds
have been found to possess anti-fungal (Korgaokar et al.,
1996), anti-depressant, anticonvulsant (Palaska et al., 2001;
Rajendra et al., 2005; Ozdemir et al., 2007; Ruhogluo et al.,
2005), anti-inammatory (Udupi et al., 1998), anti-bacterial
(Nauduri and Reddy, 1998) and anti-tumor (Taylor and
Patel, 1992) properties. The pyrazole moiety is found in
blockbuster drugs such as celecobix (Penning et al., 1997),
sildenal (Terrett et al., 1996) and rimonabant (Seltzmann
et al., 1995). Recently a very important review has been
published upon the studies of pyrazoline compounds (Kumar
et al., 2009).
2. Discussion
1,3,5-Triaryl-2-pyrazolines 3 (Li et al., 2007) have been
prepared through the reaction of chalcones and phenyl
hydrazine hydrochloride (Scheme 1) in the presence of
sodium acetate-acetic acid aqueous solution under
ultrasound irradiation.
3,4,5-Metalated pyrazoles 6 and 7 were synthesized
(Gonzalez-Nogal et al., 2007) by 1,3-dipolar cycloadditions
of silyl, disilyl, and silylstannylacetylenes with N-
phenylsydnone or trimethylsilyldiazomethane (Scheme 2).
The heterocyclics 5-(-4-(Substituted)phenyl)-3-(4-hydroxy-
3-methylphenyl)-4,5-dihydro-1H-1-pyrazolyl-2-toluidinome-
thane thione 12 and 5-(substituted) phenyl-3-(4-hydroxy-3-
Ar1
Ar2
+ Ar2
NHNH2.HCl
O
1 2
a) Ar1=C6H5, Ar2=4-CH3OC6H4 b) Ar1=C6H5, 4-CH3C6H4 c) Ar1=C6H5, Ar2=C6H5 d) Ar1=C6H5, Ar2=4-ClC6H4, e) Ar1=C6H5, Ar2=3-ClC6H4, f) Ar1=C6H5,
Ar2=2-ClC6H4, g) Ar1=C6H5, Ar2=3-BrC6H4, h) Ar1=C6H5, Ar2=4-O2NC6H4, i) Ar1=4-ClC6H4, Ar2=C6H5, j)Ar1=3-O2NC6H4, Ar2=C6H5,
Scheme 1
MR3
H2C
4 toluene
+ +
N
SiMe3 N 6
5
6a; MR3 = SiMe3; 6b; MR3= SiMe2Ph; 6c; MR3= SiPh2But; 6d; MR3= SnBu3
Scheme 2
M. Yusuf, P. Jain
methylphenyl)-4,5-dihydro-1H-1-pyrazolyl-2-methoxyanilino
methane thione 13 were obtained (Ali et al., 2007) by the
reaction between hydrazine hydrate and chalcones 10
followed by condensation with the appropriate aryl
isothiocyanate (Scheme 3).
Synthesis of 5-substituted-3-dimethoxyphosphono-pyra-
zoles 16 and 17 and 2-pyrazolines 20 and 21 has been accom-
plished (Conti et al., 2007) through 1,3-dipolar cycloaddition
of a suitable nitrile imine to monosubstituted alkynes 15 and
alkenes 19 as shown in Scheme 4.
An interesting method ha been reported by Alexander V.
Shevtson et al. (2007) for the synthesis of 1-mono- and 1,2-
diacylpyrazolidines 23 as well as 1-arylsulfonyl-2-pyrazolines
24 which is described in Scheme 5.
The compounds 1-(2,4-dinitrophenyl)-3-(3-nitrophenyl)-5-
(4-substituted phenyl)-2-pyrazolin-4-ones 30 have been
prepared by the oxidation of 1-(2,4-dinitrophenyl)-3-(3-nitro-
phenyl)-5-(4-substitutedphenyl)-4-bromo-2-pyrazolines 29
with dimethylsulfoxide (Mishra et al., 2007). The later has
been released via the reactions sequence which is depicted in
Scheme 6.
An efcient method (Joshi et al., 2008) has been reported
regarding the synthesis of 5-substituted-2-thiol-1,3,4-
oxadiazoles 32 according to the protocol as shown in
Scheme 7.
Braulio Insuasty et al. Insuasty et al. (2008) have
synthesized new bis-3,5-diphenylpyrazolines 36 from the
cyclization of bischalcones 35 with hydrazine hydrate in
acetic acid medium. The later was prepared by the Claisen
Schmidt reaction of bis-acetophenone 35 with suitable
aromatic aldehydes (Scheme 8).
Some biologically signicant bis-heterocycles (Jayashankra
and Lokanatha, 2008) bearing pyrazoline moieties 40
have been synthesized starting from pyrazolyl aldehyde
37 through the reaction sequence as described in
Scheme 9.
Ar1
N
N
CH3COONa/ AcOH/H2O
3
MR3 MR3
N
SiMe3
N
N + N
SiMe3 N
7
Synthetic and biological studies of pyrazolines and related heterocyclic compounds 555

H3C H3C
CH3
OH R OH
N
EtOH/ NaOH EtOH/ NH2NH2.H2O HN OH
H3C + RCHO
9
O R 11
O 8 10
OCH 3
CH3
EtOH EtOH
NCS
NCS

CH3
CH3 OCH3
S CH3
S
N N
NH N OH N OH
NH
R R
12
13

Scheme 3

N PO3Me2 R
HN Me2O3P Me2O3P

Br NaHCO3/ AcOEt
N
+
HC R N
N
R + N
15

14

Me2O 3P 16 17
N Me2O 3P R
PO3Me2
HN
R N
Br R N
H2C
NaHCO3/ AcOEt N + N
+ 19

18
20
R= Ph, COOMe, C4H9, C9H19 21

Scheme 4

Me ArO2S SO2Ar
SO 2Ar
Me N N
N N -ArSO2H
N ArSO2Cl

N DCM/ H2O/ NaOH

24
23
22

Ar= 4-MeC6H4, 4-BrC6H4, 4-FC6H4

Scheme 5

3,5-Diaryl carbothioamide pyrazolines 4446 designed A number of 1,3-diaryl-5-(cyano-,aminocarbonyl-andeth-

as mycobactin analogs (mycobacterial siderophore) were
reported to be potent antitubercular agents under iron limiting
condition (Jayaprakash et al., 2008). These compounds were
obtained via the usual protocol as given in Scheme 10.
1,3,5-Trisubstituted pyrazolines 47 have been oxidized to
the corresponding pyrazoles 48 in high yield with tris(4-bromo-
phenyl)aminium (TBPA) hexachloroantimonate in chloroform
at room temperature (Gang et al., 2008) (Scheme 11).
oxycarbonyl-)-2-pyrazoline, pyrrolo[3,4-c]pyrazole-4,6-dione
and 1,3,4,5-tetraaryl-2-pyrazoline derivatives 52 were prepared
(Abunada et al., 2008) by the reaction of nitrilimine with
different dipolarophilic reagents (Scheme 12).
Recently the Michael accepters (Padmavathi et al., 2008),
1-arylsulfonyl-2-styrylsulfonylethenes 53 have been used as
synthons to develop bis-pyrroles 55, pyrrolyl pyrazolines 56
and pyrrolyl isoxazolines 57 by 1,3-dipolar cycloaddition of
556 M. Yusuf, P. Jain

O O O
EtOH/ NaOH
CH3 + R H HC=CH R

27
O 2N 25 26 O 2N
Br2/ CCl4

Br H2N NH NO 2 O
O 2N

HC-CHBr R
O 2N EtOH
N Br
N O 2N
28
O 2N R

NO 2 R= H, 4-NO2, 4-OCH3, 4-Cl, 4-Br

29

H3C
S O
H3C

O 2N
N
N

O 2N R

NO 2
30

Scheme 6

N N
KOH/ CS2/ C2H5OH N SH
N CONHNH2
O

31 32

Scheme 7

tosylmethyl isocyanide, nitrile imines and nitrile oxides
(Scheme 13).
A facile, InCl3 and/or DABCO mediated synthesis
(Krishna et al., 2008) of 3,5-disubstituted pyrazolines 61 and
pyrazoles 63 and 66 has been achieved by 1,3-dipolar
cycloaddition of ethyl diazoacetate (EDA) with various
activated olens 60 under solvent-free conditions at ambient
temperature (Schemes 14 and 15).
A series of pyrazoline derivatives 69 were designed and pre-
pared (Zhao et al., 2008) by introducing methoxyacrylate
pharmacophore into the scaffold of 1-acetyl-3,5-diarylpyrazo-
line 68 according to the method which is shown in Scheme 16.
The synthesis of aryl-substituted pyrazolines 73 has been
developed by Matthias Beller and co-workers (Alex et al.,
2008) in which phenylhydrazine reacts with 3-butynol 71 in
the presence of a catalytic amount of zinc triate to give
pyrazoline derivatives through the involvement of hydrazone
72 (Scheme 17).
A series of 1-arylmethyl-3-aryl-1H-pyrazole-5-carbohyd-
razide hydrazone derivatives 75 were synthesized by
Bao-Xiang Zhao et al. Xia et al. (2008) (Scheme 18) and the
effects of all the compounds on A549 cell growth have
also been investigated. The results showed that all
compounds had almost inhibitory effects on the growth of
A549 cells. The study on structure activity relationships and
prediction of lipophilicities of compounds showed that
compounds with Log P values in the range of 4.126.80 had
inhibitory effects on the growth of A549 cell and the
hydrazones derived from salicylaldehyde had much more
inhibitory effects.
The analgesic and anti-inammatory properties of novel 3/
4-substituted-5-triuoromethyl-5-hydroxy-4,5-dihydro-1H-1-
carboxyamidepyrazoles 77 (where 3/4-substituent are H/H,
Me/H, Et/H, Pr/H, i-Pr/H, Bu/H, t-Bu/H, Ph/H, 4-Br-Ph/H
and H/Me) were determined (Sauzem et al., 2008) and these
compounds were synthesized in the exploration of the
bioisosteric replacement of benzene present in salicylamide
with a 5-triuoromethyl-4,5-dihydro-1H-pyrazole scaffold
(Scheme 19).
A series of N1-propanoyl-3,5-diphenyl-4,5-dihydro-(1H)-
pyrazole derivatives 81 were synthesized (Chimenti et al.,
2008) from the usual reaction of chalcone 80 with hydrazine
hydrate (Scheme 20).
The cyclocondensation reaction (Almeida da Silva et al.,
2008) of 4-methoxy-1,1,1-triuoro[chloro]-4-(substituted)-
alk-3-en-2-ones 82 and isoniazid (INH) led to the formation
of 3-substituted 5-hydroxy-5-triuoro[chloro]methyl-1H-1-
isonicotinoyl-4,5-dihydropyrazole 83 (Scheme 21).
Synthetic and biological studies of pyrazolines and related heterocyclic compounds 557

O O

CH3
CHO
O R
O

(CH2)n + EtOH/ NaOH (CH2)n

R O
O
34

CH3 R

O O
35
33

N2H4/ AcOH

COCH3
N N

O R

(CH2)n

R
N N
COCH3
36
R= 3,4,5-tri-OMe, 4-OMe, 4-CF3, 3,4,5,tri-OMe, 4-OMe, 4-CF3

Scheme 8

Cl
N

NC
CHO
Br
N
Cl H3C
N
K2CO3/ DMF NC
CHO
N
H3C H
37 38
PhNHNH2/ NaOAc
Cl
N N Ph
N Cl
X N
N Ph
N
H3C Z CAT, EtOH NH
N
NC Z
H3C
H2C
X NC

40
39

X = H, CH3, H, H, H, H, H, H

Y= Ph, Ph, CH3CN, CH2Cl, CH2Br, CH2OH, COOMe, COOEt

Scheme 9

One pot and regioselective synthesis (Bonacorso et al.,
2009) of a novel series of 3-aryl(heteroaryl)-5-triourometh-
yl-5-hydroxy-4,5-dihydro-1H-pyrazolyl-carbohydrazides 86
and bis-(3-aryl-5-triouromethyl-5-hydroxy-4,5-dihydro-1H-
pyrazol-1-yl)methanones 87 have been reported from the
reactions of 4-alkoxy-4-aryl(heteroaryl)-1,1,1-triouro-3-en-2-
ones 85 under the reaction conditions which are shown in
Scheme 22.
Eva Frank et al. (2009) have investigated a highly
diastereoselective Lewis acid induced intramolecular 1,3-
dipolar cycloadditions of alkenyl phenylhydrazones 90
(containing various substituents on the aromatic ring) under
558 M. Yusuf, P. Jain

R O R O R2
R1 R R3
R3 R2
CH3 a b

R4
R1 R1 42 R4
41 N N
43
H
e, b, c
d
c

R1 R
X R3
R1 R R2
R1 R R3
R2

N N R4
R4
S N N
N N S
HN
S HN
H2N
R5
45 R5

R6 X= O, S R6
44 46

a) i: R2, R3, R4-C6H2-CHO, aq. NaOH ii) HCl; b) NH2NH2/ H2O, EtOH c) R5, R6-C6H3-NCS, EtOH d)
NH2NHC(S)NH2, NaOH, MeOH, HCl e) thiophene-2-carboxaldehyde or furfuraldehyde

Scheme 10

R2 R2
hydrazines led to the formation of pyrazolines 103107.
R1 The nature of substitutent on the hydrazine moiety had
R1 TBPA, CHCl3 N
N profound effect upon the products distribution in these
N N reaction. The reaction with methylhydrazine could provide
R3 two regioisomeric pairs of pyrazolines 104, 105 and 107 and
R3 48
47 pyrazoles 103 and 106 (Scheme 25).
The compound 1,2 pyrazolines 113 have been prepared
Scheme 11 (Gowramma et al., 2009) because of the interesting
pharmacological properties associated to these substrates
Br
(Scheme 26). The synthesized compounds were screened for
NH
Ar
Ar
+ H2C R their anti-cancerous activity. It was found that 1-(bis-N,N-
N 51
N NHAr' Ar' (chloroethyl)-amino acetyl) 3,5-disubstituted-1,2-pyrazoline
50
49
showed anticancer activity.
A variety of bis(3-aryl-4,5-dihydro-1H-pyrazole-1-thiocarb-
oxamides) 115 and bis(3-aryl-4,5-dihydro-1H-pyrazole-
Ar 1-carboxamides) 116 were prepared (Barsoum and Girgis,
2009) via the reaction of bis(2-propen-1-ones) 114
Ar= 4-FC6H4, 2,4-Cl2C6H3 N R with thiosemicarbazide/KOH and semicarbazide/AcOH
Ar'= 4-NO2C6H4 N
R= 3-CN, 4-CONH2, 5-COOEt respectively (Scheme 27).
Ar' Novel series of 1-(2,4-dimethoxy-phenyl)-3-(1,3-diphenyl-
52 1H-pyrazol-4-yl) propenone 119 had been prepared (Bandgar
et al., 2009) by the ClaisenSchmidt condensation of 1-(2,4-
Scheme 12 dimethoxy-phenyl)ethanone 117 and substituted 1,3-diphe-
nyl-1H-pyrazole-4-carbaldehydes 118 (Scheme 28). The later
compounds were obtained by the VilsmeirHaack reaction of
fairly mild conditions to furnish andros-5-ene-fused acetophenone phenylhydrazones.
arylpyrazolines 93 in good to excellent yields (Scheme 23). 1-Aryl-4,4-dichlorobut-3-en-1-ones 123 were efciently syn-
The compounds 100 and 101 have been prepared from the thesized (Guirado et al., 2009) by the treatment of acetophe-
cyclization of chalcone 99 with hydrazine hydrate and guani- nones with anhydrous chloral, followed by dehydration and
dine respectively (Solankee et al., 2009). The compounds 99 reductive dechlorination (Scheme 29). The compounds 122
were released from the condensation of ketone 98 with reacted with hydrazine hydrate and methylhydrazine to give
suitable substituted aromatic/heterocyclic aldehydes under 127 and 128 respectively in high to quantitative yields.
alkaline conditions. The compound 98 was obtained via two Mohamed Abdel-Aziz et al. (Shoman et al., 2009) have
step reaction starting from 96 as shown in Scheme 24. reported the synthesis of 3,5-diaryl-2-pyrazoline derivatives
The cyclization reaction (Zsoldos-Mady et al., 2009) of 1- 132 which were obtained via the reaction of various
phenyl-3-ferrocenyl-2-propen-1-one 102 with substituted chalcones 131 with hydrazine hydrate in ethanol. The
Synthetic and biological studies of pyrazolines and related heterocyclic compounds 559

iii

O O O O
S S O O O O
O O Ar S
S Ph i
Ph S Ph
Ar
Ar
O
S
O
+
N
53 H 54 N N
H H
ii 55

iv v

O O O O
O O O O S S Ph
S S Ph Ar
Ar
O
N Ph Ar'
Ar' N N
N N 57
56
H
H
Ar= Ph, 4-MePh, 4-ClPh vi vii

Ar'= Ph, 4-OMePh, 4-ClPh

O O O O
O O O O S S Ph
S S Ph Ar
Ar
O
N Ph Ar' N
Ar' N
N N H
H 58 59

i) 2TosMIC/ NaH/ Et2O+DMSO ii) TosMIC/ NaH/ Et2O+DMSO iii) 4TosMIC/ NaH/ Et2O+DMSO iv)
Ar'-CH=NNHPh/ chloramine-T.3H 2O/ MeOH v) Ar'-CH=NOH/ chloramine-T.3H 2O/ MeOH vi) chloranil/ xylene

Scheme 13

COOEt
R EWG
EWG
N
CH2 R N
60
H
61
R= H, CH(R')OH; R'= H, alkyl, aryl; EWG = COOEt, CN etc.

Scheme 14

COOEt
N2CHCOOEt
Ph CH
N
62 Ph N
H
O 63

COOEt
EtO
N2CHCOOEt
OEt EtOOC CH
N
64 EtOOC N
O H
65 66

Scheme 15
560 M. Yusuf, P. Jain

O
R Br

NH2NH2.H2O/ AcOH N
OH N CH3 MeO COOMe CH3
N
OH K2CO3/ acetone O N O
O R
67 68 O R
O CH3

O
CH3 69

Scheme 16

H3C OH

N H3C
OH NH
N
+ Zn/ catalyst N
THF
HN
NH2
CH 72
70
71
73

Scheme 17

2
2 R
R

X
X

ArCHO/ EtOH
N N
N N
NH
NH N Ar
NH2
1 O
1 O R
R 74 75
1 2
R = H, Cl, OMe; R = H, Cl, t-Bu, X= C, N

OH OMe
O O
Ar = , , ,
O

Scheme 18

1
2 1 unsaturated ketones of estrone 3-methyl and 3-benzyl ether
2 R R R
R with nitrilimines stereoselectively furnished two regioisomers
F 3C
OR NH2NHCONH2.HCl, MeOH, Py
N of new condensed pyrazolines 140 and 141 in a ratio of 2:1
O N
CF3
HO (Scheme 31).
76 O The reaction (Khode et al., 2009) of various substituted 3-
NH2
77 aryl-1-(3-coumarinyl)propan-1-ones 147 with phenylhydrazine
in the presence of pyridine led to the synthesis of 5-
Scheme 19 (substituted)aryl-3-(3-coumarinyl)-1-phenyl-2-pyrazolines 148
(Scheme 32).
1-[(Benzoxazole/benzimidazole-2-yl)thioacetyl]pyrazoline
compounds 132 were further converted to various N- derivatives 154 were obtained (Kaplancikli et al., 2009) by
substituted derivatives 133138 according to the reaction reacting 3,5-diaryl-1-(2-chloroacetyl)pyrazolines 153 with 2-
conditions and protocol as given in Scheme 30. marcaptobenzoxazole/benzimidazole. The later compounds
Effective syntheses of endo- and exocyclic a,b-unsaturated were released starting from benzaldehydes 149 and 150
ketones as CC dipolarophiles (Mernyak et al., 2009) were according to the reactions sequence which are depicted in
carried out in the estrone series. 1,3-dipolar cycloadditions of Scheme 33.
Synthetic and biological studies of pyrazolines and related heterocyclic compounds 561

1 R
1 The reaction (Singh et al., 2009) of dibenzalacetone 165
R R
with hydrazine hydrate and formic acid yielded a novel
R
Ba(OH)2.8H2O, EtOH 2-pyrazoline 166 (Scheme 37).
+ The reaction of cholest-5-en-7-one 167 with thiosemicarba-
zide in sodium ethoxide (Scheme 38) afforded 20 -thiocarba-
O
O CH3 O
79
H
80
moyl-cholest [5,7-cd] pyrazoline 168, [X=H] 20 -
78
thiocarbamoyl-3b-acetoxycholest [X=OAc] pyrazoline 168,
C2H5COOH, NH2NH2.2H2O and 20 -thiocarbamoyl-3b-chloro cholest pyrazoline [X=Cl]
168 respectively (Shamsuzzaman Khan and Alam, 2009).
R
R
1 The synthesis of pyrazolines 170 was carried out to study
the effect of bromine on the biological activity (Kumar
et al., 2009). These compounds were brominated by using
N N bromine in acetic acid (Scheme 39). All synthesized
O
compounds were tested for antimicrobial activity against
H3C gram positive and gram negative bacteria. It was found that
81
most of the compounds were found active against all
bacteria except Escherichia coli.
Scheme 20
The substituted carboxylic acid hydrazides 171 reacted with
ethenetetracarbonitril in dimethyl formamide (Scheme 40) with
1 the formation of diacylhydrazines 172 and 5-amino-1-substiut-
R
O
ed pyrazole-3,3,4-tricarbonitriles 173 (Abdel-Aziz et al., 2009).
OMe HO
NH2NHC(O)C5H4N, MeOH N A new series of 1H-3-(40 -substituted phenyl)-5-(600 -methoxy
R
1 CX3 N napthaline)-2-pyrazolines 179 and 1H-3-(40 -substituted phe-
CX3
nyl)-5-(600 -methoxy napthaline)-2-isoxazolines 178 have been
O
82 synthesized (Jadhav et al., 2009) from the reaction of 1-(40 -
N
R1= H, Me, Ph, 4-MePh, 2-thienyl, 2-furnyl, 4-MePh, 2-thienyl, 2-furyl substituted phenyl)-3-(600 -methoxynapthaline)-2-propene-1-
83
one 177 with hydrazine hydrate and hydroxylamine
X= F, Cl
hydrochloride respectively (Scheme 41).
Scheme 21 The enaminonitrile 181 was used as the key intermediate for
the synthesis of polyfunctionally substituted heterocycles pyr-
azoles 184 (Scheme 42) incorporating benzothiazole 183 moi-
R ety via its reactions with some N-nucleophiles (Bondock
O
F 3C et al., 2009).
N
EtOH
HO N Recently Sheena Shashikanth et al Rai et al. (2009) have
H2NHN NHNH2
reported the synthesis of a series of novel 2-[1-(5-chloro-2-meth-
84 O NH
+ 86 NH2 oxy-phenyl)-5-methyl-1H-pyrazol-4-yl]-5-(substituted-phenyl)-
[1,3,4]oxadiazoles 189 from cyclization of substituted benzoic
CF 3 O F 3C
O OMe HO OH acid N-[1-(5-chloro-2-methoxy-phenyl)-5-methyl-1H-pyra-
F 3C
EtOH N N zole-4-carbonyl]-hydrazide 188 with phosphorousoxychloride
R
85 N N (Scheme 43).
R R
87 A new class of heterocycles, substituted pyrazoles 193, isox-
R = H, Me, Ph, 4-OMePh, 4-ClPh, 4-BrPh, 4,4'-biphenyl, 2-thienyl, 2-furyl
azoles 192, pyrimidines 194, thioxopyrimidines 195 were
released from the Michael adducts 190, 2-(1,2-diaroylethyl)
Scheme 22
malononitrile and 2-(1,2-diarylsulfonylethyl) malononitrile
(Padmaja et al., 2009) which subsequently underwent cyclo-
condensation with the appropriate nucleophiles to produce
Recently, N1-acetyl-5-aryl-3-(substituted styryl)pyrazolines the nal compounds (Scheme 44).
158 have been prepared (Pathak et al., 2009) from the cyclo- The compounds 1-(4-methylcoumarinyl-7-oxyacetyl)-3,5-
condensation of 1,5-substituted diphenyl-1,4-pentadien-3- dimethyl-4(arylazo)pyrazoles 198 and 1-(4-methylcoumarinyl-
ones 157 with hydrazine hydrate and a cyclizing agent such 7-oxyacetyl)-3-methyl-4-(substituted phenyl) hydrazono-2-pyr-
as acetic acid in ethanol (Scheme 34). azolin-5-ones 199 were prepared (Manojkumar et al., 2009)
Tricyclic fused pyrazolines 160 have been synthesized according to the protocol which is described in Scheme 45.
(Scheme 35) from the reaction of 3-arylidenechromanones/thi- The thiocarbamoyl derivative 200 was reacted with hydra-
ochromones 159 with (4-carboxyphenyl)hydrazine in hot zine hydrate (Fadda et al., 2009) to afford the pyrazole
anhydrous pyridine solution (Levai and Jeko, 2009). derivatives 201 (Scheme 46).
The oxidation of 1,3,5-trisubstituted 4,5-dihydro-1H-pyra- A new series of chalcones 205 were synthesized (Revana-
zoles 161 to the corresponding pyrazoles 162 has been achieved siddappa et al., 2010) from the condensation of simple
by utilizing tetrabromine-1,3,5,7-tetrazatricyclo[3.3.1.1]decane aldehydes with substituted acetophenones under alkaline
complex, Br4-TATCD, in glacial acetic acid under microwave medium (Scheme 47). The cyclization reaction of chalcones
irradiation and conventional thermal condition (Scheme 36) with 206 in the presence of glacial acetic acid provided 207.
at room temperature with excellent yields (Azarifar and a-Pyranochalcones 208 and pyrazoline derivatives 210 and
Khosravi, 2009). 214 were prepared (Warane et al., 2010) to discover chemically
562 M. Yusuf, P. Jain

CH3
O
CH3

CH3 CH3
CH3 CH3

O
AcO
AcO 89
88
RNH2NH2/ MeOH

R
N
CH3
NH
CH3 CH3 BF3.OEt2/ DCM
CH3 CH3
N
AcO
90 N AcO
H R 91 R
BF3.OEt2/ DCM
N

CH3 CH3
CH3
H
CH3 CH3
+ N AcO
N Ts
93
BF 3
AcO
92

CH3 CH3

AcO
94

Scheme 23

Cl Cl HN COCH3
H2N COCH3

N N Acetone N N N N
+ H2N C2 H5
i) 0-5 oC ii) Room temp.
DMF, reflux

Cl 96 H3CH2CHN N NHCH2CH3 NHCH2CH3

Cl N H3CH2CHN N
97 98
95

HN R RCHO/ DMF/ KOH

N N
N N H
NH2NH2. H2O
H3CH2CHN N NHCH2CH3
HN COCH=CHR
100

N N

H3CH2CHN N NHCH2CH3

NH2 99
H2N NH2
.HNO3
N N NH

HN R

N N

H3CH2CHN N NHCH2CH3
101

Scheme 24
Synthetic and biological studies of pyrazolines and related heterocyclic compounds 563

R
c N N
R
Fe
N N
R'
Fe
a / R'NHNH2 103
b R

104

O
Fe
d
102

a / R'NHNH2
OH

N N
N N
Fe
CH3 N N
Fe CH3
Fe
O 2N
105
107
106
R= H, H, H, H, H, p-OH, p-OAc, p-OAc, p-OAc
R'= H, Ac, Ph, p-NO2Ph, Me, Ph, Ph, Py, p-NO2Ph

Reaction conditions A) Hydrazinolysis with RNHNH2: EtOH, RT; AcOH, reflux; AcOH-EtOH-H2O, reflux;
MeOH, 40oC; toluene, reflux B) Acetylation with Ac2O in pyridine at 0oC; C) Dehydroaromatization of
pyrazolines to pyrazoles with Cu(NO3)2.3H2O under sonication, DCM for; b) NBS, CCl4, reflux: c) DDQ, DCM,
RT; toluene, reflux, partial oxidation during th reaction D) 11: by product

Scheme 25

O O O
R1 H + R2 CH3 R1 CH=CH R2
109 110
108

R2 R1 R2 R1
C6H6/ ClCH2COCl

N N COCH2Cl N N
112 H
CH 2CH 2OH 111
Pyridine HN
CH 2CH 2OH

R2 R1
CH2CH2OH
N N CH2 N
O CH2CH2OH
113

R1= C6H5, C6H4Cl, C6H4NO2, C4H3O, C6H4OH, C5H4N

R 2 = C 6 H5 , C 6 H5 , C6 H 5 , C 6 H5 , C6 H 5 , C 6 H5

Scheme 26

diverse anti malarial leads (Schemes 48 and 49). This is the rst 3,5-Diaryl pyrazolines analogs 217 were synthesized
instance wherein chromeno-pyrazolines have been found to be (Karuppasamy et al., 2010) from the reaction of 215 with
active antimalarial agents. hydrazine hydrate and evaluated for their monoamine
564 M. Yusuf, P. Jain

R R

114 O
O
S O
NH2 NH2
H2N NH AcOH H2N NH
KOH, EtOH

A
A

R
R R R
N N
N N N N
N N NH2
NH2 H2N
H2N O
S O
S 116

115

A= 2-O(CH2)2O-2', 4-O(CH2)2O-4'

R= Ph, 4-ClC6H4, 4-FC6H4, 4-H3CC6H4, 2-thienyl, Ph

Scheme 27

R
O O

CH3 N N N
R EtOH, NaOH, rt
H3C CH3 + H3C
O
CH3 N
O O O
117 CHO
119
118
Cl
H 3C H 3CO Cl Br H Cl Cl Cl H CO OCH 3
H 3

R= H 3C , H 3C , H 3C , H 3C , H 3C , H 3C , H 3C , H 3C , H 3C

H 3C H 3C H 3C H 3C H 3C H 3C H 3C H 3C
H 3C

Scheme 28

O O
O OH
Cl3CCHO
Ar
Ar CH3 Ar CCl3
120 CCl3 122
121
H H2N-NH2 H+
N N
O
Ar CHCl2 O
125 Ar
CH3 CHCl2 Ar
N N 124
CCl2
123
MeHN-NH2
Ar CHCl2 H
126 H2N-NH2 N N

Ar CCl3
O
127
CH3
Ar
CCl3 N N
122
Ar CCl3
MeHN-NH2
128

Ar= C6H5, 4-F-C6H4, 4-Cl-C6H4, 4-Br-C6H4, 4-CH3-C6H4, 4-CH3O-C6H4, 4-NO2C6H4, 4-Ph-C6H4, 2-C10H7, 2,4-(CH3)2C6H3

Scheme 29
Synthetic and biological studies of pyrazolines and related heterocyclic compounds 565

R1 R1
R1
O O
R2 R2 R2
R2 Ar R2
CH3 a b
+ Ar CHO c

R1 130 R1 e
131 N N
129 Ar N N Ar N
H 132 Ar N

d O CH2Br O CH2ONO2
133 134
R1
R1 R1
f

R2 R1
R2 R2
e R2
N
Ar N N N
Ar N g Ar N
N
O CHONO2 Br Ar N
O O NH
CH3 CH3
O NH
136 135
CH3
CH3
138 NOH
137 O
a)NaOH,EtOH; b)NH2NH2.H2O, EtOH; c) BrCH2COBr, K2CO3; d) CH3CH(Br)COOH, ClCOOEt, Et3N; e) AgNO3,
CH3CN, f) p-NH2 Acetophenone, K2CO3, acetone g) NH2OH. HCl, EtOH

Scheme 30

CH3 O CH3 O
CH3 O
H
Cl COOEt H
H3C NH N p-Tol
COOEt N

1
Et3N, toluene, reflux H N
N + H N
R O 1
or AgOAc, toluene R O p-Tol 1
140 R O COOEt
139
141
CH3 O
O p-Tol
CH3
N
Cl
H3C NH N N
CH2 COOEt

Et3N, toluene, reflux

1
R O COOEt
1 or AgOAc, toluene 143
R O
142 R1= Me, Bn

Scheme 31

O
CHO O O
a
CH3
+
OH H3C O CH3 O
145
O
146
144

N N O
substituted Aryl/phenyl
H substituted Aryl/phenyl
H H
O c
O O
O
148
147
Reaction conditions: a) Piperidine, stir, rt, 20 min. b) Ar-CHO, piperidine/butanol c) hydrazine derivative, pyridine, reflux

Scheme 32

oxidase (MAO) inhibitory activity (Scheme 50). These New pyrazolines derivatives 223 and 224 have been syn-
compounds were found reversible and selective toward thesized (Hussain and Sharma, 2010) according to the
MAO-A with selective index in the magnitude of 103105. protocol as given in Scheme 51. In order to introduce
566 M. Yusuf, P. Jain

O O O
R2
H R2 H
NaOH
+
R1 R3 R3 151 R1
149 150
NH2NH2

R2 R2

R3 R3
N(CH3)3

R1 N R1
N
N N
H
152
O 153 Cl
R4 N
SH
K2CO3
X

R2

R3

N R1
N
N R4
S
O
X
154

Scheme 33

O X
O NaOH/ EtOH/ U. V.
X
X
CH CH CH CH CH
CHO +
H3C CH3 157

155 156 NH2.NH2.H2O + CH3COOH

U. V. Method/ EtOH

X X
CH CH CH
N N

C O
X= H, 4-Cl, 4-OCH3, 2-OCH3, 3,4,5-(OCH3)3, 4F, 2-Cl, 3-F, 2F, 2,4-(Cl2) CH3
158

Scheme 34

X R
X R
HOOC NH NH2

Pyridine
H
O N N
159

COOH
where X= O, S, SO2
160

R= H, Me, MeO, F, Cl, Br

Scheme 35
Synthetic and biological studies of pyrazolines and related heterocyclic compounds 567

1 2 1 2 their monoamine oxidase (MAO) inhibitory property

R R R R
Br4-TATCD, AcOH, rt or MW (Scheme 52). All the molecules were found to be reversible
and selective inhibitor for either one of the isoform (MAO-A
N N N N
Ph Ph or MAO-B).
161 162
1 2
A series of 1,3,5-trisubstituted pyrazolines 234 were synthe-
where R and R are different aromatic substitutents
sized (Scheme 53) and evaluated for in vitro antimalarial
Scheme 36 efcacy against chloroquine sensitive (MRC-02) as well as
chloroquine resistant (RKL9) strains of Plasmodium falcipa-
rum (Achraya et al., 2010). Some of the compounds showed
better antimalarial activity than chloroquine against resistant
methyl group at C-16 instead of C-13, dehydocestus lactone strain of P. falciparum and were also found active in in vivo
was allowed to react with an ethereal solution of diazoethane. experiment.
The synthesis (Sahoo et al., 2010) of novel 3,5-diaryl The reaction of pregnenolone 235 with substituted benzal-
pyrazolines 226230 have been investigated in order to study dehydes resulted in the formation (Banday et al., 2010) of

O
O
NaOH/ EtOH
CH CH C CH CH
CHO + 165
H3C CH3
163 164
NH2NH2/ HCOOH

H N
N
O
166

Scheme 37

C8H17 C8H17
CH3 CH3

CH3 CH3
TSC/ NaOC2H5

X O X
HN N
167 S
H2N
X= H, AcO, Cl 168

Scheme 38

R1 R1
R4 Br R4
R2 R2

N R5 N R5
R3 N R3 N
Br2/ AcOH
NH NH
S S

R R
169 170

R= CH3, R1=R2=R3=R4=R5=H; R=OCH3, R1=OH, R2=R3=R4=H, R5=Cl; R=OCH3, R1=H, R2=Cl, R3=R4=H, R5=Cl;
R=CH3, R1=H, R2=CH3, R3=H, R4= R5=OCH3; R=OCH3, R1=OH, R2=R3=R4=H = R5

Scheme 39
568 M. Yusuf, P. Jain

R
H
DMF O N CN
R NH NH2 N
R NH NH R + CN
O O O
171 172 H2N CN
173

CH3

R= , S
CH3 , ,
CH3 N CH3
R H
N
H
N CN
O N
CN
H
NH
CN
174

Scheme 40

O
R R
+ H
KOH/ MeOH
CH3

O O
175 177
176 OCH3
MeOH, NH2NH2.H2O OCH3
NH2OH. HCl

R R

N N
N O
H

OCH3 OCH3
179
178

Scheme 41

N O Me2NCH(OMe)2 N O EtOH/ RNHNH2 N O

CN CN CN
S NH S NH S NH
180 181 NMe2 NHR NH NMe2
182

N O
NH2 Pyridine N O
S NH
CN
N R S NH
R = H, Ph N
NHR NH
184
183

Scheme 42

the corresponding benzylidine derivatives 236 and nally the
reaction of the later with hydrazine hydrate provided
pyrazoline 237 as the nal product (Scheme 54).
Novel pyrazolines 242 and 245 were synthesized (Chen
et al., 2010) from the cyclization of chalcone 240 and 243
with hydrazines 241 and 244 respectively according to the
protocol as given in the Scheme 55.
Chalcones 248 were prepared from substituted acetoph-
enones and substituted benzaldehydes (Scheme 56) and
condensed with hydrazine hydrate (Venkataraman et al.,
2010) in methanol to yield the corresponding pyrazolines
249.
Some new pyrazoline derivatives 254 were synthesized
(Ramesh and Sumuna, 2010) by reacting chalcones 252 of
Synthetic and biological studies of pyrazolines and related heterocyclic compounds 569

O O
NH2 1
O CH3 NH R
2
N N R R
CH3 CH3
N hydrazine hydrate/ EtOH N
H3CO H3CO +

Cl Cl O Cl
186 187
185

DCM/ pyridine

R
R
1
R 1
N R
N 2 O
R NH 2
O NH R
O
POCl3/ 120oC N CH3
N CH3 N
N R= H, Cl, F, NO2, CH3
H3CO
H3CO R1= Cl, F, Br, CH3
R2= H, Cl
Cl
Cl 188
189

Scheme 43

O
N O
Ar
Ar
H2N NH N N
191
O O
H2N NH2
Ar
Ar iii O
O Ar
ii Ar
192 NC CN
O 193 O

Ar
Ar = Ph, 4-MePh, 4-Cl-Ph Ar vi
O
190 H3C CH3
iv O N N
v
O HN NH
O
N N S Ar
Ar

H2N O
NH2 N N 194
O
Ar H2N
iii) NH2OH.HCl/ NaOMe
Ar NH2
O iv) NH2CONH2/ NaOMe
O Ar v) NH2CSNH2/ NaOMe
196 Ar vi) MeNHCONHMe/ NaOMe
O
195
i) CH2(CN)2, K2CO3 ii) NH2NH2.H2O/ NaOMe

Scheme 44

2-acetyl thiophene 250 with phenyl hydrazine hydrochloride in organocatalyzed aza-Michael/transimination domino reaction
the presence of alcohol and pyridine (Scheme 57). between hydrazones and enones 262 making use of a mixture
An efcient method has been established for the synthesis of heterogeneous resin-bound acid/base reagents (Scheme 59).
(Kasabe and Kasabe, 2010) of new pyrazoline derivatives A series of new succinyl spacer bis-(3,5-substituted 2-pyraz-
260 which were obtained from the reaction of chalcone 259 olines and 1H-pyrazoles) and the non-symmetrical 2-pyrazo-
with thiosemicarbazide under alkaline alcoholic condition. lines derivatives had been synthesized (Bonacorso et al., 2010).
The intermediate 259 was released from the reaction The succinyl substituted bispyrazoles 266 were obtained from
sequence as shown in Scheme 58. the cyclocondensation reactions of 4-substituted 4-alkoxy-
The synthesis (Gembus et al., 2010) of biologically impor- 1,1,1-trihaloalk-3-en-2-ones 264 (where the 4-substituents are
tant 3,4-substituted pyrazolines 263 has been achieved by an H, Me, Ph, 4-FC6H4, 4-ClC6H4, 4-OMeC6H4, 4-NO2C6H4,
570 M. Yusuf, P. Jain

O
O O O
H2N
NH

197
O CH3 CH3
R O CH3
O
O R
N N
O
CH3 N N
AcOH
AcOH CH3

O O
CH3 O
R
R N
N
NH N O O O
N N O O O N
N
H3C
H3C

199 CH3
198 CH3

Scheme 45

O O
O O
Ph CH3
Ph EtOH
CH3

+ NH2NH2
TEA HNPh NHNH2
SH 202
HNPh
O
200
CH3
Ph
N
HNPh
N
H
201

Scheme 46

OHC CH3CO

NaOH/ EtOH
+ CH=CHCO
R R'
R' 205
R 204
203 CONHNH2

AcOH
N

206

R R'
N N
O

N
207

Scheme 47
Synthetic and biological studies of pyrazolines and related heterocyclic compounds 571

N N CH3 O
O O
CH3 a CH3
CH3 CH3
O O O O
O O Ga3
Gc 208
209 b

N N
O
CH3
CH3
O O
O
210

Reagents and conditions a) NH2NH2.H2O, AcOH; b) MeOH, PhNHNH2, AcOH

Scheme 48

O
O H

CH3 O a

+ F
F HO 213
HO
212 b
211

N N CH3

HO F
214

Reagents and Conditions a) NaOH/ MeOH, rt b) NH2NH2.H2O/ AcOH

Scheme 49

O
HO HO
NH2NH2.H2O, EtOH,reflux R-C6H4-NCS, MeOH

HO X X
X
215 N N N N
H S
216
HN
R

217

Scheme 50

1-naphthyl and 2-furyl) with succinic acid dihydrazide in
ethanol as solvent under the controlled reaction conditions
(Scheme 60).
The complexes of 2-(8-quinolinol-5-yl)-amino methyl-3(4-
methyl phenyl)-5-(phenyl)-pyrazoline 272 with Cu(II), Mn(II)
and Zn(II) have been synthesized (Patel et al., 2010)
according to the method which is described in Scheme 61.
Recently, B. Vibhute et al. Mokle et al. (2010) have pre-
pared a series of 2-pyrazolines 274 from the cyclization
reaction of a,b-unsaturated ketone 273 with hydrazine
572 M. Yusuf, P. Jain

CH2 CH2 CH2 CH2

Heat
CH2N2

H2C H2C H2C + H2C

O CH2 O O O
N N CH3

O O O O
221
218 220 222

CH2N2 C2 H5 N2
C2 H5 N 2

CH2 CH2 CH2

CH3
CH3
H2C H2C H2C

O O O
N N N N N N
O O O
224
219 223

Scheme 51

OH O R
OH R OH R
d
e
R'
R'
R' N N
225 N N
S
H2N NH
HO NH
a 228
229

OH R
OH R
b
R'
R'
N N
N N O
226 H

230
OH R

R'
N N
S O
O

2
R
227

R=OH, H; R1= H, OH; R2= CH3

a) NH2NH2.H2O, EtOH; b) PhCOCl, pyridine, reflux, c) R2-C6H4SO2Cl, THF d) thiosemicarbazide, EtOH e) CH3I/ NH2OH

Scheme 52

hydrate/phenyl hydrazine using triethanolamine as the solvent
(Scheme 62).
New pyrazolines 278 were synthesized starting from the
condensation of substituted aldehydes with substituted ace-
tophenones in the presence of alkali to yield chalcones 277.
The resulted chalcones were further reacted with phenyl hydra-
zine hydrochloride in ethanol and pyridine (Das et al., 2010) to
provide 278 as the nal products (Scheme 63).
New pyrazolines have been obtained from the condensation
of chalcones of 41-piperazine acetophenone with phenyl hydra-
zine hydrochloride (Rahaman et al., 2010).
The aldol condensation reaction (Nassar, 2010) between 3-
indolaldehyde 279 and 4-methoxyacetophenone 280 afforded
chalcone derivatives 281 which were further reacted with the
cyclizing agents such as hydrazine hydrate and phenyl hydra-
zine to yield pyrazolines 282 and 281 (Scheme 64).
The heterocyclic compounds 286 have been synthesized
(Gupta et al., 2010) starting from the ClaisenSchmidt reac-
tion of aryl methyl ketones 284 and 4-chlorobenzaldehyde 285
to give 286. The reaction of chalcone with phenylhydrazine
in glacial acetic acid using ultrasonic irradiation led to the
formation of 1,3,5-triphenyl-pyrazolines 287 (Scheme 65).
Synthetic and biological studies of pyrazolines and related heterocyclic compounds 573

R4
O R5 O O
R4 HO R5 R3 NH2
CH3 H MeOH/ NaOH NH
+ +
HO R3 R1 R2
N
231 R2 O R1
232 233

n-butanol

R1 = Cl, H, Me, Br, OMe R4

HO
R2= NO2, H, Me, Br, OMe, OEt
R5 R3
R3 = Cl, H, Me, OMe
R4 = H, OMe, Br
N R2
R5 = H
N
R1
O

234
N

Scheme 53

H3C O
O
CH3 R
CH3 OHC

CH3 R CH3

EtOH/ KOH
HO HO 236
NH2NH2.H2O/ AcOH
235

CH3
O

N R
N

CH3

CH3

HO
237

Scheme 54

An efcient and simple procedure has been developed
(Azarifar et al., 2010) for the oxidation of 1,3,5-trisubstituted
4,5-dihydro-1H-pyrazoles 289 and isoxazoles 289 to their
corresponding aromatic derivatives which was promoted by
bis-bromine-1,4-diazabicyclo[2.2.2]octane complex (DABCO-
Br2) in acetic acid at room temperature (Scheme 66).
1-Benzimidazolyl-3-aryl-prop-2-ene-1-ones 291 have been
transformed into N1-substituted pyrazoline derivatives
(Rajora et al., 2010) by reacting with phenyl hydrazine,
hydrazine hydrate in the presence of formic acid under
solvent free microwave induced protocol to give 292 and 293
respectively while the reaction of 291 with thiosemicarbazide
under anhyd. K2CO3 could provide 294 (Scheme 67).
The chalcones 297 and 300 were released (Babu et al., 2007)
starting from 2-acetyl benzofuran 295 and further condensed
with different aromatic acid hydrazides to give the
corresponding pyrazolines 298 and 301 (Scheme 68).
Pawan K. Sharma and co-workers (Sharma et al., 2010)
have reported the synthesis of new pyrazolylpyrazolines 306.
These compounds were obtained by the reaction of appropri-
ate chalcones 304 with 4-hydrazinobenzenesulfonamide
hydrochloride in alcoholic medium (Scheme 69).
The pyrazoline compounds 309 and their 1-acetylated
derivatives (Congiu et al., 2010), bearing a 3,4,5-trimethoxy-
phenyl moiety combined with a variety of substituted phenyl
rings were obtained according to the reaction sequence as
shown Scheme 70 and these compounds were also evaluated
for antitumor activity. The results of the in vitro assay
against a non-small cell lung carcinoma cell line (NCI-H460)
showed several compounds to be endowed with cytotoxicity
574 M. Yusuf, P. Jain

O
O
N NaOH, EtOH N
O
H +R CH3
N
+ NH
NH2
S
239
238 241
240

EtOH, HCl R

N
S

N
N N

242 R
O
NH NH2
N O
+ H25C12 N
EtOH, HCl

O
244 C12H25

243 O N O
R

N
N N

245 R
R= H, OCH3, Cl

Scheme 55

CHO
R1 R2 R1 R2 R3
+ NaOH/ MeOH
CH3 CH=CH

O O 248
R3
246 247

R1= H, 4-OCH3, 4-CH3, 4-OH NH2NH2xH2O/ MeOH

R2= 2-OH, H
R4= 4-N(CH3)2 , 4-OCH3, 4-Cl, 4-NO2

R2 R3
R1

N N
H
249

Scheme 56

in micromolar to submicromolar range, depending on the pyridine-4-yl)-(1,3,4-oxadiazol-2-ylthiomethyl)-pyrazole-5-one

substitution pattern and position of aryl rings on 4,5-
dihydropyrazole core. Potent and selective activity was also
observed in the NCI 60 human cancer cell line panel.
An efcient preparation of compounds 314 has been
reported with the objective of discovering the novel (Scheme
71) and potent anti-inammatory agent (Chandra et al.,
2010). The compound 1-(20 ,40 -Chloroacridine-90 -yl)-3-(50 -
314 showed better anti-inammatory and analgesic activities at
the three graded dose of 25, 50 and 100 mg/kg p.o.
A series of 1-acetyl/propyl-3-aryl-5-(5-chloro-3-methyl-1-
phenyl-1H-pyrazol-4-yl)-2-pyrazolines 318 were synthesized
(Girisha et al., 2010) in one step by condensing suitably
substituted propenones 317 with hydrazine in the presence of
acetic/propionic acid (Scheme 72).
Synthetic and biological studies of pyrazolines and related heterocyclic compounds 575

KOH
CH3 + R CHO CH=CH R + HN .HCl
S S NH2
O 251 O
250 252 253

Pyridine/ EtOH

R
S
N N

254

Scheme 57

O O

NH2 MeOH NH
H2N NH2
+ H2N
N 256 N 257
255
NaNO2, E. A. A.

O O

NH NH
N N
N NaOH N
N N
O H3C O
O
O
258
CH3

NaOH/ EtOH/ NH2NHCSNH2

259 O

R = 2-NO2, 4-NO2, 4-Cl, 3-OCH3, 4-OCH3 NH

N
N N

N N
H NH2
S
260

Scheme 58

1
R O
O
O
PS-TBD/ PS-TsOH/ MeCN N N
Piperidine/ CH2O/ AcOH 3 CH2
3 R 3
R NHCOR
1
R
4 N
4 R 4
R H4 C6OMe R
261 262 263

Scheme 59

The reaction of 2-cyano-N-(9,10-dioxo-9,10-dihydro- dimethylsulphate afforded (Gouda et al., 2010) the

anthracen-2-yl)-acetamide 320 with phenyl isothiocyanate/ corresponding ketene N,S-acetal 322 which upon treatment
576 M. Yusuf, P. Jain

R N O O Ph N O O
O OMe N R
i
N NH2NH2 ii N N
(CH2)2 (CH2)2
F 3C OH OH
R F 3C OH
F 3C Cl 3C
264 265
266

R = Me, Ph, 4-OMePh, 4-NO2Ph

i= (NH2NHCOCH2)2, EtOH ii) CCl3C(OMe)R, EtOH

Scheme 60

OH-
R' COCH3 + OHC R R' COCH CH R
269
267 268
NH2NH2.H2O

R' R

N N
270
H

H2N OH
HCHO
N

R' R

N N
271 NH OH

Metal Acetate N
R' R
OH2
N N
NH O
N
M
N NH
O
N N
OH2
272 R R'

R= H, CH3; M = Cu+2, Mn+2, Zn+2

Scheme 61

R1 R1
CH3
R2 R R2 R
TEA, R4NHNH2
CH3
N
R3 Cl R3
N N
O N
273 R4 Cl
274

R = OH, H R1 = I R3= I, Cl; R4= H

R2= H, OH

Scheme 62

with hydrazine hydrate and 4-aminoantipyrine resulted in the
formation of pyrazole derivatives 323 and 324 respectively
(Scheme 73).
The treatment (Abu-Surrah et al., 2010) of 5-hydrazino-1,3-
dimethyl-4-nitro-1H-pyrazole 325 with substituted benzalde-
hydes 326 in methanol gave new substituted Schiff base
ligands 327 (Scheme 74).
Recently, synthesis and pharmacological evaluation of a
new class of human carbonic anhydrase (hCA) inhibitors,
1,5-diarylpyrrole-3-carboxamides 331 have been reported
(Gluszok et al., 2010) and these derivatives were prepared by
a solid-phase strategy involving a PS(HOBt) resin (Scheme 75).
A series of novel 5-aryl-1-arylthiazolyl-3-ferrocenyl-pyrazo-
line derivatives 335 have been synthesized (Liu et al., 2010) by
Synthetic and biological studies of pyrazolines and related heterocyclic compounds 577

R O O
R
CH3 + CHO
Alc. NaOH CH CH
O 277 O
275 276 NH
NH2

N
N O

278

Scheme 63

CHO
O
OMe
+ MeO CH3
N N
H H
279 280
281
RNHNH2/ EtOH NH2NH2/ RCOOH

O
N N
R N N
R

OMe OMe

N N
H H
282 283
R= H, Ph
R= Me, Et

Scheme 64

CH3CO OHC O

ultrasound irriadation/ NaOH

+
286 Cl
X X
Cl
284 H 2NHN
285

ultrasound irriadation/ AcOH

X N Cl
N

x= 4-H, 4-Br, 4-Cl, 4-F, 4-CH3 287

Scheme 65
578 M. Yusuf, P. Jain

1
1 2 QSAR modeling was done on a variety of 1-N-substituted
2 R R
R R DABCO-Br2/ AcOH
thiocarbamoyl-3-phenyl-2-pyrazolines 335a (Adhikari et al.,
2010). The best model was obtained by using PLS technique
N X N X with R2A and R2CV value of 88.50% and 82.90%,
289
288 respectively. Amoebicidal activity may increase when Wang
Ford charges at atom numbers 6 and 12 have large positive
X= NPh, O
values. Number of six-membered ring and sum of KierHall
Scheme 66 electrotopological states may also increase the amoebicidal
activity when these have large positive values. Increasing
value of rotatable bond fraction, approximate surface area
the reaction of ferrocenyl chalcone 383 and thiosemicarbazide and mean atomic polarizability scaled on carbon atom may
followed by the reaction with 2-bromo-1-arylethanone in be detrimental for antiamoebic activity. Decrease in values of
4890% yields (Scheme 76). electrostatic potential charges at atom numbers 1 and 12
To nd structural requirements for more active antiamoe- may be conducive for activity and the electrophilic attacks
bic agents than metronidazole, the synthesis and comparative may be favorable at these positions.

Ar
N N
ArCHO, M. W.
CH3
N N
H O 291 H O
290 Anhd. K2CO3; NH2CSNHNH2
PhNHNH2
NH2NH2/ HCOOH

N N N
Ar Ar
Ar
N N N N N NH2
Ph N N N N
H H H
CHO
292 293 294
S

Scheme 67

O COCH3
O COCH3 295
295
+
+ O CH2COOH

OHC
OHC O CH2COOH 299

296 aq. NaOH

aq. NaOH

O CH2COOH

O COCH=CH
300

O COCH=CH O CH2COOH +
297
ArCONHNH2
+
ArCONHNH2
AcOH

AcOH
O CH2COOH

O
N N
O CH2COOH
O COAr
N N 301
COAr
298

Scheme 68
Synthetic and biological studies of pyrazolines and related heterocyclic compounds 579

Ph
N N
Ph R1
N N SO 2NH2
+ MeOH/ NaOH/ THF R

R
+
CHO
302
COCH3 O
NHNH2.HCl
303
R1 305

304

C2H5OH/ AcOH, reflux

Ph
N N

H2NO2S

R
N
N

R1
306

R = H, H, H, H, CH3, CH3, CH3, F, F, Br, Br

R1= H, CH3, F, Br, H, CH3, F, H, F, H, F

Scheme 69

OMe
O
MeO
OMe OMe
CH 3
MeO MeO MeO
O NH2NH2.H2O

MeOH/ NaOH
R MeO R MeO R
307 N N
O H
308 309
R= 3-OH, 4-MeO, 4-Me2N, 4-Et2N

Scheme 70

R2 R2 R2
N N N
NH2NH2.H2O CH3COCH2COOCH2CH3

R1 R1 R1
Cl NHNH2 N N
310 311 CH3
O
312

glacial AcOH/ Br2/ EtOH

R2
R2
N
N N N
HS N
O

pyridine, 3hrs R1
R1
N N
N N N N
CH2Br
CH2S N O
O
O 313
314

Scheme 71

N R
N The reaction of 336 with primary amine leads to the forma-
S tion of pyrrole (Xue et al., 2010) while similar treatment of
336 with secondary amine provides 337 and 338 (Scheme 77).
X A convenient synthesis (Krishna and Prapurna, 2010) of
335a pyrazolines 341 is reported via DABCO mediated reaction of
580 M. Yusuf, P. Jain

H3C CHO H3C

O CH3

N N 1
Cl Cl R
N N
+ 1
KOH/ EtOH

R
316

317 NH2NH2, RCOOH

315

R
N
O N
1
H3C R

N
Cl
N

318

Scheme 72

O
O
NC OEt

AQ CN O

NH
NH2
320
O
O
319 AQ NH2
KOH/ DMF/PhNCS NH
N
PhHN N
O NH2NH2 H
O
323
AQ CN AQ CN
NH Me2SO4 NH

SK PhHN SMe O
PhHN sand bath, fusion
322 H2N AQ CN
O
321 NH
N Ph
H3C N

H3C
HNPh NH

O CH3

O N N
H3C CH3
AQ =
Ph
O
324

Scheme 73

CHO
H3C H3C NO2 R
NO2 R2
EtOH N
N
NH
NH2 + N
NH R1
N R1 N
R2
H3C R H3C
325 326 327

R = Cl, OH, H R1 = R2=OCH3, H

Scheme 74
Synthetic and biological studies of pyrazolines and related heterocyclic compounds 581

O
O
O OEt
OH
O
a R1 OEt b c
Br R1 CH3
N R1 CH3
R1 O N
O CH3
328
329

H2NO 2S
H2NO 2S
330 331
R1 = Ph, 2-napthyl, 4-biphenyl
a = i) NaH, ethyl acetoacetate, THF ii) bromo ethyl ketone b) 4-amino benzenesulfonamide, p-toluenesulfonic acid,
EtOH, c) NaOH, EtOH

Scheme 75

O S
O
N
N NH2
CH3 Ar
KOH H2N NH NH2
Fe Fe Fe
+ ArCHO S
Ar
NaOH, EtOH

334

333 O
332 Br
CH2Cl2, reflux, 1h
R

S R
N
N N
Fe
Ar

335

Scheme 76

H3C CH3
H3C CH3 CH3
CH3
O
O

NHR1R2/ THF

O O O
O O O

O
O
336 N
Br 337
R1 R2

CH3 H3C CH3

H3C CH3 CH3

O O

NH2R/ THF

O HO O O
O O
N R
O

Br 336 338

Scheme 77
582 M. Yusuf, P. Jain

NO2
AcO NO2
OAc
O EtOOC
COOEt
EtOOC
CH3 DABCO/ DCM
CH2
O
+ N2 NH + AcO

O 2N EtOOC N N
EtOOC N
340 341
339
342

Scheme 78

H3C
H3C CH3

HO OH O
H3C OH
Br

CH3 CH3
K2CO3, acetone

O 344 O
343
benzaldehyde, Ba(OH)2.8H2O
R
H3C
H3C
H3C O OH
H3C O R
OH
NH2NH2, AcOH, EtOH

O
345
N N
CH3
NH2NHCSNH2/ EtOH
346 O

H3C

H3C O R
OH

N N
NH2
S
347

Scheme 79

O O
CN
NH2 NH

N NH2 N NH2 N
N N
N N
+
H / H2 O ArCHO/ I2/ CH3CN X
O 2N
O 2N O 2N

O 2N
O 2N O 2N
348 350
349

Scheme 80

CH3
O O CH3
O H
N N

NH2NH2. H2O/ EtOH R

O O R O OH
CH3
OH CH3
OH
N CH
3 N CH
3
351
352

Scheme 81
Synthetic and biological studies of pyrazolines and related heterocyclic compounds 583

OH NH R2
H3C H3C
O O
R3 R3
N N R2NH2, HOBt, EDC
N N
N N
morpholinomethyl Polystrene

R1 R1

353 354

Scheme 82

NMe2
O CH3 O
H2N
N N
N DMFDMA, EtOH N MeNHNH2/ methoxy EtOH
N N
N H2, Pd-C, EtOH, DMF
N
355 356
CH3 CH3
358
357
RCOCl, EtN(iPr)2, DCM

O
NH
R
N
N
N

CH3
359

Scheme 83

S O
OH Cl N C S
O HN NH
O O N CH3
SOCl2/ C2H4Cl2 NH4SCN, (CH3)2CO
N N N R-C6H4-NH2 N
N N N (CH3)2CO R
363
H3C H3C H3C
360 361 362
(C2H5)3N, BrCH2COCH3
C6H5NHNH2, CH3CN

S O
H
N N H3C N N N CH3

S N
N N CH3
N R
364 365

Scheme 84
584 M. Yusuf, P. Jain

O CH3 N
O
C N H3C OMe C
N CH3
xylene, reflux
N + N
Ph
N
Ph Ph H3C OMe N CH3
366 N
367 368
Ph

EtOH, reflux

N
O
C
N
Ph N O
N
Ph
369

Scheme 85

CH3
O
O O

Cl O N
H3C H3C
dry benzene
Et3N N
NC
N Ar
N 368 or 369 Y
NH N N
Ph
370 N
Ar Ar
372
371 Ph
-YH

CH3
O

N CH3 O N
N
NC N
NH2NH2 Ar
NC N
N N
N Ph
Ph Ar N
N
Ph
Ph 374
373

Scheme 86

O
EtO CN
H2N CN
NH + EtOH, reflux
N COCl2/ Nu N
NH
NH2
N Nu
Ph N
N
375 376 N Ph
Ph O
377 378

Scheme 87

ethyl diazoacetate (EDA) with BaylisHillman acetates A series of N-substituted-3-[(20 hydroxy-40 prenyloxy)-phe-
(Scheme 78). Here the products were obtained in good to nyl]-5-phenyl-4,5-dihydro-(1H)-pyrazolines 346 and 347 were
excellent yields (7095%). synthesized (Scheme 79) and tested on human monoamine oxi-
Synthetic and biological studies of pyrazolines and related heterocyclic compounds 585

O OCH3
OH O N NH N N
CH3 CH3
i ii CH3
N N
SO 2 CH3 CH3 N
SO2 SO 2 CH3
379 380
381

iii

i) NH2NH2.H2O
ii) methyl chloro acetate/ DMF
R
NH N O NHNH2
iii) NH2NH2. H2O
O
iv) R-CHO N N N N

CH3 iv CH3

N N
CH3 SO 2 CH3
SO 2
382
383

Scheme 88

O HO
O O
R O
R NH S
SOCl2 SO 2NH2
N
Ph N N N
N Ph N N
H2N
S
SO 2NH 2 N
Ar Ar 385
384

Scheme 89

Ph
Ar O O
N SH
Ph N
Ar O N
Cl
N N Ar
N NH
Ph
S N N N
Ar N Ar
N Ar1 Ar2
Ar1 Ar
S Ar1
Ar 388
386 H Ar2
387 ArNCS

Ar1 Ar2

O N
N
NH
Ar Ph

389

Scheme 90

dase-A and -B isoforms (Fioravanti et al., 2010). The structure series of pyrazolo[3,4-d]pyrimidine derivatives 350 in a single
activity relationships and molecular modeling showed that step (Bakavoli et al., 2010) and their antibacterial activity
some substituents, such as benzyloxy or chlorine, improve was found to be comparable to Streptomycin which was
the best interaction with active site of hMAO-B. used as a reference drug (Scheme 80).
Iodocyclization of 5-amino-1-(2,4-dinitrophenyl)-1H-4-pyr- Bandgar et al. (2010) have described the synthesis of a
azolcarboxamides 349 with aromatic aldehydes 350 gave a new combinatorial library of 3,5-diaryl-pyrazole derivatives 352
586 M. Yusuf, P. Jain

R COOH
R COOH S
S
N
N O H
4N, HCl/dioxan/ Et3N O F
O CH3 N
N R
N
N CH3 S
H3C
N
DCC, HOBt
N
NH4OH 394 N
392 R CONH2
S
stirring/ (Boc)2O N O
397
N O CH3
HS O O
N H3C CH3 SH
HO
H2N OH
391 + F
R R
O H2N 393 H
H N

N N
N + N

F
395
390
396

NH2OH

R R
R S
NOH

H CN N

N SH
N
Ac2O N H2N
N N
N
NaOH

398
399 400

Scheme 91

using 8-(2-(hydroxymethyl)-1-methylpyrrolidin-3-yl)-5,7-dime- et al., 2010) via the reaction of 3-acetyl-1,5-diphenyl-1H-

thoxy-2-phenyl-4H-chromen-4-one 351 and hydrazine pyrazole-4-carbonitrile 366 with dimethylformamid-
hydrate in absolute ethanol under the reuxing conditions dimethylacetal (DMF-DMA) (Scheme 85). The heterocyclic
(Scheme 81). compound 374 has been obtained starting from 370 via
Recently, a series of N-alkyl 1-aryl-5-(1H-pyrrol-1-yl)-1H- various steps as shown in Scheme 86.
pyrazole-3-carboxamides 354 have been synthesized as new The novel dipyrazole ethandiamide compound of pyrazol-
ligands of the human recombinant receptor hCB1 (Silvestri o[3,4-d]pyrimidine 4(5H)-one 377 was synthesized (Youssef
et al., 2010). n-alkyl carboxamides brought out different et al., 2010) and reacted with a number of nucleophiles
SARs from the branched subgroup (Scheme 82). to yield 378. These compounds were tested in several
The novel 3,4-disubstituted pyrazoles 359 were prepared in vitro and in vivo assays (Scheme 87). Two compounds
(Franchini et al., 2010) according to the reaction sequence as were notable for their anti-inammatory activity that
shown in Scheme 83. was comparable to that of the clinically available
The functionally substituted pyrazole compounds 364 cyclooxygenase-2 inhibitor celecoxib. Modeling studies by
and 365 have been prepared (Nitulescu et al., 2010) and using the molecular operating environment module showed
evaluated in vitro for their antiproliferative effects on a comparable docking scores for the two enantiomers docked
panel of 60 cellular lines, according to the National in the active site of cyclooxygenase-2.
Cancer Institute screening protocol (Scheme 84). Three of A series of potential anti-oxidant and anti-bacterial N0 -aryl-
the 12 tested compounds showed moderate antitumor methylidene-2-(3,4-dimethyl-5,5-dioxidopyrazolo[4,3-c][1,2]
activity, one of them being chosen for the 5-dose assay benzothiazin-2(4H)-yl)acetohydrazides 383 were synthesized
and presented logGI50 values up to 5.75. (Ahmad et al., 2010) in a facile way starting from
The new compound 3-[(E)-3-(dimethylamino)acryloyl]-1,5- commercially available saccharine. The various steps
diphenyl-1H-pyrazole-4-carbonitrile 369 was prepared (Farag involved in these syntheses are shown in Scheme 88.
Synthetic and biological studies of pyrazolines and related heterocyclic compounds 587

O CH3
H2N NH NH
CH3 EtOH, H2SO4 N

R
1 + R
1 403

401 402 POCl3/DMF/ NaHCO3/ H2O

1
R

O CHO
2 O
R
CH3
1
R
N 2 EtOH, KOH
R N N
N

405 404

1
R

NH2NH2, AcOH/ MW NH2NH2, DMF/ MW

1 HN N
R H O

N N
N 2
N R

N 2
N R

405 a
R1=NO2, Cl
R2= NO2, F, Cl, Br, H, CH3, CH3O, 3',4'-OCH2O-

405 b

Scheme 92

H
N N OH
O O
COOEt N N O

+ K2CO3, TBAI, CH3CN

COOH NH
R
406 N R
H 408
407

R= 4-OCH3, 3-OCH3, 4-CH3, 3-CH3, 4-NO2, 3-NO2, 2-NO2

Scheme 93

Pyrazole carboxylic acid derivatives (Kasimogullari et al., inammatory activity using cotton pellet-induced granuloma
2010) of 5-amino-1,3,4-thiadiazole-2-sulfonamide (inhibitor and carrageenan-induced rat paw edema bioassays. Their
1) 385 were obtained from ethyl 3-(chlorocarbonyl)-1-(3-nitro- inhibitory activities of cyclooxygenase-1 and cyclooxygenase-
phenyl)-5-phenyl-1H-pyrazole-4-carboxylate compound (Scheme 2 (COX-1 and COX-2), ulcerogenic effect and acute toxicity
89). were also determined.
Regioselective 1,3-dipolar cycloaddition of nitrilimines with The heterocyclic compounds (E)-1-aryl-3-(3-aryl-1-phenyl-
5-arylidene-2-arylimino-4-thiazolidinones and with 2-(4-ary- 1H-pyrazol-4-yl)prop-2-en-1-ones 405 (pyrazolic chalcones)
lidene)thiazolo[3,2-a]benzimidazol-3(2H)-ones 386 afforded were synthesized (Insuasty et al., 2010) from a Claisen
(Abdel-Aziz et al., 2010) the corresponding 1,3,4-triaryl-5-N- Schmidt reaction of 3-aryl-1-phenylpyrazol-4-carboxaldehydes
arylpyrazole-carboxamides 388 and pyrazolylbenzimidazoles 404 with several acetophenone derivatives. Subsequently, the
389 (Scheme 90). microwave-assisted cyclocondensation reaction of chalcones
Adam A. Bekhit et al. (2010) have reported the synthesis of 405 with hydrazine afforded the new racemic 3-aryl-4-(3-aryl-
a novel series of 4-thiazolylpyrazolyl derivatives 400 according 4,5-dihydro-1H-pyrazol-5-yl)-1-phenyl-1H-pyrazoles 405 a or
to the reaction sequence as given in Scheme 91. All the newly their N-acetyl derivatives 405 b when the reactions were
synthesized compounds were examined for their anti- carried out in DMF or acetic acid, respectively (Scheme 92).
588 M. Yusuf, P. Jain

R1 R2

aromatic aldehyde, NaOH, EtOH

O 410

R1 thiosemicarbazide, NaOH, EtOH

CH3 R1

O R2
409 N
N2H4.H2O, CH3COOH N
S
H2N 411

R3

R4
N
N
O
H3C
412

Scheme 94

O O
O O
NH
CH3
N
O

O O N O O
N CH3

H
NH
O
O O O N O
O N
N O
415 H H3C
O 414 H3C
CHO
CH3
O
N
O N
N
O O
O CH3 413
Cl
Cl

Cl

N
Cl
N
N O
O O Cl O
H3C
417
416

Scheme 95

1-(30 -(9H-carbazol-4-yloxy)-20 -hydroxypropyl)-3-aryl-1H- A number of biologically signicant conjugates were syn-

pyrazole-5-carboxylic acid derivatives 408 have been prepared
(Nagarapu et al., 2010) by the reaction of ethyl 3-aryl-1H-
pyrazole-5-carboxylate 406 with 4-oxiranylmethoxy-9H-
carbazole 407 in moderate to excellent yields (Scheme 93).
The cytotoxicity of synthesized compounds was evaluated by
a SRB (sulforhodamine B) assay against cancer cells such as
SK-N-SH human neuroblastoma (NB), human A549 lung
carcinoma, human breast cancer MCF-7 cell lines. The
results showed that seven compounds can suppress SK-N-SH
tumor cancer cell growth.
Two series of pyrazole derivatives 411 and 412 (Lv et al.,
2010) designing for potential EGFR kinase inhibitors have
been investigated (Scheme 94). Some of them exhibited signi-
cant EGFR inhibitory activity. The compound 3-(3,4-dimeth-
ylphenyl)-5-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazole-1-car
bothioamide 411 (C5) displayed the most potent EGFR
inhibitory activity with IC50 of 0.07 lM, which was
comparable to the positive control erlotinib.
thesized by the combination of chromone-pyrimidine, chro-
mone-indolinone, chromone-pyrazole, indole-pyrimidine,
indole-indolinone and indole-pyrazole moieties (Singh et al.,
2010) according to the method which is described in Scheme
95.
Recently, Serkos A. Haroutounian et al. (Christodoulou et
al., 2010) have investigated the synthesis of a series of novel
trisubstituted pyrazole derivatives 421 and these compounds
have also been PIFA-mediated converted to molecules bearing
the fused pyrazolo[4,3-c]quinoline ring. The various steps
involved in these syntheses have been described in Schemes 96.
New 1-N-substituted-3,5-diphenyl-2-pyrazoline derivatives
430 have been synthesized (Scheme 97) and their cyclooxygen-
ase (COX-1 and COX-2) inhibitory activities have also been
evaluated (Fioravanti et al., 2010). The results of these biolog-
ical assays showed that all the new derivatives are not endowed
with improved anti-inammatory activity against COX-1,
but some of them showed a good activity against COX-2.
Synthetic and biological studies of pyrazolines and related heterocyclic compounds 589

R3 R3

R2 R4
R2 R4
R3

R2 R4 R1 R1
a b O
N CH3 N
R1 H
NH N
O CH3

418 H3C H3C c

O 419
O
420

1a, 2a,3a R1=H, R2=H, R3=H, R4=H

R7
1b, 2b,3b R1=H, R2=OCH3, R3=H, R4=H
R6 R8
1c, 2c,3c R1=H, R2=H, R3=OCH3, R4=H
1d, 2d,3d R1=H, R2=OCH3, R3=OCH3, R4=H
1e, 2e,3e R1=OCH3, R2=H, R3=H, R4=OCH3 R5
O
N
a) 4-methoxyphenyl hydrazine hydrochloride, AcOH, Et3N, EtOH H
b) TCT, DMF c) BBr3, DCM N

R3
R3 HO
R3 421 R2 R4
R2 R4
R2 R4
R1
R1 O
R1 NaClO3, H2NSO3H, acetone, H2O OEt3N, NH2OMe.HCl, TBTU, MeCN N
O NH
N
N OH N
H MeO
N
N 424
H3C
H3C O
H3C
O
O 423 PIFA, TEA, DCM
422

R7 R3
R6 R8 R4
R2
OH OMe
R5 N N
BBr3, DCM R1
O O
N N
N N

H3C
HO 426 425
O

Scheme 96

The compounds 439 have been released (Velankar et al.,
2010) starting from benzyl nitrile 431 through the multistep
reactions and their conditions have been depicted in Scheme
98. The synthesized compounds showed interleukin-2 inducible
T-cell kinase (ITK) which is one of the ve kinases that
belong to the Tec kinase family and it plays an important role
in T-cell and mast cell signaling. Various reports point to a
role of ITK in the treatment of allergic asthma.
The synthesis of a series of pyrazoles 443 has been reported
(Scheme 99) and these heterocyclics were also evaluated for
their PDE4 inhibitory activity (Biagini et al., 2010). All the
pyrazoles were found devoid of activity, whereas some of the
pyrazolo[3,4-d]pyridazinones showed good activity as PDE4
inhibitors.
3,5-Diaryl-1H-pyrazoles 446 were prepared (Shaw et al.,
2010) from the cyclization of 1,3-diketone 446 with
hydrazine hydrochloride (Scheme 100). The major interest in
the study was to obtain a molecular template which may act
as growth-inhibitory agents.
The cyclization of chalcones 450 with 2-(quinolin-8-yloxy)
acetohydrazide 451 under basic condition (Hayat et al.,
2010) led to the formation of new pyrazoline derivatives 452
(Scheme 101).
In order to nd a new class of antimicrobial agents
(Bondock et al., 2010), a series of pyrazole 460 and 462 and
other related products 458 containing benzothiazole moiety
have been reported by Samir Bondock et al. according to the
detailed protocol which is given in Scheme 102.
590 M. Yusuf, P. Jain

OHC
H3CO2S R
H3CO2S

CH3 + R Ba(OH)2.8H2O, EtOH

429
O
O 428 NH2NH2, CH3COOH, EtOH
427
NH2NHCSNH2, NaOH, EtOH

H3CO2S

R
N N
X
430

Scheme 97

CH3
N
CH3
H3C
CN O DMF CN
CH3
+ O N
433 NH2NH2.HCl, EtOH
431 CH3
H3C 432

I
I NaNO2, KI, MeoH NH2
(Boc)2O, Et3N, DCM
N
N N
N
N N
H
H
boc 435
434
436

1-(t-butoxycarbonyl)-1H-indol-2-ylborinic acid, Pd(dppf)Cl2

KOH, EtOH
COOH
COOMe
N
N N H
N N
boc 438
N H

boc amine, EDCl, HOBt, NaHCO3, DMF

437

N O
N H
N
H
439

Scheme 98

Novel 1,5-diaryl pyrazole derivatives 466 and 467 were syn-
thesized (Ragavan et al., 2010) from the condensation of 464
with phenyl hydrazine in alcoholic medium (Scheme 103).
An effective and solvent free method for the synthesis
(Kumar et al., 2011) of pyrazole-substituted chalcones 470
has been achieved by grinding pyrazole aldehydes 468 and
acetophenones 469 in the presence of activated barium
hydroxide (C-200). The products of these reactions have
been obtained in high yield and within short span of
time (Scheme 104).
A series of new 1,3,5-trisubstituted-2-pyrazolines
473 were prepared (Srinath et al., 2011) by reacting
chalcones 471 with phenylhydrazine hydrochloride 472
(Scheme 105).
Synthetic and biological studies of pyrazolines and related heterocyclic compounds 591

R1 R1

N N N N R CN
O R RCHO, MeONa, MeOH O R EtOH, NaOH
N CH=CHR2
N
N CH3 N CH=CHR2
442
O O R1
441
440
HCOONH4\/ Pd/ C, EtOH

R R1 R2

a Ph Et naphthyl
R CN
b Ph Et 2-COOH-Ph
N CH2CH2R2
c Me Me Ph
N
d Ph Me 3,4-OMe-Ph

e 4-pyridine Et naphthyl R1
443

Scheme 99

O O
O O NH2NH2.HCl, EtOH
NH N
LiHMDS, toluene

Ar CH3
+Ar' Cl Ar Ar' Ar
Ar'
446 447
444 445

Scheme 100

O O
N
CH3 H OH 453
R1
+ R2 ClCH2COOEt, K2CO3, Acetone

448 449
NaOH/ EtOH

N
O O

N
R1 R2 + O
O
454
O CH3

450 NH2 N2H4.2H2O

O NH
NaOH/ EtOH 451

N
O
N
NH2
O NH
O 451

O
N N

R
R

452

Scheme 101
592 M. Yusuf, P. Jain

N O
CN
H
N NH
N N CH3 S
N O CH3 N
CN N 2.HCl
455 CH3 NH
NH pyridine
S 456
N
Ph
H3C N N
CHO
457 H
N O N

CN N

Ph AcOH
NH NH
S EtOH/ NaOH N O H
Ph N N CH3
PhNCS, KOH/ DMF, MeI NH N
S
N
N
N N
Ph N O 458
CH3
459 CN
NH2NH2.H2O/ EtOH NH
S
HNPh SMe
N 461
O
NH2
NH NH2NH2.H2O
S
Ph NH
N
N N O
N NH2
NH
Ph S
460
HNPh NH
N
462

Scheme 102

O O O
OC2H5
CH3 LiHMDS, THF, diethyloxalate
O
Cl Cl 464
463

F
EtOH, MeOH
NH NH2

465
F
F

N N OH Li(OH)2/ THF/ MeOH N N OC2H5

O
O

Cl
467
Cl
466

Scheme 103

O
Ar CHO O
Ba(OH)2 Ph
N
N + CH3
grinding R
N R N
469 470 Ar
Ph
468

Scheme 104
Synthetic and biological studies of pyrazolines and related heterocyclic compounds 593

NHNH2.HCl HO
HO

EtOH H3C
H3C
Ar + N Ar
Pyridine
O
N
471 472

473 Ph

Scheme 105

H3CH2CO O 1
R N N O
H2C HN N 1 Et3N/ DCM
R
O
+ CH3
Cl 1 2 OCH2CH3
R R O
CH3 2
1 476
R R
474

475

2 1
2 1 R R
R R
- +
OK
O
1
+ R
1
N
R N N
N O
- +
OK

478
477

(CH3)2SO4
(CH3)2SO4

2 1
R R 2 1
R R
O
OCH3
1
R N 1
N R N
OCH3 N
O

479 480

Scheme 106

Regioisomeric spiropyrazolines 479 and 480 were synthe-
sized (Dadiboyena and Hamme, 2011) through a tandem
intramolecular cyclization/methylation reaction of a functio-
nalized 5,5-disubstituted pyrazoline in one reaction vessel
(Scheme 106).
1,3,5-Trisubstituted pyrazolines 481 are rapidly and conve-
niently oxidized (Azarifar et al., 2011) to their corresponding
pyrazoles 483 by 1,3-dichloro-5,5-dimethylhydantoin (DCH)
in solution and solvent-free conditions under microwave
irradiation (Scheme 107). The presence of silica gel as a
594 M. Yusuf, P. Jain

Cl
H
1 2 1 2
R R H3C N R R H3C N
O MW/ AcOH or solvent free O
N N
+ H3C
N N
+ H3C
N N
Ph O Cl Ph O
483
H
481 482 484

Scheme 107

3
COOR
2 2
R O R O
3 N
N COOR toluene, reflux 3
+ + PPh3 N COOR
R
1
CHO N COOR
3
R
1 +
O 486 O
485 487
3 3
COOR COOR
2
R O N N
3
N COOR
1
R = H, Me, i-Pr, Cl 1 N
R3 = i-Pr, Et R
R2 = H, Me 3
O COOR
488

Scheme 108

3
O O NaOH/ EtOH/ SOCl2/ EtOH
R 4 3 4
H + R
CH3
R R

2 1 1 O
R R 2
R
R 491
490
489

NH2NH2/ HCOOH NH2NH2/ AcOH

3
CH2
4
R R

2 1 N N
R R
O

R 492

Scheme 109

supporting agent is shown to be effective in reducing the Acknowledgment

reaction times and increasing the yields.
The zwitterionic intermediates generated from dialkyl azo- Authors are highly thankful to DST (SERC, Fast Track
dicarboxylates and triphenylphosphine displayed excellent Scheme no. SR/FT/CS-041/2010), New Delhi for providing
reactivity (Papalippou et al., 2011) toward 3-formylchro- the nancial support for this research work.
mones to afford chromeno[2,3-c]pyrazolines 487 and chro-
meno[2,3-e]tetrazepines 488 (Scheme 108). References
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