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Chapter-2 Review of Literature
Ph. D. Thesis 14
CHAPTER-2
REVIEW OF LITERATURE
Literature related to Benzofuran:
Benzofurans are bicyclic ring system with multiple applications. The Literature indicates
that compounds having Benzofuran nucleus possess broad range of biological activities,
like Griseofulvin as antifungal; Amiodarone as antiarrythmic; Benzbromarone as
uricosuric; Cloridarol as vasodilator; Oxetorone as antimigraine agent.
Antimicroabial Activity:
Koca et al. [1] synthesized new derivatives of (benzofuran-2-yl)(3-phenyl-3-methyl
cyclobutyl) ketoxime such as, O-glycidylketoxime (1), O-phenylacylketoxime (2), Alkyl,
allyl and aryl substituted N-oxime ethers (3). The syntheses of the compounds (4) were
carried out from the reaction of the compound (1) and different amines such as, isopropyl
amine, natrium azide, morpholine and piperazine. All of the synthesized compounds were
tested for antimicrobial activity against Staphylococcus aureus ATCC 6538,
Staphylococcus epidermidisATCC 12228, Escherichia coliATCC 8739, Klebsiella
pneumoniae ATCC 4352, Pseudomonas aeruginosa ATCC 1539, Salmonella typhi,
Shigella flexneri, Proteus mirabilis ATCC 14153 and Candida albicans ATCC 10231.
Among the synthesized compounds most of them are found to be active.
O N
H3C
Ph
O
O
O N
H3C
Ph
O
O
R1
(1) (2)
R1=Ph, PhCH2-, CH3
Chapter-2 Review of Literature
Ph. D. Thesis 15
O N
H3C
Ph
O
R2
O N
H3C
Ph
O
OHN
Z (3) (4)
R2= PhCH2-, CH3, PhCOCH2-, Z= -CH2, -NCH3, -NC6H5, O
CH2=CHCH2, C2H5OCOCH2-,
Alper-Hayta et al. [2] synthesized a new series of 2-(substitutedphenyl/benzyl)-5-[(2-
benzofuryl)carboxamido]benzoxazole derivatives (5). The in vitro antimicrobial activity
of the compounds was determined against some Gram-positive, Gram-negative bacteria
and fungi and their drug-resistant isolates in comparison with standard drugs.
Antimicrobial results indicated that the synthesized compounds possessed a broad
spectrum of activity.
O
NH
O
N
O
R1
R
(5)
R1=H, Br
R=H, C2H5, F, Br, Cl, CH3, C(CH3)3
Kirilmis et al. [3] synthesized some novel 1-(1-benzofuran-2-yl)-2-mesitylethanone
derivatives. Some of the synthesized compounds were tested for antimicrobial activity
against Staphylococcus aureus ATCC 6538, Escherichia coli ATCC 25922 and Candida
Chapter-2 Review of Literature
Ph. D. Thesis 16
albicans ATCC 10231. Among the synthesized compounds (E )-1-(1-benzofuran-2-yl)-2-
mesitylethanone-O-benzoyloxime (6) was found the most active derivative against S.
aureus ATCC 6538 and E. coli ATCC 25922. The other compounds exhibited moderate
activity against the other test microorganisms.
ON
Mes
O
O
(6)
Abdel-Wahab et al. [4] synthesized 1-(benzofuran-2-yl)-4-nitro-3-arylbutan-1-ones (7),
3-(Benzofuran-2-yl)-4,5-dihydro-5-arylpyrazole-1-carbothioamide (8) and 3-
(benzofuran-2-yl)-4,5-dihydro-5-aryl-1-[4-(aryl)-1,3-thiazol-2-yl]-1H-pyrazoles (9). All
the synthesized compounds were screened for their antibacterial and antifungal activities
at 100 mg concentration. Some of the compounds showed excellent antimicrobial
activities than control drugs.
O
O
Ar
NO2
O NN
Ar
S
NH2
(7) (8)
Ar= Ph, 4-Cl C6H4 Ar= Ph, 4-Cl C6H4
O NN
Ar
S
N
Ar'
(9)
Ar= Ph, 4-Cl C6H4 ; Ar’= Ph, 4-Br C6H4
Chapter-2 Review of Literature
Ph. D. Thesis 17
According to Babu et al. [5] chalcones were prepared from 2-acetyl benzofuran and
condensed with different aromatic acid hydrazides to get the corresponding pyrazolines
(10, 11). Among the compounds that were screened against two Gram-
positive(Staphylococcus aureus and Bacillus subtilis) and two Gram-negative bacteria
(Escherichia coli and Pseudomonas aeruginosa), compounds possessing p-chloro, p-
fluoro, 2-amino-5-bromo, 2-hydroxy-5-nitro and 3,5-dichloro substitutions on the phenyl
ring showed good activity against Escherichia coli and Bacillus subtilis. The activity is
comparable with the standard drug ciprofloxacin.
O NN
OCH2COOH
COAr O N
N
COAr
OCH2COOH
(10) (11)
Ar= Phenyl, 4-hydroxy phenyl, 4-chloro phenyl, 2-chloro phenyl, 4-nitro phenyl, 2-nitro
phenyl, o-tolyl, 2-hydroxy phenyl, 4-amino phenyl, isonicotinyl, 4-methoxy phenyl, 2-
amino 5-bromo phenyl, 2-hydroxy 5-nitro phenyl, 3,5-dichlorophenyl
Khan et al. [6] synthesized two series of 2-substituted benzofurans (12) and three new
diacetyl benzofurans (13). The compounds showed mild to significant growth inhibition
against antibiotic-susceptible standard and clinically isolated strains of Gram-positive and
Gram-negative bacteria as well as human fungal pathogens. Ampicillin and kanamycin
were used as references for antibacterial screening; nystatin and amphotericin B were
used for antifungal screening.
O
R
O
O CH3
O
R1R2
R3
(12) (13)
R= C6H5, 4-OCH3 C6H4, 4-CH3 C6H4 R1=R2=R3= H, Ac
Chapter-2 Review of Literature
Ph. D. Thesis 18
Rida et al. [7] synthesized and evaluated several benzofuran derivatives containing
heterocyclic ring substituents (14-18) linked to the benzofuran nucleus at C-2 by a two-
to four-atom spacer as potential antimicrobial agents. Some compounds exhibited mild
activity against S. aureus, while some compounds had mild activity towards S. aureus
and C. albicans.
O
N
CH3
N
N
S
O
R
O
N
CH3
N
N
S
CH3
R
(14) (15)
R= C4H9, CH2C6H5, C6H5, 4-CH3C6H4 R= CH2C6H5, C6H5, 4-CH3C6H4
O
N
CH3
N
N
S
R
R1
O
N
CH3
N
N
S
O
R
R1
(16) (17)
R= CH2C6H5, C6H5, 4-CH3C6H4 R= CH2C6H5, C6H5
R1=CH3, Cl R1= OCH3, Cl
O
N
CH3
N
N
O S
N
S
R
(18)
R= CH2C6H5, C6H5
Mahadevan et al. [8] synthesized some potent benzofuro Thiazolyl (19), Oxazolyl
(19), Thiadiazolyl (20) and Oxadiazolyl derivatives (20). The results revealed that the
compounds were showing antibacterial and antifungal activity.
Chapter-2 Review of Literature
Ph. D. Thesis 19
O
R1
R
N
X
NH2 O
R1
R
X
NN
NH2
(19) (20)
X= S, O; R= H, Br, NO2 X= S, O; R= H, Br, NO2
R1=H, CH3 R1=H, CH3
Basavaraja and Agasimundin [9]
synthesized Bis [2(4’-aryl-1’,2’,4’-triazol-5’-yl)]-3-
methoxybenzofuransulphides (21) and disulphides (22). The compounds synthesized
were found to exhibit appreciable antibacterial activity.
O
OCH3
NN
NS
N N
N
O
H3CO
RR
(21)
R= -C6H4 CH3(p), - C6H4 OCH3(p), C6H4 Br(p)
O
H3CO
N
N
NN
N
N
O
OCH3RRS S
(22)
R= -C6H5, -C6H4 CH3(p), - C6H4 OCH3(p)
Manna et al. [10] synthesized various 3-(1-benzofuran-2-yl)-5-phenylisoxazoles (23).
The benzofuran isoxazoles were evaluated for their antibacterial activity. Some of the
compounds have shown promising antibacterial activity.
Chapter-2 Review of Literature
Ph. D. Thesis 20
O
NO
R
(23)
R= -OH(o), -OCH3(o), -N(CH3)2(p), -COOH(o), -NO2(m), -OH(o)OCH3(p), -OH(p),
-Cl(p), -Cl(o), -NO2(o), -OCH3(p), -H, Furan ring, -Cl=CH-Ar
Prasad et al. [11] synthesized a new series of 3-[3-(3-hydroxy-1-benzofuran-2-yl)-5-
mercapto-4H-1,2,4-triazol-4-yl]-2-substituted phenyl-1,3- thiazolidin-4-ones (24). The
compounds showed moderate to weak antimicrobial activity.
O
OHNN
N
N
HS
S
O
R
(24)
R= H, 2-NO2, 3-Chloro, 2-Chloro, 2-Hydroxy, 2-Methoxy, 4-Bromo, 4-Chloro,
4-Dimethyl amino
Basawaraj et al. [12] synthesized 2-substituted-4-methoxy/ethoxy benzofuro [3,2-d]
pyrimidines (25) and 2-substituted-3,4-dihydro-4-thiobenzofuro [3,2-d] pyrimidines
(26). Some compounds shown significant activity against S. aureus and E. coli
compared with standard drug Ciprofloxacin while some compounds displayed
moderate activity against both bacteria.
ON
N R
R'
ON
N R
SH
(25) (26)
Chapter-2 Review of Literature
Ph. D. Thesis 21
R= ,
CH3
CH3
CH3 R= ,
CH3
CH3
CH3
R’= OCH3, OC2H5
Basavaraja et al. [13] synthesized a series of 3-alkyl-1,2,3,4-tetrahydro-2-thio-4-
oxobenzofuro[3,2-d] pyrimidines (27), 3,4-dihydro-3-N-alkyl/aryl-2-methylthio-4-
oxobenzofuro[3,2-d] pyrimidine (28), 3,4-dihydro-3-N-alkyl/aryl-2-hydrazino-4-
oxobenzofuro[3,2-d] pyrimidine (29), tetrazolo[1,5-a]-3-N-alkyl/aryl-4-oxopyrimido
[5,4-b] benzofurans (30), triazolo[1,5-a]-3-N-alkyl/aryl-4-oxopyrimido [5,4-b]
benzofurans (31) and 3,4-dihydro-3-N-alkyl/aryl-4-oxopbenzofuro-[3,2-d] pyrimidine-
2-thioacetic acids (32). Compounds (28) exhibited almost equivalent activity as that of
standard (Streptomycin) against both organism S. aureus and E. coli. Compounds (30)
was equally active as that of standard only against S. aureus and inactive against E.
coli only. Some compounds were active only against E. coli.
O
N
HN
S
R
O O
N
N
SCH3
R
O
(27) (28)
R= CH3, C6H5, C6H4CH3(4), C6H4OCH3(4), C6H4Cl(4)
O
N
N
NHNH2
R
O O
N
N
R
O
N
N
N
(29) (30)
R= CH3, C6H5, C6H4CH3(4), C6H4OCH3(4), C6H4Cl(4)
Chapter-2 Review of Literature
Ph. D. Thesis 22
O
N
N
R
O
N
N
HC
ON
N
R
O
S COOH
(31) (32)
R= CH3, C6H5, C6H4CH3(4), C6H4OCH3(4), C6H4Cl(4)
Basawaraj et al. [14] synthesized 2-N-arylaminoacetyl-5-chloro-3-methylbenzofurans
(33). Some compounds exhibited high antibacterial activity against S. aureus and
moderate activity against E. coli, remaining compounds have shown moderate activity
against both bacteria.
O
CH3
Cl
O
NH
R
(33)
R= H, 2-CH3, 4-CH3, 2-OCH3,4-OCH3, 2-Cl, 4-Br, 2-NO2
Gundogdu-Karaburun et al. [15] synthesized some aryl [3-(imidazol-1-yl/triazol-1-
ylmethyl/methyl) benzofuran-2-yl] ketones (34-36), aryl (3-methyl-benzofuran-2-yl)
ketoximes (37) and aryl [3-(imidazol-1-yl/triazol-1-ylmethyl)benzofuran-2-yl] ketoximes
(38). Antifungal activities of the compounds were examined and moderate activity was
obtained.
O
OH3C
R1
R2
R3
O
CH2
R1
R2
R3
N
N
XO
(34) (35,36)
Chapter-2 Review of Literature
Ph. D. Thesis 23
R1=H, CH3, Cl; R2= H, OCH3 R1=H, CH3, Cl; R2= H, OCH3
R3=H, Cl R3=H, Cl; X=CH, N
O
NOHH3C
R1
R2
R3
O
CH2
R1
R2
R3
N
N
XNOH
(37) (38)
R1=H, CH3, Cl; R2= H, OCH3 R1=H, CH3, Cl; R2= H, OCH3
R3=H, Cl R3=H, Cl, X=CH, N
Aslam et al. [16] described a novel method for the synthesis of antifungal cicerfuran
(oxygenated benzofuran) and its analogues (39).
OR2
O
OR1
O O
O
O
NHN
R1=OMe, H, Me; R2=OH, H (RO-09-4609)
(39)
According to Ebiike et al. [17] Modification of the C-2 position of a benzofuran
derivative (RO-09-4609), an N-myristoyltransferase (Nmt) inhibitor, has led us to
discover antifungal agents (40,41) that are active in a murine systemic candidiasis model.
O
O
O
NH
N
Z
X Y O
O
NH
N
(40) (41)
Chapter-2 Review of Literature
Ph. D. Thesis 24
X=H, F, CN; Y=H, F; Z= H, F, CN, Br, Cl
According to Masubuchi et al. [18] the C-4 side chain modification of lead compound
(42) has resulted in the identification of a potent and selective Candida albicans N-
myristoyltransferase (CaNmt) inhibitor RO-09-4609, which exhibits antifungal activity
against C. albicans in vitro. Further modification of its C-2 substituent has led to the
discovery of RO-09-4879, which exhibits antifungal activity in vivo.
O
O
O
O
NH
HO
O
O
O
HN N
F F
F
(42) RO-09-4879
Some aryl(benzofuran-2-yl)ketoximes (43) and their ethers (44-45) and esters (46) were
synthesized by Demirayak et al.[19] Antifungal activities of the compounds were
examined and notable activity was obtained.
O
NOH
R1
O
NOR2
R1
(43) (44)
R1=H, Cl, CH3, OCH3 R1=H, Cl, CH3, OCH3; R2= CH3,C2H5
Chapter-2 Review of Literature
Ph. D. Thesis 25
O
NOR3
R1
O
N
R1
O
O
R4
(45) (46)
R1=H, Cl, CH3, OCH3 R1=H, Cl, CH3, OCH3
R3=CH2C6H5, CH2C6H4-p-Cl R4= CH3,C6H5
Tirlapur et al. [20] synthesized 6-(5-bromo-1-benzofuran-2-yl)-2-oxo-4-9substituted
phenyl)-1,2-dihydropyridine-3-carbonitriles (47) and 6-(5-bromo-1-benzofuran-2-yl)-2-
amino-4-9substituted phenyl)-1,2-dihydropyridine-3-carbonitriles (48) by the
condensation of 5-bromo-2-acetylbenzofuran with substituted aldehydes and ethyl
cyanoacetate/malonitrile in ethanol in presence of ammonium acetate. All the synthesized
compounds were characterized and evaluated for their antitubercular, antibacterial and
antifungal activities. Some of the compounds showed significant antibacterial activity
against E. coli, p.aeruginosa, S. epidermidis and B. subtilis. Some compounds exhibited
good antifungal activity against A. niger and C. albicans.
O
Br HN
O
CN
R
O
Br N
NH2
CN
R
(47) (48)
R= C6H5, C6H4Cl(p), C6H4OH(p), C6H4Br(p), C6H4OCH3(p), C6H4N(CH3)2(p), O
Tirlapur et al. [21] synthesized a new series of Benzofuranopyrazoles (49-51). All the
synthsized compounds were characterized and screened for their analgesic, antibacterial
and antifungal activities. Some of the compounds showed good activity when compared
with standard drugs.
Chapter-2 Review of Literature
Ph. D. Thesis 26
O
Br
NNH
CH=CHCOAr
O
Br
NNH
CH=NR
(49) (50)
O
Br
NN
CHO
CH2NHR
(51)
Ar=C6H5, C6H4OCH3(p), C6H3OH(o)CH3(m), C6H3Cl(o)Cl(p), C6H4NH2(p)
R= C6H5, C6H4Cl(p), C6H4NO2(p), C6H4CH3(p), C6H4OCH3(p)
Basawaraj et al. [22] synthesized 3-Amino-5-bromo-N’-(1-substitutedphenyl-
ethylidene)-1-benzofuran carbohydrazides (52). 1-[3-Amino-5- bromo-benzofuran-2-yl
carbonyl-3-substitutedphenyl-1H-pyrazole-4-carbaldehydes were synthesized by the
reaction of X with Vilsmerier-Haack reagent. The structure of all the compounds were
established and were evaluated for anti-inflammatory and antimicrobial activities. Some
compounds exhibited high activity against P. aeruginosa and B. subtilis, when compared
to standard drug Ciprofloxacin. Some compounds showed good activity against A. niger
and C. albicans. Compounds showed good anti-inflammatory activity with percentage of
inhibition 52, 52, and 39 compared with standard drug Indomethacin whose percentage of
inhibition is 78.
O
Br
O
N
NH2 N
R
CHO
(52)
R= C6H5, C6H4Cl(p), C6H4Br(p), C6H4OCH3(p), C6H3Cl(o)Cl(p)
Chapter-2 Review of Literature
Ph. D. Thesis 27
Yadav et al. [23] synthesized a novel series of 3-aryl-1-(2-benzofuryl)-2-propen-1-one
analogues (53-54). These synthesized compounds were evaluated for their anti-
inflammatory and antimicrobial activities. Most of the compounds showed good activity
against bacteria E. coli and B. subtilis and fungi A. niger and C. albicans. Some
compounds showed significant anti-inflammatory activity while other compounds
showed weak to moderate activity.
O N
N
NHCOCH2R2
Ar
O N
N
N=CHR1
Ar
(53) (54)
Ar= C6H5, C6H4OCH3(p), C6H4Cl(p)
R1= C6H5, C6H4OCH3(p), C6H4Cl(p)
R2=NHCH3, NHC2H5, Morpholino, NHC6H5, NHC6H4Cl(p), NHC6H4CH3(p),
NHC6H4OCH3(p)
Kumar et al. [24] synthesized a new series of Benzofuran-2-carboxylic acid N’-[2-(3-
chloro-2-oxo-4-phenyl azetidin-1-yl)-thiazol-4-yl hydrazide (55). These synthesized
compounds were evaluated for their antimicrobial and anti-inflammatory activities. Three
compounds out of ten compounds were moderately active against B. subtilis and less
active against E. coli when compared to standard drug Ampicillin. These three
compounds showed weak antifungal activity against C. albicans when compared to
standard drug Griseofulvin. Three compounds out of ten compounds showed moderate
anti-inflammatory activity against standard drug Indomethacin. Remaining compounds
were less active.
O O
NHNH
S
NN
RCl
O
(55)
Chapter-2 Review of Literature
Ph. D. Thesis 28
R= C6H5, C6H4Cl(p), 3,4,5- OCH3C6H2, 4-OH 3-OCH3C6H3, C6H4N(CH3)2(p),
C6H4Br(p), C6H4I(p), 4-OCH3C6H4, 2-OHC6H4, C6H4Cl(m)
Basavaraja et al. [25] synthesized 3-Methoxy-5-nitro-2-(5’-arylamino-1’,3’,4’-
oxadiazol-2’-yl) Benzofurans (56), 3-Methoxy-5-nitro-2-(5’-arylamino-1’,2’,4’-triazol-
5’-yl) Benzofurans (57), 3-Methoxy-5-nitro-2-(5’-arylamino-1’,3’,4’-thiadiazol-2’-yl)
Benzofurans (58). All the synthesized compounds were characterized and screened for
their antimicrobial activity. Most of the compounds showed good antifungal activity.
Some of the compounds showed good antibacterial activity.
O
O2N
OCH3
NN
ONHR
(56)
O
O2N
OCH3
NN
NSH
R
(57)
O
O2N
OCH3
NN
SNHR
(58)
R= C6H5, 4-CH3C6H4, 4-OCH3C6H4, C6H4Br(p), C6H4Cl(p)
Basavaraj et al. [26] synthesized 3-(Benzofuran-2’-yl)-5-phenyl/1H pyrazolines (59-60).
These compounds were evaluated for their antimicrobial activity and some compounds
were also screened for analgesic activity. Most of the compounds showed good activity
against bacteria E. coli and S. aureus. Some compounds showed good antifungal activity
against C. albicans and A. niger. Some compounds showed good to moderate analgesic
activity.
Chapter-2 Review of Literature
Ph. D. Thesis 29
O NNH
R
(59)
O NN
R
(60)
R= C6H5, 4-OCH3C6H4, C6H4Cl(p), C6H4N(CH3)2(p), O , a-Naphthyl
Basavaraj et al. [27] synthesized a new series of 5-chloro-3-methylbenzofuran
incorporated pyrimidines (61,62) and isoxazolines (63). These compounds were
characterized and evaluated for their antimicrobial, analgesic and anti-inflammatory
activities. Most of the compounds showed good to moderate activity against bacteria E.
coli and S. epidermidis and against fungi C. albicans and A. niger.
O
ClCH3
N
NH
O
R
.
(61)
O
ClCH3
N
NH
S
R
(62)
O
ClCH3
NO
R
(63)
R= C6H5, C6H4Cl(p), 4-OCH3C6H4, C6H4N(CH3)2(p)
Chapter-2 Review of Literature
Ph. D. Thesis 30
Makrandi et al. [28] synthesized 3-Alkyl/Aryl-6-(2-Benzofuranyl)-7H-s-triazolo[3,4-
b][1,3,4]thaidiazines (64) by the condensation of 3-Alkyl/Aryl-4-amino-5-mercapto-s-
triazoles with 2-(2-bromoacetyl)benzofurans under reflux in abs ethanol. These
compounds were characterized and evaluated for their antibacterial and antifungal
activities. The compounds were found to possess mild to moderate antibacterial and
antifungal activity
O N N
S
N
N
R
(64)
R=H, CH3, C2H5, n-C3H7, n-C4H9, 4-OCH3C6H4, 3-CH3C6H4
Swamy et al. [29] synthesized 3-(3’-hydroxy benzofuranyl)-5-aryl-pyrazolines (65) by
the cyclization of 3-Hydroxy benzofuran chalcones with hydrazine hydrate in anhyd
ethanol. All the compounds were screened as antibacterial and antifungal agents. Some of
the compounds showed good antifungal activity. All the compounds showed weak
activity against S. aureus and E. coli.
O
OH
NNH
R
(65)
R= 2-OHC6H4, 4-OCH3C6H4, 2-NO2C6H4, C6H4N(CH3)2(p), 3-OCH3 4-OHC6H3, O
Makrandi et al. [30] synthesized 2-Alkyl/aryl-6-benzofuranyl imidazo [2,1-b]-1,3,4-
thiadiazoles (66) by condensation of 5-Alkyl/aryl-2-amino-1,3,4-thiadiazoles with 2-(2-
bromoacetyl)benzofurans under normal condition and under microwave irradiation. The
compounds were evaluated for their antibacterial and antifungal properties. The
compounds showed strong to moderate antibacterial activity. The compounds were found
to be inactive against fungi.
Chapter-2 Review of Literature
Ph. D. Thesis 31
O N
NR'
S
N
R
(66)
R= CH3, n-C5H11, n-C6H13, n-C7H15, C6H4Cl(p), C6H4Br(o), 3-CH3C6H4
R’=H, Cl, CH3
Basavaraj et al. [31] synthesized some triazolo thiazolidinones containing 5-chloro-3-
methyl-2-yl benzofuran moiety (67-68). All the synthesized compounds were
characterized and evaluated for antibacterial and antifungal activities. Some compounds
displayed good antibacterial and antifungal activity compared to standard drugs.
OS
N
Cl CH3
N
NS
R
S
(67)
O
ClCH3
S
N N
N
S
R
O
(68)
R=H, C6H5, 4-CH3C6H4 , 4-ClC6H4
Madhu et al. [32] synthesized some 5-substituted Benzofuran derivatives (69) and tested
for their antibacterial activities. All the derivatives showed significant activity against
gram positive and gram negative bacteria (Ciprofloxacin and Ampicillin were used as
standard).
Chapter-2 Review of Literature
Ph. D. Thesis 32
O
O2NCH3
N N
O
CH2R
S
(69)
R= 2-Hydroxy-1-naphthyl, 3,4,5-trimethoxy phenyl, 2-methoxyphenyl, 4-hydroxy-3-
ethoxy phenyl, 1-carboxypyridyl phenyl
Basavaraj et al. [33] synthesized 2-(3’,4’,5’-trimethoxyphenyl/α-naphthyl)-4-methoxy
benzofuro [3,2-d]pyrimidines (70), 2-(3,4,5-trimethoxyphenyl/α-naphthyl)-4-ethoxy
benzofuro [3,2-d]pyrimidines (71), 2-(3,4,5-trimethoxyphenyl/α-naphthyl)-3,4-dihydro-
4-thiobenzofuro [3,2-d]pyrimidines (72). All the synthesized compounds were
characterized and 1`evaluated for antibacterial and antifungal activities. Most of the
compounds showed good to moderate antibacterial and antifungal activities.
O
N
NR
OCH3, O
N
NR
OC2H5 , O
N
NR
SH
(70) (71) (72)
R=
CH3
CH3
CH3 ,
Anti-inflammatory Activity:
Dawood et al. [34] synthesized new benzotriazole and benzofuran-based heterocycles
(73-74). The newly synthesized compounds were found to possess anticonvulsant and
anti-inflammatory activities.
Chapter-2 Review of Literature
Ph. D. Thesis 33
O
O
N
N
NN S
O
R'
Ph
CH3
OS
NHPh
RO
N
N
N
(73) (74)
R’= CH3, OC2H5 R= 2-Benzofuryl, C6H5, 4-BrC6H4, CH3
Jadhav et al. [35] synthesized a series of 6-substituted and 5,6-disubstituted 2-(6-
methyl-benzofuran-3-ylmethyl)-imidazo[2,1-b][1,3,4]thiadiazoles (75). The new
compounds have been tested for their in vivo anti-inflammatory activity. Qualitative SAR
studies indicate that the chloro substitution in the imidazole ring and introduction of
formyl group at C-5 position of the imidazole ring increased the anti-inflammatory
activity.
OH3C
NN
S N
R
R'
(75)
R’= -H, -CH2OH, -CHO, -CN, CH=NOH,
O N CH2
; R= Br, Cl, NO2
Santana et al. [36] synthesized four benzofuran-3-acetic acids (76) by a novel and easily
generalized route and designed as potential non-steroidal anti-inflammatory agents.
O
COOH
R
(76)
R= 6-OH, 6-OH 7-CH3, 5-CH3, 5-OCH3
Chapter-2 Review of Literature
Ph. D. Thesis 34
Analgesic activity:
Radl et al. [37] synthesized and tested 3-Unsubstituted 1-Benzofurans, 3-amino-1-
Benzofurans (77) and 3-methyl-1-Benzofurans (78) as analgesics.
O
R1
R2
R3
NH2
R4
O
O
R3
MeO
R2
R1
O
(77) (78)
R1= H, OMe; R2= H, OMe; R3= H, OMe R1= H, Br; R2= H, Me; R3= H, OMe
R4=H, Br, Ph, 2,4-diFC6H3
Jadhav et al. [35] synthesized a series of 6-substituted and 5,6-disubstituted 2-(6-methyl-
benzofuran-3-ylmethyl)-imidazo[2,1-b][1,3,4]thiadiazoles (79). The new compounds
have been tested for their in vivo analgesic activity. Qualitative SAR studies indicate that
the chloro substitution in the imidazole ring and introduction of formyl group at C-5
position of the imidazole ring increased the analgesic activity.
OH3C
NN
S N
R
R'
(79)
R’= -H, -CH2OH, -CHO, -CN, CH=NOH, O N CH2
; R= Br, Cl, NO2
Basawaraj et al. [14] synthesized 2-N-arylaminoacetyl-5-chloro-3-methylbenzofurans
(80). Some of the compounds displayed significant analgesic activity against Analgin as
standard.
Chapter-2 Review of Literature
Ph. D. Thesis 35
O
CH3
Cl
O
NH
R
(80)
R= H, 2-CH3, 4-CH3, 2-OCH3, 4-OCH3, 2-Cl, 4-Br, 2-NO2
According to Radl et al. [38] 2-Benzoyl and 2-(pyridylcarbonyl)-1-benzofuran-3-amines
and 2-Benzoyl and 2-(pyridylcarbonyl)-1-benzothiophene-3-amines (81-84) were
prepared and from this various derivatives were synthesized. Several compounds were
found to exhibit considerable analgesic activity.
O
N
O
R2
R1
(81)
R1= Ac, COOC2H5, H, Me R2=CH2COOC2H5, Me
O
NH2
O
R1
R2
(82)
R1= OCH2COOC2H5, H, OCH2COOH, O(CH2)3NMe2, OMe, OH
R2= OCH2COOC2H5, H, OCH2COOH, O(CH2)3NMe2, OMe, OH
Chapter-2 Review of Literature
Ph. D. Thesis 36
X
NH2
O
N
(83)
X= O, S Position= 2,3,4
O
CH2
O
R
(84)
R=Me2N,
N N Me
, N MeS
Antidepressant Activity:
Dauzonnel et al. [39] synthesized a series of novel benzofuranylacryloylpiperazines (85)
which are structurally related to both cinnamamide derivatives and befuraline. Their
anticonvulsant and antidepressant activities against seizures induced by electroshock and
against tetrabenazine-induced palpebral ptosis have been evaluated in mice. Some of
them revealed interesting potencies since, although they are less active than the reference
drugs, they exhibited a higher protective index.
O
N
N
O
R4
R1
R2
R3
(85)
R1= H, OCH3, CN, Cl, CH3 ; R2= H, OCH3; R3= H, OCH3
Chapter-2 Review of Literature
Ph. D. Thesis 37
R4=phenyl, 3-CF3-phenyl, 2-C2H5O-phenyl, 2-pyridinyl, 2-pyrimidinyl, benzyl,
piperonyl, 4-Cl benzhydryl, 4-OCH3-benzyl, 4-Cl-benzyl, phenethyl,-
CH2CONHCH(CH3)2, cyclohexanyl
Venkatesan et. al. [40] prepared several benzofuran derivatives (86) linked to a 3-
indoletetrahydropyridine through an alkyl chain and evaluated for serotonin transporter
and 5-HT1A receptor affinities. The Selective serotonin reuptake inhibitors (SSRIs) have
achieved great success in treating depression and related conditions.
O
N
NH
R2
R3
R4
R1
R
(86)
R= H, 6-Cl, 5-F, 5-OCH3 R1= H, CH3 R2=H, CN, F R3=H, F R4=H, C2H5
Anticonvulsant activity:
Rajak et. al. [41] reported a series of novel N-({5-[(6-methyl-1-benzofuran-3-yl)methyl]-
1,3,4-thiadiazol-2-yl}carba-mothioyl)-2/3/4-substituted benzamide (87) were designed,
synthesized and evaluated for their anticonvulsant activity. Most of the compounds
showed anticonvulsant activity.
O
S
NN
NH
NH
S
R
O
H3C
(87)
Chapter-2 Review of Literature
Ph. D. Thesis 38
R= C6H5, (2-Cl)C6H4, (3-Cl)C6H4, (4-Cl)C6H4, (4-OCH3)C6H4,
(4-OC2H5)C6H4, (4-OH)C6H4, (4-NO2)C6H4
Patel et al. [42] synthesized new N-1’,N-3’-disubstituted-2’H,3H,5’H-spiro-(2-
benzofuran-1,4’-imidazolidine)-2’,3,5’-triones . The anticonvulsant effects of these
compounds were evaluated by standard pentylenetetrazol (scPTZ test) and maximum
electroshock seizure (MES test) models in mice. Most of the compounds showed ability
to protect against the pentylenetetrazol-induced convulsions. Compound (88) exhibited
maximum activity with ED50 of 41.8 mg/kg in scPTZ convulsion model.
O
O
NN
O
O
C2H5
NO2
(88)
Vaidya et al. [43] synthesized the Benzofuro[3,2-e]-1,4-diazepines by chloroacetylation
of 2-acyl-3-aminobenzofuran and subsequent treatment with hexamethylene tetramine in
ethanol via the complex salts. Similar reaction with ethyl 3-aminobenzofuran-2
carboxylate produced 3H-benzofuro[ 3,2-e]-1,4-diazepin2,5(1H,4H)-dione. All the newly
synthesized compounds were evaluated for anticonvulsant activities. The diazepine (89)
was found to possess considerable anticonvulsant activity, since it reduced the extensor
phase of the MES convulsions to a greater extent and comparable with that of standard
drug.
O
N
HN
O
(89)
Chapter-2 Review of Literature
Ph. D. Thesis 39
Basawaraj et al. [44] synthesized 4-Aryl-3-(5’-chloro-3’-methylbenzofuran-2’-yl)-1(H)
benzodiazepines (90) and 4-Aryl-3-(5’-chloro-3’-methylbenzofuran-2’-yl)-1(H)
dihydrobenzothiazepines (91). These compounds showed either reduction or abolition of
tonic extensor phase of convulsions produced by Chemical method using Diazepam as
standard drug.
O
CH3
Cl
N
HN
R
O
CH3
Cl
S
HN
R
(90) (91)
R= C6H5, C6H4 OH(o), C6H4 OH(p), C6H4 OCH3(p),
O
Antitumor activity:
Hayakawa et al.
[45] synthesized (4-hydroxy-3-methyl-6-phenylbenzofuran-2-
yl)phenylmethanone (92) as potent anti-tumor agent.
O
CH3OH
O
(92)
Baraldi et al. [46] synthesized a series of benzoyl and cinnamoyl nitrogen mustards (93)
tethered to different benzoheterocycles and to oligopyrroles structurally related to
netropsin consisting of two pyrrole-amide units and terminating with an amidine moiety.
The compounds with benzofuran showed 7- and 14-fold reduced cytotoxic potency than
tallimustine.
Chapter-2 Review of Literature
Ph. D. Thesis 40
O
NH
O N
NH
O
NH
NH2
HN
O
NCl
Cl
(93)
Asoh et. al. [47] synthesized a series of benzofuran-based farnesyl transferase inhibitors
(94) as antitumor agents. The compounds showed the most potent enzyme inhibitory
activity (IC50 = 1.1 nM) and antitumor activity in human cancer xenografts in mice.
O
N
N
NH2
CH3
R2
R1
R3
(94)
R1= CN,R2= NO2, CNR3= H, 3-OCH3, 3-CN, 3-F
Gaisina et. al. [48] reported the design, synthesis, and biological evaluation of
benzofuran-3-yl-(indol-3-yl)maleimides derivatives (95) and potent GSK-3β inhibitors
activities. The compounds showed antiproliferative activity against some or all of the
pancreatic cancer cells at low micromolar to nanomolar concentrations.
NH
X
HN
OO
O Y
(95)
Chapter-2 Review of Literature
Ph. D. Thesis 41
X= H, 5- F, 5-Br, 5-Cl,6-Cl, 5-I,6-I, 5-CN, 5-OCH3, 6-p-Cl-C6H4, 7-CH2OH etc.
Y= H, 5- F, 7-OCH3, 6-CH2OH, 6-CH2OCH3 etc.
Imaging activity:
Ono et al. [49] designed and synthesized small molecule-based benzofuran derivatives
(96-97) which acts as Aβ-aggregate-specific imaging agents for Alzheimer’s disease.
O
I
N
R O
I
R
(96) (97)
R= H, CH3 R= OH, OCH3
Ono et al. [50] were synthesized Novel benzofuran derivatives (98) for PET Imaging of
β-Amyloid Plaques in Alzheimer’s disease.
O
R1
R2
(98)
R1=-OMe, OH R2= -NH2, -NHCH3 -N(CH3)2
Anti-HIV activity:
Rida et al.
[7] synthesized and evaluated several benzofuran derivatives (99-103)
containing heterocyclic ring substituents linked to the benzofuran nucleus at C-2 by a
two- to four-atom spacer as potential anti-HIV-1 agents. Among these derivatives, two
compounds exhibited interesting anti-HIV-1 activity. Some compounds showed weak
anti-HIV-1 activity.
Chapter-2 Review of Literature
Ph. D. Thesis 42
O
N
CH3
N
N
S
O
R
O
N
CH3
N
N
S
CH3
R
(99) (100)
R= C4H9, CH2C6H5, C6H5, 4-CH3C6H4 R= CH2C6H5, C6H5, 4-CH3C6H4
O
N
CH3
N
N
S
R
R1
O
N
CH3
N
N
S
O
R
R1
(101) (102)
R= CH2C6H5, C6H5, 4-CH3C6H4 R= CH2C6H5, C6H5
R1=CH3, Cl R1= OCH3, Cl
O
N
CH3
N
N
O S
N
S
R
(103)
R= CH2C6H5, C6H5
Antidiabetic activity:
Several thiazolidinedione derivatives having 5-hydroxy-2,3-dihydro-2,2,4,6,7-
pentamethylbenzofuran moieties and their 5-benzyloxy derivatives and 5-hydroxy-
2,4,6,7-tetramethylbenzofuran moieties were synthesized by Reddy et al. [51]. At a 100
mg/kg/day dose of the maleate salt, compound (104) reduced the plasma glucose and
Chapter-2 Review of Literature
Ph. D. Thesis 43
triglyceride to the level of lean littermate, i.e. 8±1 mM, and is the most potent and
efficacious compound.
O
OCH2C6H5
NO
NH
S
O
O
(104)
Antitubercular activity:
Manna et al. [20] synthesized various 3-(1-benzofuran-2-yl)-5-phenylisoxazoles (105).
The benzofuran isoxazoles were evaluated for their antitubercular activity. Some of the
compounds have shown promising antitubercular activity.
O
NO
R
(105)
R= -OH(o), -OCH3(o), -N(CH3)2(p), -COOH(o), -NO2(m), -OH(o)OCH3(p), -OH(p), -
Cl(p), -Cl(o), -NO2(o), -OCH3(p), -H, Furan ring, -Cl=CH-Ar
Manna et al. [52] synthesized newer 3-benzofuran-5-aryl-1- pyrazolylcarbonyl-4-oxo-
naphthyridin (106) and 3-benzofuran-5-aryl-1-pyrazolyl-pyridyl methanone analogs
(107) by microwave irradiation method and evaluated for in-vitro and in-vivo
antitubercular activity against multidrug-resistant M. tuberculosis stains. Structure
activity relationship study was carried out and found NO2 (o) substituted 3-benzofuran- 5-
aryl-1-pyrazolylcarbonyl-4-oxo-naphthyridin was most potent antitubercular agent
against M. tuberculosis, even better than standard drug isoniazid and comparable with
rifampin16
.
Chapter-2 Review of Literature
Ph. D. Thesis 44
ON
NO
N
ON
NO
N
N
C2H5
CH3
O
RR
(106) (107)
R= OH (o), OCH3 (o), OCH3 (p), N (CH3)2 (p), COOH (o), NO2 (m), OH (o),
OCH3 (p), OH (p), Cl (o), Cl (p), NO2 (o), H, Furan Ring, CH=CH-Ar
Antioxidant activity:
More et al. [53] synthesized 2-(7-methoxy-3-methyl-1-benzofuran-2-yl)-4H-chromon-4-
ones (108). Some of the compounds showed moderate antioxidant activity.
O
O
R1R2
R3
O
H3C
OCH3
(108)
R1= H, CH3, Cl; R2= H, CH3; R3= H, CH3, Cl, F, Br
Miscellaneous:
Hagihara et al.
[54] synthesized a series of 4-(6,7-dimethoxy-1,2,3,4
tetrahydroisoquinolin-2-yl)methyl-2-arylbenzofuran and 4-(6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinolin-2-yl)methylbenzofuran-2-carboxamide derivatives as novel α2C-
adrenergic receptor antagonists. Compound (109) has been found to show the anti-L-
dopa-induced dyskinetic activity in marmosets.
Chapter-2 Review of Literature
Ph. D. Thesis 45
O
OMe
N
OMe
OMe
(109)
Choi et al. [55] synthesized a series of 2-(4-hydroxyphenyl)benzofurans. Then 5-Methyl-
3-p-toluoyl-2-[4-(3-diethylaminopropoxy) phenyl]benzofuran (110), a β-amyloid
aggregation inhibitor, was synthesized by three steps starting from 2-(4-hydroxyphenyl)
benzofurans.
O
O
O
N
(110)
Literature related to Piperazine, Piperidine and Morpholine:
Aridoss et al. [56] synthesized an array of novel N-morpholinoacetyl-2,6-diarylpiperidin-
4-ones (111) and their in vitro antibacterial activity against Staphylococcus aureus,
Escherichia coli, Pseudomonas aeruginosa and Salmonella typhi and antifungal activity
against Candida albicans, Rhizopus sp., Aspergillus niger and Aspergillus flavus were
evaluated. The compounds were exhibited excellent antibacterial and antifungal
activities.
Chapter-2 Review of Literature
Ph. D. Thesis 46
N
N
O
O
R2 R1
OR R
(111)
R= H, Cl, OMe, Me; R1=H, Me, Et, i-Pr ; R2=H, Me
Aridoss et al. [57] synthesized a series of N-(N-methylpiperazinoacetyl)-2,6-
diarylpiperidin-4-ones (112) by the base catalyzed nucleophilic substitution of N-
chloroacetyl-2,6-diarylpiperidin-4-ones obtained from their corresponding 2,6-
diarylpiperidin-4-ones with N-methylpiperazine. All the compounds were screened for
their possible antibacterial and antifungal activities against a spectrum of microbial
agents besides analgesic and antipyretic activities. The compounds were exhibited
promising antimicrobial activities and beneficial analgesic and antipyretic profile at a
concentration of 60 mg/kg and were also found to be more potent than the reference drug.
N
N
N
O
R2 R1
OR R
CH3
(112)
R= H, Cl, OMe, Me; R1= Me, Et, i-Pr ; R2=H, Me
Chapter-2 Review of Literature
Ph. D. Thesis 47
Malinka et al. [58] described the synthesis and pharmacological investigation of a new
series of derivatives of pyrrole-3,4-dicarboximide (113) possessing the 4-substituted-
piperazin-1-ylalkyl group linked to the imide nitrogen. The products were evaluated for
acute toxicity, and effectiveness in a series of CNS and arterial blood pressure tests.
Several compounds demonstrated moderate to high analgesic activity in the ‘writhing
syndrome’ test.
N
N
R
H3C
CH3
O
O
CH2
CH2 CH2
NN
R1
(113)
R= n-C4H9, 2-Pyridine, 3-Pyridine, 2-Thiazole, C6H5, 2-C5H4N
n= 0, 1, 2
R1= o-CH3O-C6H4, o-Cl-C6H4, m-Cl-C6H4, m-CF3-C6H4, 2-Pyridine, 2-Pyrimidine
Mishra et al. [59] synthesized some new N-substituted acetyl derivatives of 2-amino-5-
alkyl-1,3,4-thiadiazoles (114) and investigated for antihistaminic and spasmolytic activity
on guinea pig ileum. A few of the compounds showed encouraging effect. Some of the
compounds also showed anti-inflammatory activity.
(114)
R= CH3, C2H5
S
NN
R NH
O
X
Chapter-2 Review of Literature
Ph. D. Thesis 48
X= N
,
N
H3C
N NH
, N N CH3
, N
C4H9
CH3 , N
CH2
CH3
Geronikaki et al. [60] synthesized 4,5-disubstituted-thizolyl amides, derivatives of 4-
hydroxy-piperidine and of 4-N-methyl piperazine (115), and tested as anti-inflammatory
agents. The effect of the synthesized compounds on inflammation, using the carrageenin
induced mice paw edema model was studied. It showed that anti-inflammatory activity
depended on some structural characteristics of the synthesized compounds.
S
N
R
NHCO(CH2)nX
(115)
R= H, CH3, C6H5,C6H4OCH3
X= N N CH3
,N OH
Lipnicka et al. [61] synthesized several new compounds 4 and 5-substituted derivatives
of 3-methyl-4-isothiazolecarboxylic acid (116). The biological activites of the obtained
compounds were analyzed in the humoral immune response and delayed type
hypersensitivity reaction to sheep red blood cells (SRBC) in the mouse model, as well as
in the proliferative response of splenocytes to T-cell and B-cell mitogens in vitro.
S
N
H3C
NHCO(CH2)nR
COOC2H5
(116)
R=N
,N O
,N
CH(CH)3
H ,HN Cl
, HN OC2H5
Chapter-2 Review of Literature
Ph. D. Thesis 49
Saxena et. al. [62] synthesized a series of 1-[3-(4-substituted phenylthio) propyl]-4-
(substituted phenyl) piperazines (117) and evaluated for hypotensive activity. The QSAR
study indicates that resonance and hydrophobic parameters of the aryl substituents are
important for hypotensive activity.
N N S R
R'
(117)
R= CH3, H, OCH3, NHC2H5, Cl, F, Br, NHCOCH3
R’= 2-CH3, 3-CH3, 3-Cl, 3-CF3, 3,4-Di Cl, 4-F, 3-F
Saxena et. al. [63] synthesized a series of 2-substituted octahydropyrazinopyridoindoles
(118). Three of the five newly synthesized 2-substituted octahydropyrazinopyridoindoles
have shown potent antihistaminic H1 activity with less toxicity and sedation potential.
NH
N
N NH
OR
(118)
R= NO2, OCH3, C2H5, Cl, F
Kowalski et. al. [64] described the synthesis of a series of new n-propyl and n-butyl
chain containing 1-aryl-piperazine derivatives of quinazolidin-4(3H)-one (119) 2-
phenyl-2,3-dihydrophthalazine-1,4-dione (120) and 1-phenyl-1,2-
dihydropyridazine-3,6-dione (121) as potential serotonin receptor ligands.
N
N
O
N
N
O
Ph
O
N
N
O
Ph
O
(119) (120) (121)
Chapter-2 Review of Literature
Ph. D. Thesis 50
a=
(CH2)3 N N
b=
(H2C)3 N N
N
N
c=
(CH2)4 N N
d=
(H2C)4 N N
N
N
Kuran et. al. [65] has synthesized a set of 36 arylpiperazine derivatives with two novel
complex terminal imide fragments, 8,11-dimethyl-3,5-dioxo-4-azatricyclo[ 5.2.2.02,6]
undec-8-en-1-yl acetate (122) and 1,11-dimethyl-4-azatricyclo[5.2.2.02,6]undecane-
3,5,8-trione (123), and tested for their affinity for 5-HT1A and 5-HT2A receptors. Three
Compounds out of 14 screened in a functional model of anxiety and depression
demonstrated antidepressant activity in the forced swimming tests in mice, and was
devoid of neurotoxic effects (chimney test in mice).
N
O
O
CH3
OAc
X
NNAr
H3C
(122)
N
O
O
O
CH3
CH3
X
NNAr
(123)
Ar= o-OCH3-Ph, Pyrimidyl, Pyridyl, Phenyl, p-F-Ph, Benzyl
X= CH2, O
Chapter-2 Review of Literature
Ph. D. Thesis 51
Barbaro et. al. [66] synthesized a series of benzodioxanes (124) by adding a N-alkyl
piperazine bearing a cyclic substituent (a substituted or unsubstituted phenyl group, a
pyridine or pyridazinone ring, a furoyl moiety) at the second nitrogen atom. Structure-
activity relationships have been derived for compounds 2–17 based on their fitting to a
pharmacophore model for α1-adrenoceptor antagonists.
O
O
HN
(CH2)nN
NR
(124)
R= o-Methoxyphenyl, o-Chlorophenyl, Phenyl, 2-Pyridinyl, p-Methoxyphenyl, o-
Fluorophenyl, 2-Methyl-4-chloropyridazin-3(2H)-one-5-yl, 2-Furoyl
n= 2,3
Jolanta Obniska et. al. [67] synthesized the series of N-[(4-arylpiperazin-1-yl)-alkyl]-3-
(2-methylphenyl)- (125) and 3-(2-trifluoromethyl-phenyl)-pyrrolidine-2,5-diones (126)
and tested for anticonvulsant activity using the maximal electroshock (MES),
subcutaneous pentylenetetrazole (scPTZ) screens. Their neurotoxicity were determined
applying the rotorod test. In this series, the most active were N-[(4-phenylpiperazin-1-yl)-
methyl]-3-(2-trifluoromethylphenyl)-pyrrolidine-2,5-dione with the ED50 =20.78 mg/kg,
when given orally to rats and N-[3-{4-(3-trifluoromethylphenyl)-piperazin-1-yl}-propyl]-
3-(2-trifluoromethylphenyl)-pyrrolidine-2,5-dione with the ED50= 132.13 mg/kg after
intraperitoneally injection to mice.
N
O
OR
CH2
N
NR1
(125)
R= CH3, CF3
R1= H, 2-F, 2-OCH3, 3-Cl, 3-CF3
Chapter-2 Review of Literature
Ph. D. Thesis 52
N
O
OR
(CH2)nN
NR1
(126)
R= CH3, CF3
R1= H, 2-F, 2-OCH3, 3-Cl, 3-CF3
n= 2,3
Pawlowski et. al. [68] synthesized a series of new 3-[4-(4-arylpiperazinyl)-butyl]-β-
tetralonohydantoins (127). The compounds exhibited high affinity for 5-HT1A receptors
(Ki = 6 to 55 nM) combined with moderate-to-high 5-HT2A receptor affinities (Ki = 45 to
213 nM).
HNN
O
O
(CH2)4
N
N R
(127)
R= H, 2-OCH3, 2-F, 3-Cl, 4-F, 3-CF3
Santana et. al. [69] synthesized a series of novel long-chain arylpiperazines (128)
bearing a coumarin fragment and the compounds were evaluated for their affinity at α1A,
D2 and 5-HT2A receptors. Most of the new compounds showed high affinity for the three
types of receptors α1A, D2 and 5-HT2A which depends, fundamentally, on the
substitution of the N4 of the piperazine ring.
Chapter-2 Review of Literature
Ph. D. Thesis 53
O
R
OON
NAr
(128)
R=-OCH3, -CH3,
Ar= ,
OCH3
,
N
, N
N
Pawlowski et. al. [70] synthesized and reported the 5HT1A and 5HT2A receptor
affinities of several γ-(3’-chloro- or 2’-methoxyphenyl)-piperazinopropyl derivatives of
pyrimido[2,1-f]purines (129) or 1,3-diazepino[2,1-f]purines (130).
N
N
O
O
N
N
H3C
H3CN
(H2C)3 NN
Z
O
(129)
N
N
O
O
N
N
H3C
H3C
(CH2)n
N
(H2C)3
X
N N
Z
(130)
Chapter-2 Review of Literature
Ph. D. Thesis 54
X=CH2, CO
n= 3,4
Ar= , N
N
Z= 3’-Cl, 2’-OCH3,
Geronikaki et. al. [71] synthesized a series of thiazolyl/benzothiazolyl-N-phenyl
piperazines (131-132) and tested for anti-inflammatory activity. Their RM values were
determined as an expression of their lipophilicity. Theoretical calculation of their
lipophilicity, as clog P and logPsk also performed. The effect of the synthesized
compounds on inflammation, using the carrageenin induced mouse paw oedema model
was studied. In general, the studied compounds were found to be potent anti-
inflammatory agents (44–74.1%).
N
S
R
NHCO(CH2)nN N
(131)
R= H, CH3, Ph, Ph-OCH3,
n=1,2
N
SNHCO(CH2)nN N
R
(132)
R= H, F, OC2H5
n=1,2
Chapter-2 Review of Literature
Ph. D. Thesis 55
Achaiah et. al. [72] synthesized a series of (6-Substituted 4-Oxo-4H-chromene-3yl)
methyl N-substituted Aminoacetates (133). All the compounds were evaluated for in vitro
antihistaminic activity by inhibition of isotonic contractions induced by histamine on
isolated guinea pig ileum. These compounds exhibited significant protection against
histamine induced convulsions in guinea pig at the dose of 50 μmol.
O
R
O
CH2OCOCH2NR1R2
(133)
R=H, CH3, Cl
-NR1R2= R1= H, R2= pyridyl, Morpholino, 4-Methyl pipaerazino, 4-ethyl pipaerazino
piperidino,
Strappaghetti et. al. [73] designed and synthesized a new series of arylpiperazine
derivatives (134-135). The pharmacological profile of these compounds was evaluated
for their affinity and selectivity toward α1-AR, α2-AR and toward 5HT1A serotoninergic
receptor.
NN
(CH2)n
O CH3
NN
R
(134)
R=H, o-OCH3, o-C2H5, o-OCH(CH3)2, m-Cl, m-CF3
n=2,4,7
NN
(CH2)n
O CH3
R
Chapter-2 Review of Literature
Ph. D. Thesis 56
(135)
R=
NN
O
,
NN
N
N
, N
N
O
O
n=4,7
New arylpiperazines (136) related to buspirone, gepirone and NAN-190 were designed
by Ashwell et. al. [74] and screened in silico for their 5-HT1A affinity and potential sites
of metabolism by human cytochrome P450 (CYP3A4). Modifications to these structures
were assessed in silico for their influence on both 5HT1A affinity and metabolism.
N
O
O
R3
R2
NNR4
R1
(136)
R1= H, Me
R2= H, Me, OH
R3= H, Me
R4= Pyrimidine, 5-F Pyrimidine, p-F Phenyl, 2-Pyrazine, p-OMe Phenyl
Chapter-2 Review of Literature
Ph. D. Thesis 57
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