Review of literature Chapter-II - Information and Library...
Transcript of Review of literature Chapter-II - Information and Library...
Chapter – II Review of Literature
30
2.0 REVIEW OF LITERATURE
2.1 Computer Aided Drug Design
Kadam RU et al., 2007 reported the computational techniques for identifying
drug-like molecules, ranging from simple counting schemes to sophisticated machine
learning techniques such as neural networks, along with their application and challenges.
Bakht et al., 2010 reported the octanol/water partition coefficients, solubilities,
absorption, molecular volumes and polar surface areas, rotatable single bonds, hydrogen
bond donors acceptors and lipophilicities for a set of 28 oxadiazoles and reported
synthesis, antibacterial, antifungal activity.
Dwivedi PB et al., 2009 reported drug likeliness of N-(furan-2-ylmethyl) -2-(1H-
tetrazol-5-yl) acetamide and its 14 hypothetical analogs based on toxicity, lipophilicity,
solubility and molecular weight. Properties were calculated by Osiaris molecular property
explorer. Lipophilicity of N-(furan-2-ylmethyl)-2-(1H-tetrazol-5-yl) acetamide is low.
Drug likeness was predicted based on atomfragment based contribution. Overall drug
score combines all other into one grand total. Heat of formation and lipophilicity of all
analogs is also calculated.. In early stages of designing antiinflammatory and analgesic
drug based on N-(furan-2-ylmethyl) -2-(1H-tetrazol-5-yl) acetamide, it is beneficial to do
this in-silico study before synthesis work is under-taken with the aim of avoiding the
synthesis of compounds.
Wager et al., 2010 reported properties for 119 marketed CNS drugs and a set of
108 Pfizer CNS candidates in understanding the relationships between physicochemical
properties, in vitro ADME attributes, primary pharmacological binding efficiencies and
in vitro safety data for these two sets of compounds.
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Ursu et al., 2010 reported drug-likeness filter (DLF), starting from molecular
fragments and molecular weight a key property relevant in drug design. The molecular
fragments were selected from extended connectivity atom environments based on their
occurrence ratio in our collection of drugs and "nondrugs".
Huang et al., 2010 reported a new pharmacophore-based de novo design method
of drug-like molecules. The method first generates a set of new molecules that
completely conform to the requirements of a given pharmacophore model, followed by a
series of assessments to the generated molecules, including assessments of drug-likeness,
bioactivity and synthetic accessibility.
Jihane F et al., 2011 reported the design and molecular properties of some
aldazines derivatives on the basis of hypothetical antibacterial pharmacophore sire , to
interact with gram positive and negative bacteria. Lipinski rule of five, drug likeness and
physic-chemical properties of drugs are described.
Aliasghar J et al., 2012 reported the design and molecular properties often azo
Shiff bases on the basis of hypothetical antibacterial pharmacophore sire , to interact
with Gram positive and Gram negative bacteria. The antibacterial activity of the azo
Schiff bases was discussed on the basis of the theoretical calculations by using Petra,
Osiris, molinspiration.
Taibi Ben Hadda et al., 2012 reported the rational design of bioactive
pharmacophore sites as antiviral candidates based on X-ray structures of drugs and
reported the correlation between the theoretical predictions of bioavailability using Petra,
Osiris, molinspiration.
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Mohammed Afroz Bakht et al., 2010 reported the synthesis and antimicrobial
activity of some newer 1,3,4- oxadiazole analogies based on molecular properties
prediction and reported drug-likeness by Molinspiration and Molsoft softwares.
Lipophilicity and solubility parameters using ALOGPS 2.1 program.
Peter E et al., 2000 reported the new approach for the calculation of the Polar
surface area belonging to polar atoms to correlate well with positive molecular transport
through membranes and reported this new methodology may used for fast bioavailability
screening of virtual libraries having millions of molecules.
Ahmed M Alafeefy et al., 2011 reported the molecular docking to understand he
structural features responsible for anti-inflammatory activity of quinazoline derivatives.
Aliasghar J et al., 2012 reported the development of a computational model for
the rational design of bioactive pharmacophore sites as an antibacterial , antifungal and
antiviral candidates based on available X-ray structures of bis-Schiff bases.
Mohammed Jawed Ahsan et al., 2011 reported the synthesis antimicrobial and
antitubercular activity of 1,5-dimethyl-2-phenyl-4-{[(5-aryl-1,3,4-oxadiazol-2-yl) methyl]
amino} -1,2-dihydro-3H-pyrazol-3-one based based on molecular properties prediction,
and reported drug-likeness by Molinspiration and Molsoft softwares. Lipophilicity and
solubility parameters using ALOGPS 2.1 program.
Ravi G et al., 1996 reported the structural basis for selective inhibition of
cyclooxygenase-2 by anti-inflammatory agents.
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Vittorio Limongell et al., 2010 reported molecular basis of cyclooxygenase
enzymes selective inhibition using advanced computational technique and dissociation
process of the a highly potent and selective inhibitor , sc-558 in both COX-1 and COX-2.
Parvesh Singh et al., 2011 reported the synthesis of thiophene compounds,
additionally the binding conformations of these compounds and anti-inflammatory drugs
were determined by their docking in the active site of the COX-2 enzyme.
Arumgam M et al., 2012 reported the cyclooxygenase inhibitory activity of
flavonoids using Auto Dock 4.2, in silico docking studies. Three important parameters
like binding energy, inhibition constant and intermolecular energy were determined.
2.2 Chemistry and Pharmacology
It is seen from the literature that such efforts have led to the development of a
number of potent molecules synthetic methods and activities derived from
benzimidazoles, thiadiazoles, triazoles, oxadiazoles and Schiff base derivatives.
Benzimidazoles
Vinodkumar R et al., 2007 reported synthesis of a series of novel and functioned
benzimidazole derivatives 6 by the condensation of o-phenylenediamine with 4-Bromo
benzoic acid and subsequent reactions of the product obtained with phenyl acetylene and
6-ethynyl-4,4-dimethylthiochroman utilizing Sonogashira coupling. The Sonogashira
coupling products were then alkylated at the benzimidazole –NH with different
electrophilic reagents leading to functionalized derivatives. All the compounds
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synthesized were screened for their potential anti-bacterial, anti-asthmatic and anti-
diabetic properties, which exhibited moderate activities in screening studies in vitro.
NH
N
Br
NH
N
ArAlkylating Agent
Aryl Acetylene
6
Kam RV et al., 2007 reported the synthesis of a series of novel class of N-
substituted-2-9 benzo[d] isooxazol-3-ylmethyl)-1H benzimidazoles 7 by the condensation
of o-phenyl enediamine with benzo[d] isooxazol-3-yl aceticacid and subsequent reaction
with different types of electrophiles. These compounds were screened for antibacterial,
antiasthmatic and antidiabetic activity. Compound with CH2C6H5-Br substitution on
ortho position of the benzimidazole ring showed good antibacterial activity.
NH2
NH2
+ N
N
NO
reflux / 6 h
R-X or Ar-X
Base
N
N
NO
R
R = CH3, CO=CH3, CO-CH2-CH2CH3, CH2-C6H4-Br
4N HCl
HO
N
CH2COOH
7
Guven OO et al., 2007 reported the synthesis of some novel furyl and
benzimidazole substituted benzyl ethers 8. These compounds were screened for
antibacterial activity. Compounds substituted with phenyl ring having two chlorine atoms
at different positions showed good activity.
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O
CH3
O 1H, Benzimidzole
NNO
NNO
NNO
OAr
Ar =
Cl
Cl Cl
Cl
F Cl
Cl
Br
NaBH4
NaH
ArCH2X
Br2
8
Duhiya R et al., 2007 reported the synthesis of substituted benzimidazolyl-
benzoic/ salicylic acids by interaction of 5,6-dimethyl-6-nitrobenzimidazole with
diazotized substituted and unsubstiruted aminobenzoicacids in the presence of cupric
chloride. The coupling of these compounds with different amino acid ester
hydrochlorides, dipeptides, tripeptides methyl esters afforded novel benzimidazolo-
peptide derivatives 9, 10. These compounds were screened for antimicrobial, cytotoxic
and anthelmintic activity. All the compounds were found to have good activity.
H3C
H3C NH
N R1
CO-X-OH
R29
R3
R4 NH
N
OH
CO-X-OH
10
R1 = R2 = H; R3 = H, CH3; R4 = NO2, CH3
X = Aminoacids, dipeptides, tripeptides, tetrapeptides.
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Thiadiazoles
Nizamuddin et al., 1992
reported the synthesis of several 3-substituted-6-
arylamino-1,2,4-triazolo (3,4-b) -1,3,4 thiadiazoles 11, 12. Synthesis of 1,3,4-thiadiazoles
was carried out in following way. Refluxing of 2-arylamino-5-mercapto-1,3,4-
thiadiazoles with hydrazine hydrate in methanol yielded 2-arylamino-5-hydrazino-1,3,4-
thiadiazole which on treatment with formic acid, aryloxyacetic acid, methyl
chloroformate and carbondisulphide yielded required compounds. These compounds
were screened for antifungal activity. Among all the active compounds methoxy
substituted compound showed good activity.
NH
N
S
N
NN
CH2O
R'
R
11
NH
N
S
N
NN
R
H
12
R = 4-OCH3, 4-CH3, H, 4-Cl R’ = 4-OCH3, 4-Cl, H, 4-CH3
Nizamuddin et al., 1988 reported the synthesis of several 1-(5’substituted-phenyl-
1’,3,4’- thiadiazol-2’-yl) -3-chloro-4-substituted-2-azitidinone 13 by the annulations of
acid chlorides on anils using Et3N and were screened for antifungal activity. All the
compounds were found to have good activity.
NH
N
S
N
N H
HHO
R1
R
13
R = 2Cl, 2, 4-(CH2)2. R1= C6H6, C6H4.Cl-ρ.
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Dogan HN et al., 2002
reported the synthesized 2,5-disubstituted-1,3,4-
thiadiazole 14 by following way. First 1,3,4-thiadiazoles were formed by the dihydrative
cyclization of thiosemicarbazides acidic media, which on acetylating with acetic
anhydride yielded acetylated thiadiazole derivatives. These compounds were screened for
anticonvulsant and antimicrobial activity. Compounds with p-fluorophenyl and m-
trifluoromethylphenyl substitution at R position showed good antibacterial activity.
Compounds with phenyl ethyl and p-methoxy phenyl substitution at R position showed
good anticonvulsant activity.
S
NN
NCOCH3
R
OCOCH3
14
R= Phenylethyl, p-bromophenyl, p-chlorophenyl, p-fluorophenyl, m-trifluoromethyl
phenyl.
Rollas S et al., 2004 reported the synthesis of 2,5, disubstituted-1,3,4,
thiadiazoles 15. For the synthesis of these compounds first 4-substituted benzoic acid
hydrazides were refluxed with arylisothiocyanates in ethanol, this afforded
thiosemicarbazides, which were cyclized into thiadiazoles. The compounds were
screened for antitubercular activity. Compound with 4-fluorophenyl substitution at
thiadiazole moiety was found to be more active.
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R COCl + HO R COO
NH2NH2
CH3OH
R CONHNH2HN R1CHNHNCAr
O S
NH2NH2
CH3OH
N
S
N
Ar NH
R1
NaOH
NaOH
15
Ar = C6H5, 4-Br-C6H4, 4-Cl-C6H4, C6H5
R1 = C6H5, 4-Br-C6H4, 4-Cl-C6H4, C6H5
Mohan J et al., 2002 reported the synthesis of 2,6 diarylimidazo (2,1-b) -1,3,4-
thiadiazole by the reaction of α haloketones with 2-amino-5-(3,5-dinitrophenyl) -1,3,4-
thiadiazole. Bromination of which furnished 5-bromo-2, 6, -diarylimidazo (2, 1-b) -1,3,4-
thiadiazole 16. These compounds were screened for antimicrobial activity.
O2N
NO2
S
NN
NH
Br
R16
R= Cl, H
Schenone S et al., 2008 reported the synthesis of new 1,3,4-thiadiazole 17
derivatives by cyclizing the acyl thiosemicarbazides with phosgene in anhydrous THF.
The corresponding alkyl thiosemicarbazides were obtained by treating the benzene
sulphonyl hydrazides with different alkyl isothiocyanates in anhydrous THF. The
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compounds were screened for analgesic and anti-inflammatory activities. Compound with
p-fluoro phenyl substitution at R’ position was found to be more active.
R S NH NH2
O
O
+ S C N C R
OTHF anhyd.
rt, 3daysR S NH NH
O
O
C NH C R'
S O
CH3COONa anhyd.
phosgene
R SO2N
S
N
NHO C R1
O
17
R = H, CH3, R1
= Phenyl, 4-Methoxychlorophenyl, 4-Chlorophenyl, 4-fluorophenyl,
4-Trifluoro methyl phenyl.
Andanappa K et al., 2008 reported the synthesis of a series of 2-trifluoro methyl
sulfonamide -5,6-diarylsubstituted imidazo [2,1-b] -1,3,4-thiadiazole derivatives 18 by
the reaction of 2-amino-5-trifluoromethyl/sulfonamide-1,3,4-thiadiazoles and
appropriately substituted α-bromo-1,2-(p-substituted) diaryl-1-ethanones. The selected
compounds were evaluated for their preliminary in vitro cyclooxygenase inhibitory
activity against COX-2 and COX-1.
O
Br
R1
R
EtOH, P2OH5
N
S NH2R2R1
N
NN
SR2
18
R = H, OCH3; R1 = H, F, CH3, OCH3; R
2 = CF3, SO2NH2
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Triazoles:
Georeg T et al., 1970 reported the synthesis a series of 5-alkyl-4-amino-5-
triazole-3-thiols 19 and screened for analgesic and anti-inflammatory activity.
N N
R SH
NH2
19
R= CH3, (CH2)2CH3, (CH2)3CH3, (CH2)-4CH3, CH2CH (CH3)2, C2H5.
Milcent R et al., 1984 reported the synthesis of 2-substituted-4-amino-5-alkyl-or
aryl-2,4-di- hydro-1,2,4-triazol-3-ones 20 and 2-substituted-5-alkyl or aryl-4-(5 nitro-2-
furfuraldehyde) amino-2,4-dihydro-1,2,4 triazol-3-ones 21, and screened for their
antibacterial activities.
N N
NR' O
CH2CH2SH
NH2
20
N N
NR1 O
R2
N CHO NO2
HH.2CH3 COOH
21
R’ = aryl or alkyl R
1 = aryl or alkyl
R2=CH2OCOC2H5, CH2OCOCH3
Reiler J et al., 1990 reported the synthesis of 1,5-diaryl-3-alkylthio-1H-1,2,4
triazoles 22 and corresponding sulfoxides and sulfones (23) by reaction of
phenylhydrazines with potassium thiocyanate in refluxing ethanol produced the
phenylthiosemicarbozide. Acylation of phenylthiosemicarbozide followed by cyclization
afforded an intermediate which on alkylation gave expected alkyl thioester. These
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compounds were evaluated for antiarthritic activity. Among all the compounds the p-
halogen compounds were found to be more active as antiarthritic agents.
N N
NR2 SOnR3
R1
22
N
N
N
R1
R2SOnR3
23
R1
= R2= substituted phenyl R
1 = H, 4F, 4Cl, 4-NO2
R3 = Alkyl R
2 = H, 4F, 4Cl, 4-NO2
n = 0-2 R3 = CH3, CH2CHF2; n = 0
Andotra GS et al., 1998 reported the synthesis of substituted aryl-6-ρ-chloro
phenyl 5-thione (1H)-1,2,4-triazole (1,5-a) s- triazines-7-ones 24 from 2-substituted-
1,2,4-triazole derivatives and screened for various antibacterial and antifungal activities.
N
NH
N N Cl
OR2R1O
R
S
S
24
R = C2H5, n- C3H7, n-C4H9; R1= CH3, C2H5; R
2 = CH3, C2H5
Shivaram Holla B et al., 1991 reported the synthesis of 5-mercapto-s-triazolo (3,
4,6) -as- triazino (5,6-b) indoles 25 and their mannich bases 26 by the reaction of as
triazino (5,6-b) indol-3-ylhydrazines with carbon disulfide in the presence of methanolic
potassium hydroxide, which gave the title compound through angular cyclization. On
subjecting the title compound to mannich reaction, the NH of the triazole ring underwent
dimethylation reaction.
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N
R O
O K2CO3/H2O N N
NN
SH
N2H4.H2O
N N
NN
NHNH2
R1
CS2/KOH
N N
NN
R1 N
N
HS
N N
NN
R1 N
N
CH2S N
R2
R3
25
26
RI
NHR2
R3
HCHO
NH2NHCSNH2
MeOH
R1
R = H, Cl, Me, R1 = H, Et, Me, R
2,R
3 = morphine, piperedine.
Udupi RH et al., 2000 reported the synthesis of 3-pyridyl -4-[N-substituted
phenyl carboxamido] -5-mercapto-1,2,4-triazoles 27 by heating the potassium dithio
carbonate and acid hydrazides. Potassium dithiocarbazinate was prepared by condensing
the isonicotinic acid hydrazide with carbon disulphide in ethanolic potassium hydroxide.
The compounds were evaluated for antibacterial, antifungal and antitubercular activity.
Compounds with 4-chlorophenyl, 2-methylphenoxymethyl, 4-bromophenoxy methyl, 2-
chlorophenoxymethyl, 4-chlorophenoxymethyl substitution at Ar position were found to
have good antibacterial activity.
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N CONH NH2
alcoholic KOHN CONH NH C S K
NN
NN
SH
HN C Ar
CS2
ArCONHNH2
O
27
O
Ar=Phenyl, 4-Chlorophenyl, Benzyl, 2-Methylphenoxyphenyl,4-Bromophenoxy methyl,
2-chlorophenoxymethyl, 4-chlorophenoxymethyl.
Oxadiazoles:
Omar FA et al., 1996 synthesized substituted 1,3,4-oxadiazole derivatives 28.
The target compounds were obtained by cyclodisulfurization of thiosemicarbazides, using
dicyclohexylcarbodiimide. Thiosemicarbazides are readily accessible through conversion
of the carboxylic acids to the reactive hydrazides followed by treatment with appropriate
isothiocyanate derivatives. These compounds were screened for anti-inflammatory
activity. All compounds were found to have good activity.
N
O
N
R NHR1
28
R =
N N
R1 = CH2CH3,
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Sarvaman J et al., 1998 synthesized 2-substituted amino (2-methyl oxadiazol-5-
yl) -4,5,6,7-tetrahydro benzo (b) thiophenes 29. The target compounds were obtained by
displacement reactions with nucleophiles of 3-(2-methyl oxadiazolol-5-yl) -2-(w-chloro
acetamido)-4,5,6,7 tetrahydro benzo (b) thiophene, which was obtained by treatment of
2-amino-3-(2-methyl oxadiazol-5-yl) -4,5,6,7-tetrahydrobenzo (b) thiophene with chloro
acetyl chloride. These 4,5,6,7-tetrahydrobenzo (b) thiophene with chloroacetyl chlorides.
These compounds were screened for antimicrobial activity. Compound with chlorine
substitution at X position was found to have good antibacterial activity.
S NH
O
NN
CH3
C CH2
O
29
X
X= Cl, -OAc, Marphelinyl, NHNH2
Zarghi A et al., 2005 reported the synthesis of new 2-substituted-5-(2-
benzyloxyphenyl) -1,3,4 oxadiazoles 30. The designed compounds were synthesized in
the following way. The reaction of methylsalicylate with appropriate benzyl chloride in
alkaline hydromethanolic solution afforded corresponding 2-benzyloxy benzoic acid
methyl ester which on treatment with hydrazine hydrate in methanol gave 2-benzyloxy
benzoic acid hydrazides. The hydrazides were converted to 2-amino-5-(2-
benzyloxyphenyl)-1,3,4-oxadiazoles using cyanogen bromide in methanol. 5-(2-
benzyloxyphenyl) -2-mercapto-1,3,4-oxadiazole was prepared by reaction of hydrazides
with carbon disulphide under basic condition which on sonication in the presence of
suitable alkali halide in alkaline media afforded 2-alkylthio-5-(2-benzyloxyphenyl) 1,3,4-
oxadiazoles.
Chapter – II Review of Literature
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O
O
NN
R2
CH2
R1
30
R1 = H, F, Cl
R2 = NH2, SH, SCH3, SC2H5
Tan TMC et al., 2000 reported the synthesis of 2-benzenesulfonyl alkyl-5-
substituted-sulfonyl-(1,3,4)-oxadiazoles 31 and evaluated for antihepatitis-B virus
activity. All compounds were found to have good activity.
SO2
R1
O
NHNH2
SO2
R1
O
OR
SO2NaR1
O
OR
Br
SO2
R1 O
NHN
S
SO2
R1 O
NN
S R2
THF
KI, DMF
NH2NH2
CH3OH
R2X, K2CO3
rt, 24h
X = Br, I
rt, 24 h
31
R1 = CH2CH3, CH3, H; R
2 = (CH2)4CH3, CH2-CO-CH3,
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Schiff Base:
Zhang L et al., 2007 reported the synthesis of novel 4-(arylmethylidene) amino-5-
(2-ethoxyphenyl) -3-mercapto-4H-1,2,4-triazoles 32 by means of the reaction of 3-(2-
ethoxyphenyl) -3-mercapto-4H-1,2,4-triazole with various aromatic aldehydes.
OC2H5
N
NHN
S
NH2
OC2H5
N
NHN
S
NCH
R
EtOH+ RCHO
Reflux
32
R = 2-HOC6H5, C6H5, 4-CH3C6H4, 4-ClC6H4
Kulig K et al., 2001 reported stereocontrolled synthesis of the enantiomers of 1-
[2-hydroxy-3-(4-phenyl-1-piperazinyl) -propyl] -pyrrolidin-2-one (37).
N
O
NHO N
37
Preliminary biological studies showed that compound 37 prevented or
ameliorated the adrenaline, barium chloride induced arrhythmia and statistically
diminished arrhythmias associated with coronary artery occlusion and reperfusion in the
isolated rat heart. Compound 37 demonstrates potent local anesthetic properties and
depressed the depolarization phase of the action potential of cardiac cells. According to
Williams classification compound 37 is in a class of antiarrhythmic drugs (Vaughan
Williams, 1981). Compound 37 also showed hypertensive effects and displayed α1 and α2
adrenergic blocking activities.
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According to K. Kulig procedure, the required non-racemic epoxies were obtained
via the Shar- Pless AD and epoxidation. As the starting material for their synthesis, 1-
allylpyrrolidin-2-one was used. The compound was obtained by reaction between
tetrahydrofuran-2-one and allylamine. Oxidation of Compound by standard procedures
with commercially available admix α or β provided the dose (S) -(+) -33 or (R) -(-) -34 in
70-80% yield. AD-mix α or β is a mixture of potassium osmate, K3 [Fe (CN) 6], K2CO3
and (DHQ) 2-PHAL (AD-mix α) and (DHQD) 2-PHAL (AD-mix β), resp- ectively. The
diols (S) -(+) -33 and (R) -(-) -34 were easily converted to the epoxides (S) -(+) -35 and
(R) -(-) -36 using the process based on the acetoxonium ion-mediated formation of
acetate esters of halohydrins.
O
O
1-AllylamineN
O
N
O
OHOH
N
O
OHOH
N
O
N
O
O O
N
O
NHO N
(S)-(+)-37or (R)-(-)-37
(R)-(-)-33 (S)-(+)-34
t-BuOH/H2O, O oC
(S)-(+)-36(R)-(-)-35
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Subsequently, base-mediated ester saponification and cyclization give the
enantiomeric epoxides (S) -(+) -35 and (R) -(-) -36. Finally the aminolysis of compounds
(S) -(+) and (R) -(-) with 1-phenylpiperizine gave the enantiomers of compound (S) -(+) -
37 and (R) -(-) -37.
Later Barbara Filipek et al., 1997 reported the synthesis of 1-[2-hydroxy-3-(4-
phenyl-1-piperazinyl) -propyl] -pyrrolidine (38) by the reduction of 1-[2-hydroxy-3-(4-
phenyl-1-piperazinyl) -propyl] -pyrrolidin-2-one (37) with lithium aluminum hydride
(LAH), which was isolated as free base and water-soluble dihydrochloride salt (39).
N
O
NHO N
37
N
NHO N
38
LAH
N
NHO N
39
HCl
.2HCl
Later Lingaiah Nagarapu et al., 2011 reported the synthesis of some 3-phenyl-N-
[3-(4-phenylpiperazine-1yl) propyl] -1H-pyrazole-5-carboxamide (42) derivatives by the
reaction of 3-aryl-1H-pyrazole-5- carboxylic acids (40) with 3-(4-phenylpiperzine-1-yl)
Propan-1-amine (41) in the presence of peptide coupling reagents EDC. HCl and HO Bt
to excellent yields.
Chapter – II Review of Literature
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NHNCOOH
+
H2N NN
EDC.HCl
HOBt, DIPEA
CH2Cl2,rt,12h
NHN
O
HN N
N
40 41
42
Derivatives of benzimidazole have been described for biological importance.
Compounds of oxadiazole have shown biological activity against the bacterium triazole
nucleus are having antibacterial and fungicidal properties
Mazzone G et al., 1992 reported the synthesis and biological evaluation of 5-
aryl-2-amino-oxadiazoles (43) and 2-(methylamino) -5-[3,4-methylene dioxy phenyl] -
1,3,4-oxadiazoles (44) and reported high degree of anti inflammatory activity.
N
O
N
R NHR1
43
N
O
N
NHMe
O
O 44
Rao AD et al., 1986 described the synthesis and biological activity of 3-[5-aryl-
1,3,4-oxadiazol-2-yl-methyl] -2-methyl-4-(3H) -aquinazolinones of general structure (45)
and some of the compounds exhibited good analgesic and anti-inflammatory in the rat
paw edema test.
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50
Several 2, 5-disubstituted 1,3,4-oxadiazoles were tested for anti-convulsant
activity and maximum protection was observed with 2-[4-bromophenyl amino-5-(4-
tertiary butyl-2-bromophenoxy methyl)] -1,3,4-oxadiazole (46).
Bhat AR et al., 1984
reported 3-[1,3,4-oxadiazole-2-yl]-2-aryl-4-thiazo-
lidinones (47) useful as anti-convulsant and anti-inflammatory agents.
Shah MH et al., 1969 reported a series of 4H-1,2,4-triazoloderivatives were
synthesized and tested for uretic activity. Amongst the compound tested the following
two compounds (48a) and (48b) exhibited potent diuretic activity.
N
N N
C H 2 C H 2
S H
R
48a , R = H
H
48b , R = Cl
N N
O R N
S O
R 2
R 1
47
O
B r
H
N O
N N
B r (C H 3 ) 2 C
46
N N
O
C H 2
N
N
C H 3
O
R
R 2
R 1
R = R 1 = H, Br R 2 = ph, CH 2 Ph, Substituted Ph
45
Chapter – II Review of Literature
51
Cazin JC et al., 1974 reported a series of 1-(2-dialkylaminoethyl) -1,2,4-
triazoles (49) were prepared and tested in vivo for their action on CNS and
cardiovascular system.
Wade PC et al., 1982 reported With a view to develop an effective non acidic
anti-inflammatory agent possessing an enhanced therapeutic ratio in comparison with
currently marketed acidic agents a series of 1-acyltriazoles were synthesized and
reaction as a test system. Compounds represented by general formula (50) were
evaluated in (MAA) reaction.
Cavalitto CJ et al., 1973 Triazolo [3,4-b] isoquinalines (51) have been claimed
by mallinkrodt chemicals works USA to posses anti-inflammatory action of various
forms of arthritis edema in man and mammals.
N
N N
R
51
R = H or CF 3
N
N
N C
R 1
R 2
50
R = H, CH 3 , Cl or CF 3 R = CH 3 , or C 2 H 5 R 2 = CH 3 , C 2 H 5 or C 6 H 5
N N
N
C H 2 C H 2 N R R 1
49
R = H, CH 3 , C 2 H 5 cyclic amine
R 1 = H, CH 3 or C 2 H 5
Chapter – II Review of Literature
52
Srivastava SK et al., 1999 reported Synthesis of new carbazolyl- thiadiazol-2-
azetidines as antimicrobial, anticonvulsant and anti-inflammatory agents
Baruah J.N et al., 1984 reported Synthesis and antibacterial activity of 1-(2,4-
dichlorobenzoyl) -4-substituted thiosemicarbazides, 1,2,4-triazoles.
Mary Mader et al., 2008 reported the synthesis of benzimidazole derivatives
(52) which have exhibited anti inflammatory activity.
N
N
NH2NH
NR1
R2
R3 (52)