chapter-1 general introduction and...
TRANSCRIPT
CHAPTER-1
GENERAL INTRODUCTION AND OBJECTIVES
1
1.1. Introduction
Heterocyclic compounds are organic compounds containing at least one carbon atom and at least
one element other than carbon, such as sulfur, oxygen or nitrogen within a ring structure. The name
comes from the Greek word “heteros” which means “different.” A variety of atoms, such as N, O, S, Se,
P, Si, B can be incorporated in to ring structures. By far the most numerous and most important
heterocyclic systems are those of five and six members. Heterocyclic make up an exceedingly important
class of compounds more than half of all known organic compounds are heterocycles. Almost all the
compounds we know as drugs, vitamins, and many other natural products are heterocycles. Since in
hetrocycles non-carbons usually are considered to replace carbon atoms, they are called heteroatoms e.g.
different from carbon and hydrogen. A ring with only heteroatoms is called homocyclic compound and
heterocycles are the counterparts of homocyclic compounds. Thus incorporation of oxygen, nitrogen,
sulfur or an atom of a related element into an organic ring structure in place of a carbon atom gives rise
to a heterocyclic compound. These structures may comprise either simple aromatic rings or non-
aromatic rings. The heterocyclic compounds usually possess a stable ring structure which does not
readily hydrolyzed or depolymerized. Heterocycles with three atoms in the ring are more reactive
because of ring strain. Those containing one heteroatom are in general, stable. Those with two hetero
atoms are more likely to occur as reactive intermediates.
Heterocyclic chemistry is one of the most interesting, applied branches of organic chemistry and
of utmost practical and theoretical importance. As a result, a great deal of research carried out in
chemistry is devoted to heterocyclic chemistry. It is vast and expanding area of chemistry because of
obvious application of compounds derived from heterocyclic rings in pharmacy, medicine, agriculture,
plastic, polymer and other fields. Heterocyclic compounds are widely distributed in nature. By virtue of
their therapeutic properties, they could be employed in the treatment of infectious diseases. Many
heterocyclic compounds synthesized in laboratories have been successfully used as clinical agents.
2
Heterocycles form by far the largest of classical organic divisions of organic chemistry and are of
immense importance biologically and industrially. The majority of pharmaceuticals and biologically
active agrochemicals are heterocycles while countless additives and modifiers used in industrial
applications ranging from cosmetics reprography, information storage and plastics are heterocycles in
nature. One striking structural features inherent to heterocycles, which continue to be to great advantage
by the drug industry, lies in their ability to manifest substituents around a core scaffold in defined three
dimensional representations. For more than a century, heterocycles have constituted one of the largest
areas of research in organic chemistry. They have contributed to the development of society from a
biological and industrial point of view as well as to the understanding of life processes and to the efforts
to improve the quality of life. Among the approximately 20 million chemical compounds identified by
the end of the second millennium, more than two-thirds are fully or partially aromatic and
approximately half are heterocycles. The presence of heterocycles in all kinds of organic compounds of
interest in electronics, biology, optics, pharmacology, material sciences and so on is very well known.
Among heterocycles, nitrogen-containing heterocyclic compounds have maintained the interest
of researchers through decades of historical development of organic synthesis [1]. Nitrogen-containing
heterocycles have been used as medicinal compounds for centuries, and form the basis for many
common drugs such as Morphine (1) Captopril (2) and Vincristine (3) (cancer chemotherapy). Nitrogen-
containing heterocycles occur in a diversity of natural products and drugs and are of great importance in
a wide variety of applications. Aromatic nitrogen heterocycles may contain another heteroatom, such as
the oxygen in isoxazoles, oxazoles, 1,3,4-oxadiazoles, and 1,2,4-oxadiazoles. Among the drugs
containing aromatic five-membered nitrogen heterocycles are cholesterol-reducing Atorvastatin (4),
anti-inflammatory Celecoxib (5), antiulcerative Cimetidine (6), antifungal Fluconazole (7), and
antihypertensive Losartan (8).
3
Table-1.1: Some of nitrogen containing heterocyclic drugs
O
NH
HO
HO
H
1
Morphine
(Analgesic)
N
OHS
OH
O
2
Captopril
(For treatment of hypertension)
NH
N
OH
H
OO
ON
O H
H
N
O
OOHO
O
H
3
Vincristine
(Cancer chemotherapy)
N
OH OH
OH
O
NH
O
F
4
Atorvastatin
(Cholesterol-reducing)
4
N N F
F
F
SO
OH2N
5
Celecoxib
(Anti-inflammatory)
HNN
SNH
HN
N
N
6
Cimetidine
(Antiulcerative)
N
N
N
NN
N
F
F
OH
7
Fluconazole
(Antifungal)
N
N
OH
Cl
N
NHN
N
8
Losartan
(Antihypertensive)
All these natural and synthetic heterocyclic compounds can and do participate in chemical
reactions in the human body. Furthermore, all biological processes are chemical in nature. Such
fundamental manifestations of life as the provision of energy, transmission of nerve impulses, sight,
5
metabolism and the transfer of hereditary information are all based on chemical reactions involving the
participation of many heterocyclic compounds, such as vitamins, enzymes, coenzymes, nucleic acids,
ATP and serotonin [2].
Heterocyles are able to get involved in an extraordinarily wide range of reaction types.
Depending on the pH of the medium, they may behave as acids or bases, forming anions or cations.
Some interact readily with electrophilic reagents, others with nucleophiles, yet others with both. Some
are easily oxidized, but resist reduction, while others can be readily hydrogenated but are stable towards
the action of oxidizing agents. Certain amphoteric heterocyclic systems simultaneously demonstrate all
of the above-mentioned properties. The ability of many heterocycles to produce stable complexes with
metal ions has great biochemical significance. The presence of different heteroatoms makes
tautomerism ubiquitous in the heterocyclic series. Such versatile reactivity is linked to the electronic
distributions in heterocyclic molecules. Evidently, all the natural products and the synthetic drugs
mentioned above good examples of nature’s preference for heterocycles whose biological activity
cannot be determined by one or a combination of two or three of the above mentioned properties.
The fast growing literature on heterocycles in recent years demonstrates their increasing
significance in the pharmaceutical field. An interesting feature of many heterocyclic compounds is that
it is possible to incorporate functional groups either as constituents or as part of the ring system itself.
For example, atoms of nitrogen can be included both as amino constituents and as part of a ring. This
shows that their structures are particularly versatile as a means of providing, or of mimicking, a
functional group.
In view of the general observation that the biological activities are invariably associated with a
large variety of nitrogen heterocyclic systems such as Chromeno-pyrimidine, Pyrazole, Oxadiazole,
Pyrimidine moitis.A large number of their new derivatives have been synthesized and extensively
6
studied for various pharmacological properties. Also series of beta amino ketones and homoallylamines
containing few heterocyclic groups are synthesized. These homoallylamines are powerful and useful
precursors for the construction of diverse saturated nitrogen heterocycles. This chapter briefly describes
about introduction of such compounds.
1.2 Biological importance of nitrogen containing heterocyclic compounds
1.2.1. Chromeno Pyrimidines
Chromene moiety is the important structural component in both biologically active and natural
compounds. Chromene fragment occurs in alkaloids, flavonoids, tocopherols and anthocyanins.
Polyfuctionalized pyran derivatives are common structural subunits in variety of important natural
products including alkaloids pheromones, carbohydrates, antibiotics, insecticides and herbicides [3,4].
Fused pyrimidines continue to attract considerable attention of researchers in different countries because
of their great practical usefulness, primarily, due to a very wide spectrum of their biological activities.
Chromenopyrimidines occupy a special position among these compounds.
4H- Chromene derivatives are an important class of heterocycles, which have attracted
considerable interest due to their useful biological and pharmacological properties, examples including
anticoagulant, spasmolytic, diuretic, anticancer [5] and antianaphylactic characteristics [6]. 4H-Pyrans
are also structural features of various natural products [7] and also possess useful photochemical
properties [8]. In view of these useful properties, it is not surprising that the development of synthetic
approaches to these ring systems has attracted considerable interest over the years. Moreover, nitrogen-
containing heterocycles are also of broad pharmaceutical interest and significance, which justifies our
continuing efforts in exploring synthetic strategies which lead to structures formed from a combination
of both types of heterocycles, an area which could also provide useful information regarding structural-
activity relationships in this area [9].
7
The development of a novel class of nonsteroidal human progesterone receptor (hPR) agonists,
5-aryl-1,2-dihydro-5H-chromeno[3,4-f]quinolines (9) was described by Zhi et al, (1998) [10].
O
NH
R
R1
R2
9
Fig. 1.1: 5-aryl-1,2-dihydro-5H-chromeno[3,4-f]quinolines
Zhuravel et al, (2005) have described the synthesis and biological activity for a series of novel 2-
(N-aryl) imino-5-hydroxymethyl-8-methyl-pyrano [2,3-c]pyridin-3-(N-aryl) carboxamides (10). These
compounds appeared to be potent inhibitors of several pathogenic bacterial and fungal organisms [11].
NO
NH
O
N
HO
CH3
R1
R2
10
Fig. 1.2: 2-(N-aryl) imino-5-hydroxymethyl-8-methyl-pyrano [2,3-c]pyridin-3-(N-aryl) carboxamides
Evdokimov et al, (2007) have synthesised heterocyclic privileged medicinal scaffolds involving
pyridine, 1,4-dihydropyridine, chromeno [2,3-b]-pyridine, and dihydro-1,4-dithiepine frameworks (11-
14) are prepared via a single-step multicomponent reaction of structurally diverse aldehydes with
various thiols and malononitrile [12]. These molecules were screened for cardiovascular disorders and
also for selective agonists/antagonists of calcium, sodium, and potassium ion channels as well as G
protein-coupled receptors.
R, R1, R
2 = Cl, F, Br, -OMe, CF3,
Me,-CO2Me
R1, R
2 = Et,-OMe, F, di-OMe
8
R H
OCN
CN
R1SH
Et3N, EtOH, Reflux, 3h
CN
CN
NH
R
SR1
CNNC
H2N
R= O, O1-disubstituted Ar
S
S
R
NC
H2N
R= O substituted Ar
O N
SR1 NH2
CN
NH2
X
R= O,-OH,-Ar
NH2N
NC
R
CN
SR1
R= Ar, HetAr, Alk 11
12
13
14
Scheme -
1.1: Synthesis of Chromenopyrimidine scaffold
El-Saghier et al, (2007) developed a new class of pyrano [3,4-c]chromene, (16)
benzo[c]chromene, (17) chromeno [3,4 c]pyridine (18) and studied their antibacterial activity [13].
Most of the chromene derivatives showed moderate to high antibacterial activity.
O
Ph
O
O
15
O
O
O
PhOC
Ph
O
PhCOCH2COOEt
EtOH, Piperidine
16
O
OPhOC
Ph
O
17
O
N
O
PhOC
Ph
O
18
PhCOCH2COOMe
EtOH, Piperidine
NH
O O
O
EtOH, Piperidine
Scheme -1.2: Synthesis of pyrano [3,4-c]chromene derivatives
9
Derivatives of 4-chloro-2,2-dialkyl chromene-3-carbaldehyde (19 a-b) have been synthesized
and their anti-inflammatory and ulcerative activity were studied by Hegab and co- workers (2008) [14].
O
Cl
N
HN
R
(19 a-b)
Fig. 1.3: 4-Chloro-2,2-dialkyl chromene-3-carbaldehyde
Mohammed et al, (2009) reported full synthetic approaches to several heterocyclic systems
derived from 4H-pyrans (chromenes), represented by the title compound (21), which was subsequently
used as intermediates and building blocks for additional heterocycles (22-30) [15].
OHO
CH3 Ph
CN
NH2
21
HCO2H
Heat
OHO
CH3 Ph
22OHO
CH3 Ph
CN
O23
OHO
CH3 Ph
24
OHO
CH3 Ph
25
OH3COC
CH3 Ph
26
OHO
CH3 Ph
OHO
CH3 Ph
30
N
NH
O
HCONH2
DMF,Reflux
N
N
NH2
PhNCS, Pyridine NH
N
O
Ph
S
Ac2O,Pyridine
Reflux
N
O
O
RNH2, Heat
OH3COC
CH3 Ph
27N
N
O
R
Ac2O, H3PO4
Heat
OH3COC
CH3 Ph
28N
NH
O
NH
N
NH
S
NH2
29
NH2NHCONH2,
Fusion
NH2CONH2
Fusion
NH
N
O
NH2
CH3
OHHO
PhCH=C(CN)2
EtOH,K2CO3
RT, 3h OHO
CH3 Ph
CN
NH2
20 21
Scheme -1.3: Synthesis of 4H-pyrans containing heterocycles
a: R= 4-NO2Ph
b: R= 2,4-(NO2)2Ph
10
1.2.2. Chromeno- Oxadiazoles
Among a wide variety of aryl groups, oxadiazole is a heteroaryl group that is often used in
medicinal chemistry. It is considered to be a bio-isoster of carboxylic functionalities and can be used to
replace an ester group to achieve compounds that are resistant to enzyme-catalyzed hydrolysis [16, 17,
18]. Oxadiazoles have often been described as bio-isosteres for amides and esters [19]. Due to
increased hydrolytic and metabolic stabilities of the oxadiazole ring, improved pharmacokinetic and in
vivo performance is often observed, which make these heterocycles an important structural motif for the
pharmaceutical industry.
Compounds containing heterocyclic ring systems are of great importance both medicinally and
industrially. As an example, five-membered ring heterocycles containing two carbon atoms, two
nitrogen atoms, and one oxygen atom, known as oxadiazoles (Figure 1.4), are of considerable interest in
different areas of medicinal and pesticide chemistry and also polymer and material science [20].
NO
N
R1
R2 NO
NR2
R1
N
O
N
R2R1N
ON
R1 R2
1,2,4-Oxadiazoles
1,3,4-Oxadiazoles 1,2,5-Oxadiazoles
31
31a 31b
Fig. 1.4: 3-Different types of oxadiazoles
Within drug discovery and development, a number of compounds containing an oxadiazole
moiety are in late stage clinical trials, including Zibotentan (32) as an anticancer agent and Ataluren
(33) for the treatment of cystic fibrosis. So far, one oxadiazole containing compound, Raltegravir (34),
Where R1, R
2 = Alky, aromatic or
heterocyclic substituents
11
an antiretroviral drug for the treatment of HIV infection, has been launched onto the marketplace. It is
clear that oxadiazoles are having a large impact on multiple drug discovery programs across a variety of
disease areas, including diabetes [21], obesity [22], inflammation [23], cancer [24] and infection [25].
32 Zibotentan 34 Raltegravir33 Ataluren
N
SO
HN
N
N
OO
NN
O
OH
ONO
N
F
N
N
O
OH
HN
O
NN
O
HN
O
F
Fig. 1.5: Drugs containing Oxadiazole ring
In 1889, Tiemann reported the first synthesis of a 1,2,4- oxadiazoline derivative via
cyclocondensation of benzamidoxime with acetaldehyde [26]. This route is one of the most robust and
direct approaches to the synthesis of 1,2,4- oxadiazolines. Many groups have used this or a slightly
modified route for the synthesis of these compounds.
Haugwitz et al, (1985) have synthesised a series of Isothiocyanatophenyl- 1,2,4-oxadiazoles
derivatives and studied their anthelmintic activities [27]. In the primary anthelmintic screen, 3-(4-
isothiocyanatophenyl)-1,2,4-oxadiazole (35) showed 100% nematocidal activity. The two most active
members of this series, (35) and (36), were active against the gastrointestinal nematodes of sheep at 100
mg/kg. In addition, (35) was also found to be active against hookworms in dogs at a single, oral dose of
200 mg/kg.
SCN
N O
N
O N O
N
NCS
35 36
Fig. 1.6: Isothiocyanatophenyl- 1,2,4-oxadiazoles derivatives
Street et al, (1990) reported the synthesis and biochemical evaluation of novel 1, 2, 4-
oxadiazole-based muscarinic agonists which can readily penetrate into the central nervous system
12
(CNS) [28]. Efficacy and binding of these compounds are markedly influenced by the structure and
physicochemical properties of the cationic head group. Compounds (37, 38) are the most efficacious and
potent muscarinic agonists.
HNN
ON
N
NH2
H
ON
NMe
37 38
Fig. 1.7: Oxadiazole-based muscarinic agonists
Alkyl/aryl amidoximes, prepared from the corresponding nitriles and N-alkylhydroxylamines,
have readily undergone consecutive Michael additions to electron-deficient alkynes and provided highly
substituted 1,2,4-oxadiazolines (43) in good yields in homogeneous aqueous solution reported by Naidu
et al, (2005) [29].
CNPh ClH.HNEtOH/H2O
Na2CO3 Heat
N
OH
HN
Ph
R1O
R2
RTN
NO
Ph
O
R1
R2
R1, R2= Et, Me, OEt
4339 40 41 42
Scheme -1.4: Synthesis of substituted 1,2,4-oxadiazolines
A class of 3,5-diphenyl-1,2,4-oxadiazole based compounds have been identified as potent
sphingosine-1-phosphate-1 (S1P1) receptor agonists with minimal affinity for the S1P2 and S1P3
receptor subtypes. Analogue (44) (S1P1 IC50 ) 0.6 nM) has an excellent pharmacokinetics profile in the
rat and dog and is efficacious in a rat skin transplant model, indicating that S1P3 receptor agonism is not
a component of immunosuppressive efficacy reported by Zhen et al, (2005) [30].
13
O N
N
N
CO2H
44
Fig. 1.8: 1-(4-(5-(4-Iobutylphenyl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylic acid
Koo et al, (2007) have reported synthesis of a novel series of DPPIV inhibitors with 1,2,4- and
1,3,4-oxadiazolyl ketone derivatives and its structure–activity relationships. Compound (45) showed
good inhibitory activity against DPPIV and favourable pharmacokinetic properties [31].
N
ONH
F
O O
NN
HO
45
Fig. 1.9: 1-((2S,4S)-2-(2-Tert-butyl-1,3,4-oxadiazole-5-carbonyl)-4-fluoropyrrolidin-1-yl)-2-(1-
hydroxy-2-methylpropan-2-ylamino)ethanone
Farooqui et al, (2008) have synthesised a series of 3-(4-acetamido-benzyl)-5-substituted-1,2,4-
oxadiazoles (46, 47) and screened for analgesic and in vivo anti-inflammatory activities using acetic
acid writhing in mice model and carrageenan-induced paw oedema method in mice, respectively. The
analgesic and anti-inflammatory activity of compounds (46) and (47) is superior to Diclofenac sodium
[32].
HN O
N
ON
HN
O
O
O
HN O
N
ON
HN
ON
4647
14
Fig. 1.10: 3-(4-Acetamido-benzyl)-5-substituted-1,2,4-oxadiazoles
Synthesis, biological evaluation, and SAR dependencies for a series of novel aryl and heteroaryl
substituted N-[3-(4-phenylpiperazin- 1-yl)propyl]-1,2,4-oxadiazole-5-carboxamide inhibitors of GSK-
3β kinase are described by Koryakova et al, (2008) [33]. The most potent compounds from this series
contain within the phenyl ring and 3-pyridine fragment connected to the 1,2,4-oxadiazole heterocycle
(48, 49). These compounds selectively inhibit GSK-3 β kinase with IC50 value of 0.35 and 0.41 lM,
respectively.
N
NHN
O
ON
N
N
48
N
NHN
O
ON
N
NO
49
Fig. 1.11: N-[3-(4-phenylpiperazin- 1-yl)propyl]-1,2,4-oxadiazole-5-carboxamide drivatives
1.2.3. Pyrazolo- oxadiazoles
The simple doubly unsaturated compound containing two nitrogen and three carbon atoms in the
ring, with the nitrogen atoms neighbouring, is known as pyrazole. For a long time no pyrazole
derivative had been found in nature, but in 1959 β-(1-pyrazolyl) alanine was isolated from the seeds of
water melons (Citurllus lanatus) (L. Fowden). Pyrazole is a tautomeric substance; the existence of
tautomerism cannot be demonstrated in pyrazole itself, but it can be inferred by the consideration of
pyrazole derivatives. Amongst the various heterocycles, pyrazole classes of compounds play an
important role in medicinal chemistry. Pyrazole and its derivatives, a class of well known nitrogen
containing heterocyclic compounds, occupy an important position in medicinal and pesticide chemistry
with having a wide range of bioactivities. Nitrogen hetrocycles, those containing the pyrazole nucleus
15
have been shown to possess high biological activities as herbicides, fungicides, analgesics, etc.
Herbicidally active pyrazolylpyrazoles have been reported previously [34, 35].
N
NH
HN
N
1
2
3 4
5
1
2
3 4
5
50 51
Fig. 1.12: Resonance structure of pyrazole
Very few pyrazole derivatives are naturally occurring may be due to the difficulty of living
organisms to construct the N-N bond. Owing to the widespread applications, synthesis and biological
activity evaluation of pyrazoles and their derivatives has been a subject of intensive investigations as
revealed by enormous literature covering the subject.
Lee et al, (2009) reported the new oxadiazole-diarylpyrazole 4-carboxamides (52) as
cannabinoid CB1 receptor ligands [36].
N N
Cl
Cl
Cl
ONH
R1
O
NN
R2
Where R1 = Ph, 2-Pyridyl
R2 =t-Butyl, 4-(chlorophenyl), cyclopropyl
52
Fig. 1.13: Oxadiazole-diarylpyrazole 4-carboxamides
Mitchel et al, (2010) have reported the synthesis and its potency against the phosphodiesterase
(PDE4) of 1-ethyl-5-(3-methyl-1,2,4-oxadiazol-5-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-
b]pyridin-4-amine derivatives (53) [37].
16
N
NN
NH
ON
N
RO
Where R = 4-Fluorophenyl,Benzyl, Pyrrolidinyl
53
Fig. 1.14: 1-Ethyl-5-(3-methyl-1,2,4-oxadiazol-5-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-
b]pyridin-4-amine derivatives
Mohan et al, (2010) have synthesized a series of some novel sulphur bridged pyrazole
derivatives [38]. The synthesized pyrazole derivatives were tested for antibacterial activity against both
gram positive and gram negative bacteria such as Staphylococcus aureus, Bacillus subtilis from gram
positive organisms and Escherichia Coli, Pseudomonas aeruginosa from gram negative organisms as
well as for antifungal activity against Candida albicans. Among the various pyrazoles prepared above,
the pyrazole derivative, (54) showed activity against Bacillus subtilis from gram positive organisms and
Escherichia Coli from gram negative organism.
N N
OS N
O
N
ON
NH2
54
Fig. 1.15: 5-Amino-3-methoxy-1-(2-(5-phenyl-1,3,4-oxadiazol-2-ylthio)acetyl)-1H-pyrazole-4-
carbonitrile
Sivakumar et al, (2010) synthesized a series of (4Z)- 3-methyl-1-[(2-oxo-2H-chromen-4-yl)
carbonyl]- 1H-pyrazole-4, 5-dione 4-[(4- substitutedphenyl) hydrazone] [39]. The titled compounds
were screened for their anti-inflammatory and analgesic activity. Among the synthesized compounds,
compound (55) exhibited significant anti-microbial activity.
17
O
O O
N
N
O
NHN
55
Fig. 1.16: (E)-3-methyl-1-(3-oxo-3,4-dihydro-1H-isochromene-4-carbonyl)-4-(2-phenylhydrazono)-
1H-pyrazol-5(4H)-one
Zaid et al, (2011) have reported the synthesis and anti-tumor activity of oxadiazole
thioglycosides. Among synthesised compounds, compound (56) showed high antitumor activity [40].
NH
N
O
NN
S
56
Fig. 1.17: 2-(Ethylthio)-5-(4-isobutyl-1H-pyrazol-3-yl)-1,3,4-oxadiazole
Yang et al, (2011) have synthesized a series of pyrazolo[1,5-a]pyridine containing 2,5-diaryl
1,3,4-oxadiazole derivatives (57) and studied their X-ray crystal and optical properties [41].
O
NN
N N
R
57
Where R = Ph, Nathyl, Chlorophenyl
Fig. 1.18: Pyrazolo[1,5-a]pyridine containing 2,5-diaryl 1,3,4-oxadiazole derivatives
Bondock and Co-workers (2012) have synthesised a series of Pyrazolo oxadiazole derivatives
(58, 59) and studied their antitumor and Cytotoxic assay [42].
18
N
N
H2N
RPhHN
NN
OPhOCHN
NN
OPhOCHN N
S
Ph
R
CN
58 59
Where R = H, Ph
Fig. 1.19: Most active Pyrazolo oxadiazole derivatives
A number of novel compounds based on a conformationally restricted pyrazolo-oxadiazole
framework have been designed as potential antagonists by Baraldi et al, (2012) [43].
N
N
O
O N N
O N
ON
OMe
60
Fig. 1.20: 6-(3-((5-(3-methoxyphenyl)-1,2,4-oxadiazol-3-yl)methoxy)-1-methyl-1H-pyrazol-5-yl)-
1,3-dipropyl-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione
1.2.4. Homoallylamines
N-Substituted but-3-enylamines, namely homoallylamines are emerging as powerful and useful
precursors for the construction of diverse saturated nitrogen heterocycles. These precursors have several
important biochemical aspects. The homoallylamines are stable, available and cheap initial materials.
Diverse homoallylamines possess a particular skeleton in which chemical units (C=C double bond, NH
and/or N-Ar and N-Bn substituted groups as well as aryl or heteroaryl substituents at the position C-1 of
unsaturated chain) might be involved in the construction of heterocyclic rings of different size.
Moreover, making asymmetric synthesis of homoallylic amines, they could offer real facilities to
assemble chiral heterocycles in a straight way. Finally, being biogenic amines, the homoallylamines
represent very attractive biological targets. Thus, it is not surprising that these relatively simple
19
compounds have attracted the attention of a wide range of organic, heterocyclic and medicinal chemists,
which address often to prepare bioactive N-heterocycles. N-Substituted but-3-enylamines
(homoallylamines) are considered as CH2-analogs of allylamines, which chemistry has been well
studied. Moreover, allylic and propargylic amines play a prominent role in organic synthesis, and their
importance continues to grow with time [44]. Enantiomerically pure homoallylamines are valuable
synthons for the preparation of biologically active compounds such as β-amino acids or esters, 1,3-
amino alcohols, and 1-amino-3,4-epoxides as illustrated in Scheme-1.5 [45].
R1
NHR2
Homoallylamine
R1
NHR2
R1
NHR2
R1
NHR2
OH
R1
NHR2
OH
O
O
Beta-aminoacid
Butylamines
Amino alcohols
1-Amino-3,4-epoxide
R1,R2- Aromatic, aliphatic, heterocyclic
61 64
62
63
65
Scheme- 1.5: Synthesis of enantiomerically pure homoallylamines
Recently, homoallylamines proved to be key building blocks for the preparation of pyrrolidines
and piperidines (Scheme- 1.6) via a ring closing metathesis (RCM) approach [46, 47].
20
N
CbzN
HN
CbzN
HGrubbs catalyst
66 67
Scheme- 1.6: Synthesis of pyrrolidines and piperidines
Homoallylic amines are important fundamental building blocks for the synthesis of many
nitrogen containing natural products and biologically or synthetically active compounds [48, 49].
Garibotto et al, (2011) have synthesised ten N-aryl-N-benzylamines and evaluated for their
antifungal activity, which was compared with their homoallylamine analogues that possessed an allyl
group in the carbon next to the nitrogen atom. Results indicated that the absence of the allyl group
caused an enhancement of the antifungal activity [50].
NH
R
68
R = 4-OH & 3-OCH3, 2,4-Cl, 2,6-Cl, 2,4-Br, 2,6-Br, 2-OH, 4-N(CH3)
Fig. 1.21: N-aryl-N-benzylamine derivatives
Mendez, et al, (2010) have prepared a series of homoallylamines using both standard Grignard
and Barbier procedures with prepared in situ allyl bromide magnesium in ether and with allyl
bromide/indium/methanol system, respectively [51].
21
R
N
N
MgBr
Ether/THF
R
NH
N
85% H2SO4
80-90oC
R
NH
N
N
N
6970
71
72
R
Where R = 4-OH & 3-OCH3, 4-SO3H, 4-CH3
Scheme- 1.7: Synthesis homoallylamine derivatives
Vargas, et al, (2003) reported the synthesis, in vitro antifungal evaluation and SAR studies of
101 compounds of the 4-aryl-, 4-alkyl-, 4-pyridyl or -quinolinyl-4-N-arylamino-1-butenes series and
related compounds. Active structures showed to inhibit (1,3)-β-D- glucan and mainly chitin synthases,
enzymes that catalyze the synthesis of the major fungal cell wall polymers [52].
NH
R
NH
R
NH
R
NH
N
NH
R
NH
RR1 R1
73 74 75
76 77 78
Where R & R1
= -OH ,-OCH3, -CH3, Br,-OCH2CH3
Fig. 1.22: Homoallylamine derivatives
1.2.5. β- amino ketones
Multi-component reactions (MCRs) have been considered as an important method in organic
synthesis with the advantages ranging from lower reaction times, increased reaction rates to higher
yields, and reproducibility. The Mannich reaction is a 3-component condensation reaction involving
22
active hydrogen containing compound, formaldehyde, and a primary or secondary amine [53]. The
Mannich reaction is one of the most important carbon–carbon bond forming reactions in organic
synthesis. This reaction provides the formation of β-aminocarbonyl compounds, which are important
intermediates for the construction of various nitrogen-containing natural products and pharmaceuticals.
The aminoalkylation of aromatic substrates by Mannich reaction constitutes a major strategy for the
preparation of several modifications of biologically active compounds. Enantiomerically pure β-
aminoketones are useful bifunctional intermediates for the synthesis of many biologically active
molecules [54]. Specifically, these amino ketones can serve as key precursors of syn-and anti-1,3-
aminoalcohols and syn and anti-1,3-diamines. Some of the functional group tranformations from beta
amino ketones is listed in Scheme-1.8.
R
O
R1
NHAc
R
NH2
R1
NHAc
R
OH
R1
NHAc
R
OH
R1
NHAc
R R1
NHAc
79 82
83
81
80
Where R, R1 = Aromatic, Aliphatic, Heterocyclic
Scheme- 1.8: Functional group transformations from β- amino ketones
23
Some important pharmaceutical products bearing these functionalities are illustrated below.
H2N
O
HO
HN
OH
Ph
84 Labetalol(Antagonist)
NH
NCO2H
O
O O
85 Benazapril(Hypertension)
HN N
O
O
HN
OH
NH
O
O
86 Kaletra(HIV/AIDS)
Fig. 1.23: Drugs containing β- amino ketone functional group
The trimethylsilyl trifluoromethanesulphonate catalyzed condensation of silyl ketene acetals
with imines afforded beta-amino esters with prevalent anti relative diastereo selectivity (up to 100%).
Some anti beta-amino esters have been then cyclised to trans beta lactams. Guanti et al (1987) [55].
ROMe
OTMSR2 N
R1TMSTf
R1
R2HN
O
O
R
R1
R2HN
O
O
R
Where R, R1, R2 = Ph, Bu, -OMe, -OMePh
87 8889 90
Scheme- 1.9: Synthesis of β-amino esters
Phukan et al, (2006) have used iodine as catalyst for a Mannich reaction between an aryl
aldehyde, an aryl ketone and benzyl carbamate, eventhough this is a less reactive amine, to produce
Cbz-protected b-aryl β-amino carbonyl compounds in high yields [56].
24
Where R, R1 = Ph, Cl, Br, -OMe, F
CHO
R
O
R1
O NHCbz
R
R1
Iodine
91 92 93
Scheme- 1.10: Synthesis of β-amino esters using Iodine catalyst
1.3. Scope and Objective of current work
Infectious diseases have emerged as a serious cause of morbidity and mortality, with 16.2
percent (equivalent to 57 million) deaths each year worldwide. Hence, WHO has listed such diseases in
2nd
place among the lead cause of death. Now, medicinal world has conquered many deadly infectious
diseases and immensely brought down the mortality rate to some extent. But still diseases like
pneumonia, tuberculosis (TB), typhoid, H1N1, dengue and HIV are matter of big concern at present.
Further, emerging antimicrobial resistance has created a major public health dilemma, compounded by a
dearth of new antimicrobial options. In addition, the alarming rates of emerging and reemerging
microbial threats coupled with increasing antimicrobial resistance, particularly in regard to multi drug-
resistant Gram-positive bacteria and Mycobacterium, are major concerns to the public health as well as
scientific communities worldwide.
Antimicrobial drugs have caused a dramatic change not only of the treatment of infectious
diseases but of a fate of mankind. Antimicrobial chemotherapy made remarkable advances, resulting in
the overly optimistic view that infectious diseases would be conquered in the near future. Antimicrobial
resistance is a global public health concern that is impacted by both human and non-human
antimicrobial use. The consequences of antimicrobial resistance are particularly important when
pathogens are resistant to antimicrobials that are critically important in the treatment of human disease.
However, in reality, emerging and re-emerging infectious diseases have left us facing a counter charge
25
from infections. Infections with drug resistant organisms remain an important problem in clinical
practice that is difficult to solve.
The greatest impact of the synthesis of heterocyclic chemistry is the development of new
pharmaceutically active and efficient compounds. Inventing and developing a new medicine is a long,
complex, costly and highly risky process that has few peers in the commercial world. Research and
development (R&D) for most of the medicines available today has required 12-24 years for a single new
medicine, from starting a project to the launch of a drug product. In addition, many expensive, long-
term research projects completely fail to produce a marketable medicine. Each step of a synthesis
involves a chemical reaction, reagents and conditions need to be designed to give a good yield and pure
product. The discovery of new methods and reagents grab the attention of chemists across the world.
Optimization is where one or two starting compounds are tested in the reaction under a wide variety of
conditions of temperature, solvent, reaction time etc, until the optimum conditions for product, yield and
purity are found. Then the researcher tries to extend the method to a broad range of different starting
materials to find the scope and limitations.
Heterocyclic compounds by virtue of their specific activity could be employed in the treatment
of infectious diseases. Review of literature indicated that nitrogen containing heterocycles find a
significant place in the development of pharmacologically important molecules. Chromeno-pyrimidines,
chromeno-oxadiazoles are the two classes of compounds containing two different mofits. This gives us
an opportunity to explore new molecules. Also the biological activity, stability and toxicity of the
individual mofits are encouraging and well documented. This class of compounds are not yet
completely explored compared to many other nitrogen containing compounds. Keeping in view of these
observations it was planned to synthesize some nitrogen containing heterocycles especially chromeno-
pyrimidines, chromeno-oxadiazoles.
26
The present research work involves synthesis, characterization and biological studies of new
nitrogen heterocycles carrying interesting pharmacophore like chromeno-pyrimidines, chromeno-
oxadiazoles, pyrazolo-oxadiazoles. Also series of β- aminoketones and homoallylamines containing
heterocyclic groups are prepared and used for the biological study. The study of structure-activity
relationship (SAR) of the new compounds will impart structural elements for new drug designing. Also,
the results of research may be useful in understanding the mechanism of drug action.
The main objectives of the present research work are as follows:
• Synthesis of new nitrogen heterocycles carrying interesting pharmacophores like
chromenopyrimidine, chromeno-oxadiazole, pyrazole oxadiazoles.
• Synthesis of Homoallylamines and β-amino ketones which are precursors for many nitrogen
containing heterocyclic compounds.
• Development of synthetic routes and purification methods for the newly prepared compounds.
• Characterization of new compounds by IR, 1H NMR, 13C NMR, Mass spectral studies and also by
elemental analysis.
• Evaluation of biological activities of new compounds, such as antimicrobial activity using
different bacterial stains.
• Study of structure activity relationship with reference to biological activity.
The thesis comprises of seven chapters.
Chapter 1: This is an introductory chapter, which deals with a brief account of synthesis, reactions and
biological activities of heterocycles carrying interesting pharmacophores like chromeno-pyrimidine,
chromeno-oxadiazole, pyrazolo-oxadazoles, homoallylamines and β-amino ketone derivatives based on
the publications appearing in the chemical literature up to September 2012. Main objectives of the
present research work were also explained here.
27
Chapter 2: This chapter deals with the synthesis, characterization and biological studies of some new
Chromeno[2,3-b]-pyrimidine derivatives. 2-Imino-2H-chromene-3-carbonitrile was prepared using
salicylaldehyde and malononitrile in the presence of triethylamine .Which was reduced using sodium
borohydride in methanol to give 2-amino-3,4-dihydro-2H-chromene-3-carbonitrile. Further this amine
was converted into imine using N, N-dimethylacetaldehyde dimethyl acetal to give core intermediate.
This was used for the preparation of chromeno-pyrimidine library, using acetic acid and different amine
in microwave irradiation. These compounds are confirmed by recording their IR, 1H NMR,
13C NMR
and mass spectra and also by elemental analysis. New compounds were further screened for their
antibacterial activities. The results of antimicrobial studies are described in chapter-6.
Chapter 3: This chapter describes synthesis, characterization and biological studies of some new
chromene incorporated oxadiazole derivatives. In the present study, a series of new 1,2,4-oxadiazole
derivatives containing 3,4-dihydro-2H-chromen-2-amine moiety were synthesized by efficient
microwave reaction of 2-amino-N'-hydroxychroman-3-carboxamidine and suitable aldehyde. Structures
of all the synthesized compounds were confirmed by spectral studies and C, H, N analyses. Newly
synthesized compounds were screened for their antimicrobial properties. The results of antimicrobial
studies are described in chapter-6.
Chapter 4: In this chapter, synthesis of 1H-pyrazol-3-yl-1,2,4-oxadiazole derivatives have been
described. 1H-pyrazol-3-yl-1,2,4-oxadiazole derivatives are prepared by cyclising (Z)-N'-hydroxy-1H-
pyrazole-3-carboxamidine with different aldehydes in microwave irradiation. The newly synthesized
compounds were characterized by IR, 1H NMR, 13C NMR, mass spectral study and also by C, H, N
analyses. New compounds were screened for their antimicrobial activity. The results of antimicrobial
studies are described in chapter-6.
28
Chapter 5: In this chapter brief introduction about multicomponent reactions (MCR) is given. Using
these multicomponet reactions two series of compounds are prepared. An efficient catalytic three-
component reaction of aldehydes, amines and allyltributylstannate has been successfully developed to
produce homoallylic amines at 25oC, in excellent yields, in the presence of 1 mol % of trifluoroacetic
acid an inexpensive catalyst. In another series three-component Mannich reaction of different ketones
with aromatic aldehydes and different amines in microwave irradiation under solvent free condition to
get β-amino carbonyl compounds in good to excellent yields is carried out. This method proved as a
novel and improved modification of the reported three component component Mannich reaction in
terms of milder reaction conditions, reaction times, and clean reaction profiles, using very small
quantity of catalyst and simple workup procedure. Newly synthesized compounds were characterized by
IR, NMR, mass spectral and C, H, N elemental analyses. All the newly synthesized compounds were
screened for their antimicrobial. The results of antimicrobial studies are described in chapter-6.
Chapter 6: This chapter includes a concise account on antimicrobialstudy of synthesised compounds. It
also covers different antimicrobial screening methods available for testing antimicrobial susceptibility
of a substance. Also SAR of all synthesised compounds is discussed.
Chapter 7: The summary and conclusions of present research work have been discussed in this chapter.
29
1.4. References
1. Garcia-Valverde, M., Torroba, T. “Sulfur-Nitrogen heterocycles” Molecules. 2005, 10, 318-320.
2. Dua, R., Shrivastava, S., Sonwane, S.K., Srivastava, S. K. “Pharmacological Significance of
Synthetic Heterocycles Scaffold: A Review” Advances in Biological Research. 2011, 5 (3), 120-
144.
3. Ramazani, A., Fattahi-Nujokamberi, G. R. “Synthesis of 2H-1-Benzopyran derivatives with a
strongly electron-withdrawing substituent at 6-position” Indian J. Chem. 2002, 41B, 407-408
572-574.
4. Kim, J. N., Lee, K.Y. “Synthesis of Cyclic Compounds from the Baylis-Hillman Adducts” Curr.
Org. Chem. 2002, 6 (7), 627-645.
5. Foye, W.O. “Prinicipi di Chemico Farmaceutica” Piccin: Padova, Italy 1991, 416.
6. Singh, K., Singh, J., Singh. H. “A synthetic entry into fused pyran derivatives through carbon
transfer reactions of 1,3-oxazinanes and oxazolidines with carbon nucleophiles” Tetrahedron.
1996, 52, 14273-14280.
7. Wang, X. S., Shi, D. Q., Tu, S.T., Yao. C. S. “A Convenient Synthesis of 5-Oxo-5,6,7,8-
tetrahydro-4 H -benzo-[b]-pyran Derivatives Catalyzed by KF-Alumina” Synth. Commun. 2003,
33(1), 119-1126.
8. Armesto, D., Horspool, W. M., Martin, N., Ramos, A., Seaone, C. “Synthesis of cyclobutenes by
the novel photochemical ring contraction of 4-substituted 2-amino-3,5-dicyano-6-phenyl-4H-
pyrans” J. Org. Chem. 1989, 54 (13), 3069-3072.
9. Ife, R. J., Brown, T. H., Blurton, P., Keeling, D. J., Leach, C. A., Meeson, M. L., Parsons, M. E.
and Theobald, C. J. “Reversible Inhibitors of the Gastric (H+/K+)-ATPase. 5. Substituted 2,4-
Diaminoquinazolines and Thienopyrimidines” J. Med. Chem. 1995, 38, 2763-2773.
30
10. Zhi, L., Tegley, C. M., Kallel, E. A., Marschke, K. B., Mais, D. E., Gottardis, M. M., Jones, T. K.
“5-Aryl-1,2-dihydrochromeno[3,4-f]quinolines: A Novel Class of Nonsteroidal Human
Progesterone Receptor Agonists” J. Med. Chem. 1998, 41, 291- 302.
11. Zhuravel, I. O., Kovalenko, S. M., Ivachtchenko, A. V., Balakin, K. V., Kazmirchuk, V.V.
“Synthesis and antimicrobial activity of 5-hydroxymethyl- 8-methyl-2-(N-arylimino)-pyrano[2,3-
c]pyridine-3-(N-aryl)-carboxamides” Bioorg. Med. Chem. Lett. 2005, 15, 5483-5487.
12. Evdokimov, N. M., Kireev, A. S., Yakovenko, A. A., Antipin, M. Y., Magedov, I. V., Kornienko,
A. “One-Step Synthesis of Heterocyclic Privileged Medicinal Scaffolds by a Multicomponent
Reaction of Malononitrile with Aldehydes and Thiols” J. Org. Chem. 2007, 72, 3443-3453.
13. El-Saghier, A. M. M., Naili, M, B., Rammash, B. K., Saleh, N. A., Kreddan, K, M. “Synthesis
and antibacterial activity of some new fused chromenes” ARKIVOC. 2007, 16, 83-91.
14. Hegab, M. I., Yousef, N. M., Nour, H. F., Ellithey, M., Arbid, M. S. “Synthesis and
pharmacological activities of some condensed 4-chloro-2,2-dialkyl chromene-3-carbaldehyde
derivatives” Acta Pharm. 2008, 58, 15-27.
15. Mohammed, F. K., Soliman, A.Y., Ssawy, A., Badre, M. G. “2-Amino-5-hydroxy-4-phenyl-7-
methyl-4H [1-chromeno-3-carbonitrile as a key precursor for the synthesis of several chromene
based heterocyclic systems” Journal of Chemical and Pharmaceutical Research. 2009, 1(1), 213-
224.
16. Lima, L. M., Barreiro, E. J. “Bioisosterism: a useful strategy for molecular modification and drug
design” Curr. Med. Chem. 2005, 12, 23-49.
17. Andersen, K. E., Lundt, B. F., Jørgensen, A. S., Braestrup, C. “Oxadiazoles as bioisosteric
transformations of carboxylic functionalities. II” Eur. J. Med. Chem. 1996, 31, 417-425.
31
18. Diana, G. D., Volkots, D. L., Nitz, T. J., Bailey, T. R., Long, M. A., Vescio, N., Aldous, S.,
Pevear, D. C., Dutko, F. J. “Oxadiazoles as Ester Bioisosteric Replacements in Compounds
Related to Disoxaril. Antirhinovirus Activity” J. Med. Chem. 1994, 37, 2421-2436.
19. Young, J. R., Devita, R. J. “Novel synthesis of oxadiazoles via palladium catalysis” Tetrahedron.
Lett. 1998, 39, 3931-3934.
20. Pace, A., Pierro, P. “The new era of 1,2,4-oxadiazoles” Org. Biomol. Chem. 2009, 7, 4337-4348.
21. Jones, R. M., Leonard, J. N., Buzard, D. J., Lehmann, J. “GPR119 agonists for the treatment of
type -2 diabetes” Expert Opin. Ther. Pat. 2009, 19, 1339-1359.
22. Lee, S. H., Seo, H. J., Lee, S., Jung, M. E., Park, J., Park, H., Yoo, J., Yun, H., Na, J., Kang, S.Y.,
Song, K., Kim, M., Chang, C., Kim, J, Lee, J. “Biarylpyrazolyl oxadiazole as potent, selective,
orally bioavailable cannabinoid-1 receptor antagonists for the treatment of obesity” J. Med. Chem.
2008, 51, 7216-7233.
23. Unangst, P. C., Shrum, G. P., Connor, D. T., Dyer, R. D., Schrier, D. J. “Novel 1,2,4- oxadiazoles
and 1,2,4-thiadiazoles as dual 5-lipoxygenase and cyclooxygenase inhibitors” J. Med. Chem.
1992, 35, 3691-3698.
24. Zhang, H. Z., Kasibhatla, S., Kuemmerle, J., Kemnitzer, W., Ollis-Mason, K., Qiu, L., Crogan-
Grundy, C., Tseng, B., Drewe, J., Cai, S. X. “Discovery and structure-activity relationship of 3-
aryl-5-aryl-1,2,4-oxadiazoles as a new series of apoptosis inducers and potential anticancer
agents” J. Med. Chem. 2005, 48, 5215-5223.
25. Cottrell, D. M., Capers, J., Salem, M. M., DeLuca-Fradley, K., Croft, S. L., Werbovetz, K. A.
“Antikinetoplastid activity of 3-aryl-5-thiocyanatomethyl-1,2,4-oxadiazoles” Bioorg. Med. Chem.
2004, 12, 2815-2824.
26. Tiemann, F. Ber. 1889, 22, 2412-2417.
32
27. Haugwitz, R. D., Martineqt, A. J., Venslavsky, J., Angel, R. G., Maurer, B.V., Jacobs, G. A.,
Narayanan, V. L., Cruthers, L. R., Szanto, J. “Antiparasitic Agents. 6.' Synthesis and Anthelmintic
Activities of Novel Isot hiocyanatop henyl- 1,2,4-oxadiazoles” J. Med. Chem. 1985, 28(9), 1235-
1241.
28. Street, L. J., Baker, R., Book, T., Kneen, C. O., MacLeod, A. M., Merchant, K. J., Showell, G. A.,
Saunders, J., Herbert, R. H., Freedman, S. B., Harley, E. A. “Synthesis and Biological Activity of
1,2,4-Oxadiazole Derivatives: Highly Potent and Efficacious Agonists for Cortical Muscarinic
Receptors” J. Med. Chem. 1990, 33, 2690-2697.
29. Naidu, B. N., Sorenson, M. E. “Facile One-Pot Synthesis of 2, 3, 5-Substituted 1,2,4-
Oxadiazolines from Nitriles in Aqueous Solution” Org. Lett. 2005, 7(7), 1391-1393.
30. Zhen, L., Chen, W., Hale, J. J., Lynch, C. L., Mills, S. G., Hajdu, R., Keohane, C. A., Rosenbach,
M. J., Milligan, J. A., Shei, G., Chrebet, G., Parent, S. A., Bergstrom, J., Card, D., Forrest, M.,
Quackenbush, E. J., Wickham, L.A., Vargas, H., Evans, R. M., Rosen, H., Mandala, S. “Discovery
of Potent 3,5-Diphenyl-1,2,4-oxadiazole Sphingosine-1-phosphate-1 (S1P1) Receptor Agonists
with Exceptional Selectivity against S1P2 and S1P3” J. Med. Chem. 2005, 48(20), 6169-6172.
31. Koo, K. D., Kim, M. J., Kim, S., Kim, K. H., Hong, S. Y., Hur, G. C., Yim, H. J., Kim, G. T., Han,
H. O., Kwon, O. H., Kwon, T. S., Koh, J. S., Lee, C. S. “Synthesis, SAR, and X-ray structure of
novel potent DPPIV inhibitors: Oxadiazolyl ketones” Bioorg. Med. Chem. Lett. 2007, 17, 4167-
4172.
32. Farooqui, M., Bora, R., Patil, C. R. “Synthesis, analgesic and anti-inflammatory activities of novel
3-(4-acetamido-benzyl)-5-substituted-1,2,4-oxadiazoles” Eur. J. Med. Chem. 2009, 44(2), 794-
799.
33
33. Koryakova, A. G., Ivanenkov, Y. A., Ryzhova, E. A., Bulanova, E. A., Karapetian, R. N., Mikitas,
O. V., Katrukha, E. A., Kazey, V. I., Okun, I., Kravchenko, D.V., Lavrovsky, Y. V., Korzinov, O.
M., Ivachtchenko, A. V. “Novel aryl and heteroaryl substituted N-[3-(4-phenylpiperazin- 1-
yl)propyl]-1,2,4-oxadiazole-5-carboxamides as selective GSK-3 inhibitors” Bioorg. Med. Chem.
Lett. 2008, 18, 3661-3666.
34. Uwe, H., Gabriele, D., Helga, F., Jeans, G., Gerhard, J., Richard, R. “New substituted
pyrazolylpyrazoles, processes for their preparation, as well as intermediates, and their-use as
herbicides” U.S. Patent 5405829, 1995.
35. Fraley, M. E., Rubino, R. S., Hoffman, W. F., Hambaugh, S. R., Arrington, K. L., Hungate, R. W.,
Bilodeau, M. T., Tebben, A. J., Rutledge, R. Z., Kendall, R. L., McFall, R. C., Huckle, W. R, Coll,
K. E., Thomas, K. A. “Optimization of a pyrazolo[1,5-a]pyrimidine class of KDR kinase
inhibitors: improvements in physical properties enhance cellular activity and pharmacokinetics.”
Bioorg. Med. Chem. Lett. 2002, 12, 3537-3541.
36. Lee, S. H., Seo, H. J., Kim, M. J., Kang, S.Y., Song, K.S., Jung, M.E., Kim, J., Lee, J.
“Oxadiazole-diarylpyrazole 4-carboxamides as cannabinoid CB1 receptor ligands” Bioorg. Med.
Chem. Lett. 2009, 19 (7), 1899-1902.
37. Mitchel, J. C., Ballantine, S. P., Coe, D. M., Cook, C. M., Delves, C. J., Dowle, M. D., Edlin, D.
C., Hamblin, J. N., Holman, S., Johnson, S.R., Jones, P. S., Keeling, S. E., Kranz, M., Lindvali,
M., Lucas, F. S., Neu, M., Solanke, Y. E., Somers, D. O., Trivedi, N. A., Wiseman, J. O.
“Pyrazolopyridines as potent PDE4 inhibitors: 5-Heterocycle SAR” Bioorg. Med. Chem. Lett.
2010, 20, 5803-5806.
38. Mohan, S., Ananthan, S., Murugan, K. R. “Synthesis, Characterization and Biological activity of
Some Novel Sulphur Bridged Pyrazoles” Inter J of Pharma Sci and Res. 2010, 1, 391-398.
34
39. Sivakumar, K. K., Rajasekaran, A., Ponnilavarasan, I., Somasundaram, A., Sivasakthi, R.,
Kamalaveni, S. “Synthesis and evaluation of antimicrobial and analgesic activity of some (4Z)-
3methyl-1-[(2-oxo-2H-chromene-4-yl)] 1H-pyrazole-4,5-dione-4-[(4-substitutedphenyl)
hydrazone]” Der Pharmacia Lettre. 2010, 2, 211-219.
40. Zaid, M. A. A., Telbani, E. M. E., Elgemeie, G. H., Nawwar, G. A. M. “Synthesis and anti-tumor
activity of oxadiazole thioglycosides” Eur. J. Med. Chem. 2011, 46, 229-235.
41. Yang, H., Mu, J., Chen, X., Feng, L., Jia, J., Wang, J. “Synthesis, X-ray crystal structure and
optical properties of novel 2,5-diaryl-1,3,4-oxadiazole derivatives containing substituted
pyrazolo[1,5-a] pyridine units” Dyes and Pigments. 2011, 91, 446-453.
42. Bondock, S., Adel, S., Etman, A. H., Badria, A. F “Synthesis and antitumor evaluation of some
new 1,3,4-oxadiazole-based heterocycles” Eur. J. Med. Chem. 2012, 48, 192-199.
43. Baraldi, P. G., Baraldi, S., Saponaro, G., Preti, D., Romognoli, R., Piccagli, L., Cavalli, A.,
Recanatini, M., Moorman, A. R., Zai, A. N., Varani, K., Borea, P. A., Tabrizi, M. A. “Novel 1,3 –
Dipropyp-8-(3-benzimidazol -2-yl- methoxy-1- methylpyrazol-5-yl)xanthines as potent and
selective A2B Adenosine receptor Antagonists” J. Med. Chem. 2012, 55, 797-811.
44. Johannsen, M., Jørgensen, K.A. “Allylic Amination” Chem. Rev. 1998, 98, 1689-1708.
45. (a) Laschat S., Kunz, H.“Carbohydrates as chiral templates: diastereoselective synthesis of N-
glycosyl-N-homoallylamines and .beta.-amino acids from imines” J. Org. Chem. 1991, 56, 5883-
5889. (b). Juaristi, E., Leon-Romo, J. L., Reyes, A., Escalante, J., “Recent applications of α-
phenylethylamine (α-PEA) in the preparation of enantiopure compounds. Part 3: α-PEA as chiral
auxiliary. Part 4: α-PEA as chiral reagent in the stereodifferentiation of prochiral substrates”
Tetrahedron: Asymmetry. 1999, 10, 2441-2495.
35
46. Wright, D. L., Schulte II, J. P., Page, M. A. “An Imine Addition/Ring-Closing Metathesis
Approach to the Spirocyclic Core of Halichlorine and Pinnaic Acid” Org. Lett. 2000, 2, 1847-
1850.
47. Francois-Xavier., Girard, S., Vo-Thanh, G., Robins, R. J., Villieras, J., Lebreton, J. “Efficient
Enantiomeric Synthesis of Pyrrolidine and Piperidine Alkaloids from Tobacco” J. Org. Chem.
2001, 66, 6305-6312.
48. Yamaguchi, R., Moriyasu, M., Kawanisi, M. “Highly regioselective .alpha.-allylation of N-
(alkoxycarbonyl)pyridinium salts by means of allyltin reagents” J. Org. Chem. 1985, 50, 287-288.
49. Bloch, R. “Additions of Organometallic Reagents to C=N Bonds: Reactivity and Selectivity”
Chem. Rev. 1998, 98, 1407-1438.
50. Garibotto, F. M., Sortino, M. A., Kouznetsov, V. V., Enriz, R. D., Zacchino, S. A. “Synthesis and
antifungal activity of N-aryl-N-benzylamines and of their homoallyl analogues” ARKIVOC. 2011,
7, 149-161.
51. Mendez, L. Y. V., Zacchino, S. A., Kouznetsov, V. V. “Synthesis of new 4-methyl-2-(4-pyridyl)-
1,2,3,4-tetrahydroquinolines as potent antifungal compounds” J. Braz. Chem. Soc. 2010, 21(1),
105-111.
52. Vargas, L. Y. M., Castelli, M. V., Kouznetsov, V. V., Urbina, J. M. G., Lopez, S. N., Sortino, M.,
Enriz, R. D., Ribas, J. C., Zacchino, S. “In Vitro Antifungal Activity of New Series of
Homoallylamines and Related Compounds with Inhibitory Properties of the Synthesis of Fungal
Cell Wall Polymers” Bio org. Med. Chem. 2003, 11, 1531-1550.
53. Kouznetsov, V. V., Mendez, M. L. “Recent developments in three component Grignard-Barbier-
type reactions” Synthesis. 2008, 4, 491-506.
36
54. Sujith, K. V., Rao, J. N., Shetty, P., Kalluraya, B. “Regioselective reaction: Synthesis and
pharmacological study of Mannich bases containing ibuprofen moiety” Eur. J. Med. Chem. 2009,
44, 3697-3702.
55. Guanti, G., Narisano, E., Banfi, L. “Diastereoselection in trimethylsilyl trifluoromethane
sulphonate catalyzed reaction of silyl ketene acetals with imines” Tetrahedron. Lett. 1987, 28 (37),
4331-4334.
56. Phukan, P., Kataki, D., Chakraborty, P. “Direct synthesis of Cbz-protected β-amino ketones by
iodine-catalyzed three-component condensation of aldehydes, ketones and benzyl carbamate”
Tetrahedron. Lett. 2006, 47, 5523-5525.