Post on 29-May-2018
CHAPTER-I
INTRODUCTION
Medical and pharmacological research provides a basis for the development
of new approaches to combat human disease. The research has the effect of
obviating established therapies in favour of newer modalities, which are safer and
more effective.
The efficacy of heterocyclic compounds exhibited various biological and
pharmacological activities. Number of heterocyclic form an important
pharmacophore in several medicines and natural products, possessing biological
properties also they have found to possesses heterocyclic moieties, such as
thiophene, furan, pyridine, pyrimidine imiadazole, quinoline etc. In particular,
literature is well documented with the biological and pharmacological efficacy of
pyrimidines and thiophene derivatives. In view of these facts, the work of
synthesis of heterocyclic analogs of pyrimidine and thiophene molecules, and
investigation of their biological and pharmacological activity was undertaken.
Pharmaceutical chemistry is a science that makes use of the general laws of
chemistry to study drugs, i.e., their preparation, chemical nature, composition,
structure, influence on an organism and studies of the physical and chemical
properties of drugs, the methods of quality control and the conditions of their
storage.
Pharmaceutical chemistry occupies the most important place among the
related science' viz., drug technology, toxicological chemistry and
pharmacognosy. At the same time, pharmaceutical chemistry, being a specialized
science, depends on other branches of chemistry, (inorganic, organic, analytical,
1
CHAPTER-I
physical, colloid chemistry etc.,) and also on medico biological (pharmacology,
physiology, biological chemistry) disciplines.
Heterocyclic synthesis has emerged as powerful technique for generating
new molecules useful for drug discovery'. Heterocyclic compounds provide
scaffolds on which pharmacophores can arrange to yield potent and selective
drugs^.
Heterocyclic compounds containing two nitrogen atoms in pyrimidine,
pyrazole imidazole and piperazine are represents a very important group of
organic compounds because many of them exhibit significant biological activity,
so these properties predetermine them inter alia for the preparation of wide
spectrum of medicinal drugs^.
Pyrimidine is a heterocyclic aromatic organic compound similar to benzene
and pyridine, containing two nitrogen atoms at positions 1 and 3 of the six-
member ring. It is isomeric with two other forms of diazine. Pyrimidine has many
properties in common with pyridine, as the number of nitrogen atoms in the ring
increases the ring n- electrons become less energetic and electrophiliCiaromatic
substitution gets more difficult while nucleophilic aromatic substitution gets
easier. An example of the last reaction type is the displacement of the amino
group in 2-aminopyrimidine by chlorine and its reverse Reduction in resonance
stabilization of pyrimidines may lead to addition and ring cleavage reactions
rather than substitutions. One such manifestation is observed in the Dimroth
rearrangement. Compared to pyridine, N-alkylation and N-oxidation is more
difficult, and pyrimidines are also less basic: The pKa value for protonated
CHAPTER-I
pyrimidine is 1.23 compared to 5.30 for pyridine. Pyrimidine also found in
meteorites, although scientists still do not know its origin. It decomposes
photolytically into Uracil under UV light" ' .
Pyrimidines have been the subject of substantial attention by synthetic and
medicinal chemists due to the role of such class of heteroaromatic ring in many
biological systems. Pyrimidines, being an integral part of DNA and RNA, impart
to diverse pharmacological properties as effective bactericide and fungicides.
Certain pyrimidine derivatives are also known to exhibit antimalarial antifilarial,
antileishmanial and anti-HIV activities. Some of the 3,4-dihydropyrimidines
(DHPM) have emerged as integral backbones of several calcium channel
blockers, antihypertensive agents, adrenergic and neuropeptide antagonist Several
alkaloids containing 3,4-dihydropyrimidine have been isolated from marine
sources and among them are the batzelladine alkaloids are found to be potent
HIV-gp-120-CD4 inhibitors*"'^
Currently, fifteen out of twenty-five drugs approved by US-FDA (United
States Food and Drug Administration) for the treatment of viral diseases'^ are
purine and pyrimidine derivatives; Idoxuridine, Trifluridine, Acyclovir,
Ganiciclovir for herpes; Zidividine and Lamividine for HIV and Ribavarine for
RSV infection in children.
Tamara Fursy and Alexi^° have reported synthesis of novel pyrimidine-4-
yl derivatives. Synthesized compounds have been evaluated as anticancer agents
at National Cancer Institute's (USA) Drug Discovery program, against leukemia,
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non small cell lung cancer, colon, CNS cancer, melanoma, ovarian cancer, renal,
prostrate and breast cancer; proven as potential drug candidates.
Some of the structures of functionalized pyrimidines^' and examples of
drugs containing these nuclei are shown below.
o
O^J O^^^ O ^ N ' .-V"'
H HO-A O 5-Florouracil W
H 0 - \ /O
HO " ° Triflorothymine ARA C
During the last few years interest in these areas W^PC focused on synthesis
and evaluation of biological activity of various pyrimidines either fused or
bridged with other hetero partner.
The above discussions reveal the importance of pyrimidines and their
biodynamic property, which prompted us to design pyrimidine derivatives
simulating pharmacophores and substituents responsible for diverse
pharmacological activities.
Methods of synthesis of Pyrimidine derivatives
01. From C-C-C and N-C-N units condensation"
A very important general method for preparing pyrimidines is the
condensation between at^he carbon of the type YCH2Z, where Y & Z = COR,
COOR, CN, and compounds having^amidirie, urea^_guanidine, thiourea andjheir
derivatives „on condensation is carried out in the presence of sodium hydroxide or
sodium ethoxide.
CHAPTER-I
NH
Acetamidine
O^ ^CH,
O O
EAA
O
HN
OH
- ^ HN
2,6-Dimethylpyriniidin-4(3//)-one
M INH2
fl + Thiourea
NC
Malonitrile
NH, NH,
HS' N NH N NH2 H
4,6-Diaminopyrimidine-2-thiol
Y s
Thiourea
NC O. ^CH,
O O
Ethylcynoacetate
i,- HN
OH
i. HS N NH. HS' N NH.
6-Ainino-2-inercaptopyrimidin-4(3i^-one
Antithyroid activity was first found in pyrimidine series. The simplest
compound to show this activityVmethyl thiouracil/is prepared ^fliHte'simply by
condensation of ethyl acetoacetate with thiourea. Further work in this series
shows that better activity was obtained by incorporating of lipophilic side chain.
Example: propylthiouracil 23
^ C O O E t
o • HjN
NH,
H3C
OH
Propylthiouracil
Condensation of ethylcyanoacetate with guanidine in the presence of
sodium ethoxide affords the starting pyrimidine. Reaction with phosphorus
CHAPTER-I
oxychloride tjjeffserves to replace the hydroxyl group by chlorine. Treatment of
this intermediate with metachloroperbenzoic acid results in specific oxidation of
the nitrogen at the 1 ' position. Displacement of the halogen with piperidine
affords minoxidil. This drug, minoxidil is an extremely effective hypertensive
agent acting by means of vasodilatation.
N C — \ COOEt
» . II I _ Ti T ^ " N NH ^-^^ ^ ^ N \ i ^ ' ^ ^N
CI NH, O " CI
Minoxidil N
02. From condenseation of C-N and C-C-C-N units
One of the important pyrimidine synthesis involves the condensation
between a molecule containing the C-C-C-N unit and a molecule containing C-N
unit, e.g. A^-Phenylbenzene carboximidoyl chloride, isocyanatomethane with
(C-C-C-N) unit and e-gr" l-ethoxyprop-l-en-2-amine, 3-ethoxypent-2-en-2-
• 22
amme .
0
N
P h ' " ' ^ XI +
H5C2O
CH3
HEAT
P h ' - ^ N ' ^ CH3
6-Methyl-5-ethyl-2,3-diphenylpyriinidin-4(3fl)-one
03. From substituted chalcones
Substuited chalcones are treated with urea or thiourea to get substituted
thio/oxa-pyrimidines^^ respectively. These substituted pyrimidines/screened for
many biological activities.
CHAPTER-I
HjN
X
R
b + NH2
R
R " ^ N ^ X H
04. From malonic ester synthesis
Bis-homologation of benzaldehyde, (for example, reduction of aldehyde to
alcohol, alcohol to halide and then to malonic ester), affords the hydrocinnamic
acid. Formation with ethyl formate and base gives the hydroxymethylene
derivative, pyrimidine, by a scheme similar to that above. The hydroxyl group is
then converted to the amine by successive treatment with phosphorus oxychloride
and ammonia. Thoro ig^ius obtained the antimalarial agent, Trimethoprim^^L>4 6c>^^^t^^4
MeO
J—^ \—COOEt MeO
05. Condensation of phenylacetonitrile with ethyl propionate
2,4-Diaminopyrimidines inhibit the growth of microorganisms by
interfering with their utilization of folic acid led to an intensive search for anti-
infective agents in this class of heterocyclic compounds. This work led to the
development of at least two successful antimalarial agents. Condensation of
phenylacetonitrile with ethyl propionate in the presence of sodium ethoxide gives
CHAPTER-I
the cyanoketonertreatment with diazomethane affords the methyl enol ether jifeel
undergoes condensation with guanidine/afford^ pyrimethamine .
NH2
N C O N C V.W3 I 1, „n2
3-Oxo-2-phenylpentanenitrile ^^3 Pyrimethamine
06. Condensation of ethoxymethylene malononitrile with acetamidines
Coccidia are protozoans that can wreak havoc in a flock of poultry b the
infection known as coccidiosis. Agents that control this disease -coccidiostats -
are in view of the world's heavy dependence on poultry as a source of protein, of
great economic significance. One of the more important drugs for treatment of
this disease incorporates the primidine nucleus. Condensation of ethoxymethylene
malononitrile with acetamidine affords the substituted pyrimidine. This reaction
involves conjugate addition of the amidine nitrogen to the malononitrile followed
by loss of ethoxide, addition of remaining amidine nitrogen to one of the nitrile
will then lead to the pyrimidine. Reduction of the nitrile gives the corresponding
amino methyl compound* exhaustive methylation of the amine followed by
displacement of the activated quartemary nitrogen by bromide ion affords the key
28 intermediate#dj«placement of the halogen by a-picoline gives amprolium
N C ^ + HjN-^ >-OEt CH3 N C ^ ^ ^ ^ ^ N ^ ^ ^ ^ A ^ N
H NH, CI
Amprolium NHj
CHAPTER-1
07. From imino-ethers
Knoevenagel type of condensation ijiy0lv©s-tWpphene-2-carbaldehyde with
cynoacetic acid gives the corresponding unsaturated nitrile. This is then
methylated in the presence o^'strong acid to affords the imino-ether^(condensation
with N-methyl propolene 1,3- diamino proceeds probably by addition-elimination
of each amino group in turn with the iminoether. There is thus obtained pyrantal.
The analog, morantaP^ is obtained by the sequence using 3-methylthiophene-2-
carboxaldehyde.
NH
I X -CH,
ij CN
CH,
Morantal
08. From three-component condensation (TCC)
A novel and efficient protocol is developed for the synthesis of various
spiro-2-amino pyrimidinones 1 via the three-component condensation of alkyl
cyanoacetates, guanidinium carbonate and N-substituted 4-piperidinones in
ethanol at reflux. High yields, neutral conditions, and short reaction times are
advantages of this method^°.
o NH
CO3
N ' I
R
X ^ + CN
HjN- // NC
NH2 ^ 2 , N .
R= Bn, -CH2CH2Ph, X=COOMe, COOEt
O
N
^N NH2 H
CHAPTER-I
09. From Biginelli reaction
Multicomponent one-step fusion of a variety of pharmacologically pertinent
pyrimidine heterocycles has efficiently been achieved from their respective
aldehydes, P-dicarbonyl compounds, and urea/thiourea in the presence of a
catalytic amount of tetrachlorosilane in DMF/AN mixture at normal ambient
3 . 1 temperature . '
X
H2N NHj
O-^ . H SiCl4(10mol%) R
DMF/AN(1:2)
Ambient temp. 4hr
10. From four-component Biginelli-type reaction
4-Aryl-2-cyanoimino-3,4-dihydro-l//-pyrimidine derivatives 3 have been
prepared using multicomponent reaction by reacting a mixture of arene or
heteroarenecarbaldehyde, 1,3-dicarbonyl compounds, and cyanamide under acidic
conditions. The novelty of this approach derives from its use of cyanamide as a
building block in a four-component Biginelli-type reaction^^. Varying the reaction
conditions led to the formation of either jV-(2-imino-6-phenyl-l,3,5-oxadiazinan-
4-ylidene) cyanamide or 3,4-dihydropyrimidin-2(l//)-one. The type of
heterocycle skeleton synthesized depends on the nature of the acid catalyst as well
as the reaction conditions employed.
10
CHAPTER-I
H,N^^^ 0
I 0
-R^ HCl/ AcONa/EtOH
0 R'
H
3 R'
0
I 0
-R^
78 °C / 4hr
0 R'
H
3
11. From a,p-unsaturated imines
A series of polysubstituted pyrimidines 4 were synthesized from in situ
generated a,p-unsaturated imines and the corresponding amidine or guanidine
derivatives in a convenient one-pot procedure^^.
R
Ar " Ar
R . ^ R . . ^ ^
Ar, ^NH Ar, N R
12. From Aza-Michael addition
A novel and expeditious synthetic protocol for functionalized pyrimidines
using unprotected aldoses as biorenewable resources is reported. The synthesis
involves aza-Michael addition "* of aromatic amines to aldose-derived 1,3-oxazin-
2-ones (thiones) followed by dehydrative ring transformation to afford 4-
polyhydroxyalkylpyrimidin-2-ones (thiones) This is a one-pot Montmorillonite K-
10 clay-catalyzed amine-driven process proceeding under solvent-free microwave
irradiation conditions.
11
CHAPTER-I
OHC
(CHOH)„ •
HOH2C
D-xylose n=3 D-giucose n=4
(H0HC)2 ,CH,OH
Ar. ^N'
5
? Nilo Zanatta^^ et al., have _©cfT found new cruzain inhibitors,^nw 2-(A' '-
benzylidenehydrazino)-4-trifluoromethyl-pyrimidines.
H2N
HN
H -N
F3C
N I V O R R N
6
NH N^ ^Ar
Synthesis of fused pyrimidines
Synthesis of fused pyrimidines like furo[2,3-</]pyrimidines 7 and 8 from
keto alcohols treated with malononitrile in dimethylformamide in the presence of
diethylamine to l-amino-2-cyano-3,4-disubstituted furan. Ring closure by two
different methods gives amino and hydroxy furo[2,3-<3f]pyrimidines, biological
evaluation as AKtl kinase Inhibitors 36
NH2 R'
Furo[2,3-d]pyrimidines
^ N ^ ^ O
12
CHAPTER-I
The synthesis of several 2-aminothiophene-3-carboxylic acid derivatives 9
by two-minute microwave irradiation allowed their efficient transformation to
thieno[2,3-<^pyrimidin-4-ones^^ and the corresponding 4-chloro derivative is also
reported under microwave irradiation.
1) HCOOH-H2SO4 CI
HO S NCCH^CN ?^ MW-15m.n / ^ Y " ^ N
MW -2min ^ MW - 2xl0min '
Recent synthetic strategies in synthesis and biological activity of pyrimidines
Pyrimidines have been important lead molecules due to their diverse
pharmacological activity and have a long and distinguished history extending
from the days of their discovery as important constituents of nucleic acids to their
current use in the chemotherapy of AIDS. We have emphasized on some of the
novel synthetic strategies for the synthesis of biologically active pyrimidines
which also includes microwave synthesis and one pot synthetic techniq<ie&, with
an aim to help medicinal chemist to explore more biologically potent analogs.
Clifford Jones^* et al., have Jjedi developed a novel series of imidazole
pyrimidine amides 10 as cyclin-dependent kinase (CDK) inhibitors, afe-descnbcdr
Optimizations of inhibitory potency against multiple CDK's (1, 2 and 9) resulted
in imidazole pyrimidine amides with potent in vitro anti-proliferative effects
against a range of cancer cell lines.
13
CHAPTER-I
N N AZD5597 H
H3C 10 ^
Series of 4,6-bis-anilino-l//-pyrrolo[2,3-cr]pyrimidines 11 have been
synthesized and these molecules reported as IGF-IR (IGF-IR) receptor tyrosine
kinase inhibitors".
NH2 F
Osamu Irie'**' et al., have Jjectf* described active and brain-penetrant
cathepsin S selective inhibitors 12. The brain-penetrating cathepsin S inhibitors
demonstrate potential clinical utility for the treatment of multiple sclerosis and
neuropathic pain.
. C H ,
HjC^
Huang, Daniel'*' et al, have b^eJiaesigned a series of pyrimidinopyridones
and shown to be potent and selective inhibitors of the FMS tyrosine kinase.
14
CHAPTER-1
Micheal''' et al, discovered series of 4-amino-6-piperazin-l-yl-pyrimidine-
5-carbaldehyde oximes and developed as potent FLT3 tyrosine kinase inhibitors
14. Mahbub Alam"* et al., developed a series of novel 2-aminopyrimidines 15 as
inhibitors of c-Jun N-terminal kinases is described.
15
CHAPTER-I
Tricyclic pyrimidines
Ayoob Bazgir'*'* et al, reported one-pot and efficient method for the
synthesis of pyrazolo[4',3'5,6]pyrido[2,3-</] pyrimidine-dione derivatives 16 by
condensation reaction of barbituric acids, l//-pyrazol-5-amines and aldehydes
under solvent-free conditions jc reported: These products have been evaluated in-
vitro for their antibacterial activities.
Ph Ar
1 0 u
M ' ^ fS P^NH N
/ K^ N - ^ Y
= ^ H 16
H
X
Series of pyriniido[4,5-6]quinolines, triazolo[4',3':l,2]pyrimido[4,5-*]-
quinolines and tetrazolo[4',3':l,2]pyrimido[4,5-i]quinolin-5-one and [1,3]-
pyrazolo[3',2':l,2] pyrimido[4,5-Z>]quinolines and 2-pyrazolyl-pyrimido[4,5-6]-
quinolines'*^ 17 have been synthesized and some of the new compounds were
tested against various bacteria and fungi species. In addition, the analgesic and
anti-inflammatory activities are reported.
Ar O Ar O
17
The pyrimido[4,5-6]quinoline'*^ ring system is of interest because of its
structural similarity to the pyrimido[4,5-Z)]quinoxaline system of naturally
16
CHAPTER-I
occurring flavins. Synthesis of several pyrimido[4,5-6]quinolines 18, 19 have
been reported in the literature, with a view to develop new chemotherapeutic
agents.
Recently, Althuis"* et al., have synthesized and tested a number of
pyrimido[4,5-Z)] quinolines for their antiallergic property. Among the compounds
tested, 20 was found to possess high oral activity. Pyrimido[5,4-Z>]quinolines 21,
which are regarded as 10-dezaflavins have been synthesized and are found to be
inhibitors of riboflavin synthesis.
Rj = H CH3, R3 = Pentyl
/cC U.S. Patent describes the preparation of polyfluorinated mono and dioxo
tricyclic quinolines 22. These compounds are reported to display antifungal
activity against Trichophyton rubrum and Epidermophyton floccosum at 1.6 and
0.39 mg/ml.
17
CHAPTER-I
Biological significance of pyrimidine derivatives
Pyrimidines have a long and distinguished history extending from the days
of their discovery as important constituents of nucleic acids to their current use in
the chemotherapy of AIDS.
Alloxan is known for its diabetogenic action in a number of animals'* .
Uracil, thymine and cytosine are the three important constituents of nucleic acids.
o o NH
O
0=" "^N'^O
"NH
H
O H3C. A
H
NH,
-N
N ^O H
H
Alloxan Uracil Thymine Cytosine
The pyrimidine ring is found in vitamins like thiamine , riboflavin and folic
I 50 acid . Barbitone, the first barbiturate hypnotic sedative and anticonvulsant is a
pyrimidine derivative 49
o HOHjCHjCC-v^ \
\ -N^ a HjC
A^Nx^, , .^^CH3 HN- ^ r y
O ^ N ^ N - ^ ^ ^ - ^ C H ,
CH2OH
Thiamine Riboflavine
OH
-. J^ /NH /t:.
V'^^r /COOH
H5C6 JT
O ^ N - ^ O
Folic Acid S [ . ^^COOH H Phenobarbitone
18
CHAPTER-1
During the last two decades, several pyrimidine derivatives have been
developed as chemotherapeutic agents and found wide clinical applications.
Antineoplastics and anticancer agents
There are large number of pyrimidine-based antimetabolites structurally
related to the endogenous substrates that they antagonize. The structural
modification may be on the pyrimidine ring or on the pendant sugar groups. One
of the early metabolites prepared was 5-fluorouracil'^' (5-FU), a pyrimidine
derivative S-jChiouracil also exhibits some useful antineoplastic activities'^.
o H
« ^ o N / ^N. /O
NH ^^^<^'^ CI / \ A .NH N
X=0, R = F, Ri = H, 5 -Thiouracil ^ CI Uramustine Tegafur
X = O, R = SH, R, = H, 5 -Fluorouracil
The antineoplastic compounds'^ possessing the guanine nucleus, in
azathioprine, mercaptopurine, thioguanine and tegafur'"*" etc. were discovered
after formulation of the antimetabolite theory by Woods and Fildes in 1940.
These drugs prevent the utilization of normal cellular metabolites'^. There are
many more in recent times, like mopidamol, nimustine, raltitrexed, uramustine
and trimetrixate, 1-P-D-Arabinosylcytosine (Ara-C,) is also an example of a
pyrimidine antimetabolite in which the sugar is arabinose having a beta
configuration. It is mainly used as an anticancer agent and also exhibits
significant therapeutic effects in patients with herpes virus infections and herpes
19
CHAPTER-!
encephalitis. Gemcitabine, a pyrimidine antimetabolite, shows excellent
antitumour activity against marine solid tumours^*' .
ABPP induces high levels of interferons in mice when administered orally. It has
shown antitumour activity in some experimental animal models^''.
2-Ainino-5-broino-6-phenylpyriinidin-4(3^-one(ABPP)
Drugs for hyperthyroidism
2-Thiouracil and its alkyl analogue, thiobarbital are effective drugs against
hyperthyroidism. Propylthiouracil is used as a drug for hyperthyroidism with
minimum side effects^'.
O R = R, =R2 = H, X = S 2-Thiouracil
R^-V^NH R = R, = H R2 = C3H7 X = S Propylthiouracil
R N X R = R, =C2H5 R2 = 0 X = S Thiobarbitol
Antifolates, antibacterials and antiprotozoals
In 1948, Hitchings made an important observation that a large number of
2,4-diaminopyrimidines and some 2-amino-4-hydroxypyrimidines are antagonists
of folic acid^'. Since then, a large number of 2,4-diaminopyrimidines have been
synthesized as antifolates. It was eventually proved that these pyrimidines are
inhibitors of the enzyme
20
CHAPTER-I
dihydrofolate reductase (DHFR) ' . Notable amongst the 2,4-diaminopyrimidine
drugs are pyrimethamine a selective inhibitor of the DHFR of malarial plasmodia;
trimethoprim, an antibacterial drug which selectively inhibits bacterial DHFR and
most importantly, the very potent but non selective DHFR inhibitors,
methotrexate and aminopterin both used in cancer chemotherapy^"*. 3',5'-
Dichloromethotrexate which is less toxic and more readily metabolized than
methotrexate, has recently been introduced for anticancer therapy^^. Brodimoprim
is also found to be an effective antibacterial compound^^.
OCH,
H3C0 H3C0
Trimethoprim Brodimoprim
Sulfa drugs
Pyrimidine derivatives of sulfa drugs, namely sulfadiazine, sulfamerazine
and sulfadimidine are superior to many other sulfonamides and are used in some
acute urinary tract infections, cerebrospinal meningitis and for patients allergic to
pencillins^'. Sulfanamide-trimethoprim combinations are used extensively for
opportunistic infections in patients with AIDS^^. Sulfadoxine^^^ a short and
intermediate acting sulfonamide with a half-life of 7-9 days is used for malarial
prophylaxis. Sulfisomidine with a half-life of 7 hours is used as a combination
sulfa therapy in veterinary medicine™. Sulfadiazine, sulfamerzine and
21
CHAPTER-I
sulfadimidine possess good water solubility and therefore carry minimum risk of
kidney damage, which makes them safe even for patients with impaired renal
functions.
In 1959, sulfadimethoxine^' was introduced with a half-life of
approximately 40 hours. The related 4-sulfanamidopyrimidine, sulfamethoxine
having two methoxy groups in 5 and 6 positions, has by far the longest half-life of
about 150 hours. Methyldiazine has a half-life of 65 hours. Also,
sulfamethoxydiazine possesses good half-life. A new broad-spectrum
sulfonamide, sulfamethomidine ' relatively nontoxic and patients do not need
extra fluid intake or alkalization. Sulfacytine has been reported to be 3-10 times
more potent than sulfaisoxazole and sulfisodimidine^'.
OCH,
N' n o O
V H3C' " N ' "N' ' H
Sulfamethomidine NH.
CHo
k N ' - - T O O
Sulfacytine
NH,
Antiviral and anti-AIDS drugs
Recently, pyrimidine derivatives have generated widespread interest due to
their antiviral properties. 5-Iododeoxyuridine'^ is an antiviral agent of high
selectivity. IDU (5-iodo-2'-deoxyuridine) has been extensively utilized for viral
infections. 5-Trifluromethyl-2'-deoxyuridine (F3 TDR) has been found useful
against infections resistant to IDU therapy. Ara-A 9-yS-D-arabinofiiranosyl
22
CHAPTER-I
adenine, a relatively new antiviral drug, is effective against herpes infections of
eye, brain and skin. It is especially effective against IDU-resistant herpes virus^^.
Some purine nucleosides are equally noteworthy. Retrovir (AZT-16) is a
potent inhibitor of the in-vivo replication and cytopathic effects of HIV and has
been recently approved for use against AIDS and severe ARC'^. At present
Acyclovir is the only remedy for genital herpes. The oral formulation of
Acyclovir is effective against both first and second-degree recurrence-genital
herpes with minimal side effects '*. Ganciclovir''^ (DHPG-2) has shown good in-
vivo activity against HCVi and HCV2.
Several members of a series of acyclic nucleosides, which contain a fused
pyrimidine ring (mainly purine), are found to be effective antivirals. Famiciclovir
and valacyclovir are drugs used for several DNA viruses, including Hsv types 1
and 2, Varicella-zoster virus and Epstein-Barr virus^^. Penciclovir^' is useful for
topical treatment of recurrent herpes, Libialis. Cidofovir, an antimetabolite for
deoxycytosine triphosphate is used for treatment of cytomegalovirus (CMV) in
AIDS patients. Lamivudine 23 is an effective anti-AIDS drug when used in
combination with zidovudine. Zidovudine^^ is an analogue of thymidine in which
the azido group is substituted at the 3-position of the dideoxyribose moiety. It is
active against RNA tumour viruses (retroviruses) that are the causative agents of
AIDS and T-cell leukaemia. It is used in AIDS and AIDS-related complex (ARC)
to control opportunistic infections by raising absolute CD4* lymphocyte counts.
Also, zalcitabine is another useful alternative drug to zidovudine. It is given in
combination with zidovudine, when CD4+ cell counts fall below 300 cells/mm .
23
CHAPTER-1
Didanosine^^ is a purine dideoxynucleoside, which is an analogue of inosine.
Didanosine inhibits HIV RT and exerts a virustatic effect on the retroviruses.
Combined with zidovudine, antiretroviral activity of didanosine is increased.
Stavudine is a pyrimidine nucleoside analogue that has significant activity against
HIV-1 after intracellular conversion of the drug to a D4T-triphosphate. It is more
effective than zidovudin or didenosine for treatment in patients for delaying the
progression of HIV infection. It is recommended for patients with advanced HIV
infection.
Abacavir sulfate was approved in 1998 as a NRTI (Nucleoside Reverse
Transcriptase Inhibitor) to be used in combination with other drugs for the
treatment of HIV and AIDS. The major use of abacavir appears to be in
combination with other NRTIs.
NH,
=N
N ^O I R
R = Cidofovir
O Lamivudine
-OH
HO
O
O^N-J
N3 Zidovudine
CH, NH,
HO O ^ N - ^
O \
Zalcitabine
HN
HO O.
HjN N
\
Abacavir
24
CHAPTER-I
Antibiotics
There are few examples of pyrimidine antibiotics. The simplest of all is
bacimethrin (5-hydroxymethyl-2-methoxypyrimidin-4-amine), which is active
against several staphylococcal infections^''. Gourgetin, a cytosine derivative is
active against mycobacteria as well as several Gram(+) and Gram(-) bacteria*'.
There are more derivatives of cytosine, namely amicetin and plicacetin which
exhibit activity against acid fast and Gram-(+) bacteria as well as on some other
organisms. Puromycin has a wide spectrum of antitrypanosomal activity.
Aminoglycoside antibiotics phleomycin, bleomycin and related families are wide-
spectrum antibiotics containing the pyrimidine ring. Another antibiotic
tubercidine is reported to exhibit antitumour properties. In addition, they have
antineoplastic activity. Bleomycin is already in clinical use against certain
tumours like Hodgkin's lymphoma and disseminated testicular cancer .
CH3
Y"2 _ ^ ^ .NH . ^ , ^ J ^ __^ .NH,
N CH3
Bacimethrin
O' > ^ n T NH^N' O NH2
H,N'' " N ' ^ O Gourgetin
HO OH 6
Amicetin
H3C
HO OH
Plicacetin
25
CHAPTER-I
Antifungals
Pyrimidines also exhibit antifungal properties. Flucytosine*^ is a fluorinated
pyrimidine used as nucleosidal antifungal agent for the treatment of serious
systemic infections caused by susceptible strains of Candida and cryptococcus*"*.
Hexitidine*^ is mainly used for the treatment of aphthous ulceration.
NH,
N
H
Flucytosine
Antitubercular drugs
Capreomycin produced by Streptomyces capreolus is a second-line
bacteriostatic antituberculin drug containing pyrimidine^ '*''. Viomycin is more
tuberculostatic than p-aminosalicyclic acid. It is effective in the treatment of
experimental tuberculosis.
O CHjR H O NH,
Capreomycin
NH V ^ CH,
N - ^ O O
26
CHAPTER-I
HOH2C j ^
N ^ ^CHjOH
PiN^ N OH H
Viomycin
CNS active agents
Sedative/hypnotic/antiepileptic agents
Agents of the anxiolytic, sedative and hypnotic group include a wide variety
of barbiturates used as sedative and hypnotics and are classified as drugs having
short, intermediate and long duration of action**'* . Allobarbital , aprobarbital ,
pentobarbital, phenobarbital and secobarbital are frequently used clinically as
hypnotic barbiturates^^. Hexobarbital, cyclobarbital and propallylonal are some of
the current drugs in the market used as sedative hypnotics^'. Barbiturates as
sedative hypnotics have a long and fascinating history. In fact Eli Lilly^^ patented
secobutabarbital in 1932, while baritone, the first of the barbiturates was
introduced in 1903.
R
O^ Ji^ / O
o Barbiturates
27
CHAPTER-I
Anxiolytic agents
Few of the pyrimidine derivatives were also used as anxiolytics. Most
important of these is Buspirone (azaspirodecanediones), indicated in the
management of anxiety disorders accompanied with or without depression. It
lacks sedative, anticonvulsant and muscle-relaxant effects and most importantly
abuse potential. Buspirone lacks affinity to benzodiazepine receptors, but binds
avidly to one subclass of serotonin receptors, the
5-HTiA subtype 93-94
CI
H3C. / ^
,A. X H ,
H3C' . N
N N N ' H
Ritanserin Mezilamine
Ritanserin, a 5HT2 antagonist with anxiolytic activity is a pyrimidine
derivative^^. A simple pyrimidine derivative, mezilamine is classified as an
antipsychotic agent . Risoperidone is an antipsychotic drug, which is a structural
hybrid of butyrophenone and can be used as anxiolytic, antidepressant and
antiparkinsonism drug 97
. N ^ ^CH
Risoperidone
28
CHAPTER-I
Pyrimidine anaesthetics
Thimylal is a short acting general anaesthetic drug, which is also a
pyrimidine analogue ' . Saxitoxin^^ is a naturally occurring pyrimidine
containing anaesthetic agent, but is too toxic to be of clinical use. Saxitoxin is
isolated from some marine dinoflagellates.
o ^ ^ ^ "2 , /^ ; H,N^ ^O
CH2 CH3 o
HN .A. N
\ = N H 2
Saxitoxin
Diuretics, uricosurics
Several xanthine derivatives containing fused pyrimidine ring systems like
caffeine"'^ and analogs of caffeine are, etamiphylline"", lomiphylline"'^,
etophylline'*' , theophylline'^" and theodrendaline'°'* are known to promote a weak
diuresis by stimulation of cardiac function and by a direct action on the nephron,
acting as adenosine receptor antagonists'"".
O R
I CH3
There are a few examples of diuretics which contain a pyrimidine ring.
Noteworthy are quinethazine , metolazone'"^ and triamterene'"^.
29
CHAPTER-I
HjNOjS
R = C2H5, R =H Quinethazine
R = CH3, R, = 2-CH3-C6H5- Metolazone
HjN N / . N ^ ^NH2
A H5C6 N f
NH2
Triamterene
Cardiac agents
Antihypertensives
Several pyrimidine ring-containing drugs have exhibited antihypertensive
activity. Prazosin , a quinozoline derivative, is a selective oi-adrenergic
antagonist"^^"^*. Its related analogues bunazosin'°^, terazosin"" and trimazosin'"
are potent anti hypertensive agents.
o
NH.
R = H3C
-COCH2CH2CH3
Bunazosin
-COOCH2COCH2(CH3)2
Trimazosin Tetrazosin
Another quinazoline derivative, ketanserin"^ having a similar effect is an
antagonist of both a 1-adrenergic and serotonin-S receptors. Its mechanism of
action however is still controversial. A triaminopyrimidine derivative, minoxidil,
whose mechanism of action and therapeutic action are similar to prazosin, has
been introduced in therapy for its side effects, in the treatment of alopecia, male
baldness"^. Besides these, some more pyrimidine derivatives given below were
found to be antihypertensives"'*'"^.
30
CHAPTER-I
N O Ketanserin H
.114 Alfiizocin , a prazocin analogue and an a 1-adrenoceptor antagonist as well
as urapidil"^ are used especially in urinary obstruction caused by benign prostate
hyperplasia.
HjC^
Alfuzocin
H , C '
N
Urapidil
CH3
NH
O
Vasodilators
A series of xanthine derivatives are used as peripheral and cerebral
vasodilators. Especially, pentifylline and pentoxyphilline are used in
cardiovascular disorders"^. Other derivatives like xantinol nicotinate"^, a
vasodilator with general properties like nicotinic acid used in cerebral and
peripheral vascular disorders and pimephylline and pyridophylline are
noteworthy.
31
CHAPTER-I
H,C^
I CH,
Pentifylline R = -H R = -CH3 R = -CH3 A ^ Pimephylline R = ''^^^NH
Pentoxyphilline R,= =0 R, =-CH, R,-CH, • ' ^ 3 3 3 Pyridophylline R = —\
A new dopamine receptor stimulant, pirebidil"^ is reported to have
produced significant improvement in ADL (Activity of Daily Living) in patients
suffering from Parkinson's syndrome.
r ^ N Pirebidil
Cardiotonics, bronchodilators
Several xanthine derivatives theophylline, aminophylline'^° and
proxyphylline'^° exhibit good bronchodilator activity.
OH o
° H H3C. , X _ N * "3 "3C.^/>V^N
I CH3 CH3
Aminophylline Proxyphylline
32
CHAPTER-I
Antihistaminic pyrimidines
Taziphylline is ten times more potent than either astemizole or terfenadine
in its affinity for Hi-histamine binding site and appears to be devoid of CNS
activity'"^'. Another pyrimidine containing antihistaminic drug, temelastine is
comparable to mepyramine'^^. Radiolabelled studies have indicated that it does
not penetrate the CNS appreciably. Icotidine, a structural analogue of temelastine
lacks CNS activity and is a dual antagonist of both H] and H2 receptors'^^.
OH
o H , C .
N N
•~N -N
I
Taziphylline
I CH3
N CH,
1 _ 2 _ Temelastine ^ - Br R - CH3
Icotidine R, = H Rj = OCH 3
Analgesics and NSAID drugs
Acetiamine' "*, bentiamine'^^ and fursultiamine'^^ are new lipid-soluble
forms of thiamine (vitamin Bl) having therapeutic use in beriberi, polyneuritis,
encephalopathy, pain, malnutrition and alcoholism and especially in the treatment
of long-standing insulin-dependent diabetes mellitus. Fursultamine has been
reported to inhibit the arachadonic acid cascade-line activation and reverse the
increase in CBF (Coronary Blood Flow).
33
CHAPTER-I
O
Acetiamine R
R CHO fT V ^
CH,
-CH,
NH, O
H 3 C ^
Bentiamine R -C6H5 C6H5
0 = ^ S ^
N^ ^CH,
Fursultamine
Ademetionine'^^ is primarily used in conjunction to glucosamine and
chondroitin therapy. Octotiamine'^°, a vitamin Bl derivative also exhibits anti
inflammatory activity. Proquazone'^', a condensed pyrimidin-2-one derivative has
been reported to exhibit good NSAID.
° H3C CH3
N^ ^CH,
Octotiamine Proquazone
34
CHAPTER-I
Metabolic electrolytes
Orotic acid' ^, a simple pyrimidine derivative and its mineral forms are used
in metabolic therapy, especially for cardiovascular patients to prevent heart failure
in cardiomyopathy. Oroate is needed as a key intermediate in biosynthesis of
pyrimidine nucleotides, which are building blocks for DNA and RNA required for
the final protein synthesis.
H 0 \ N /O
NH
COOH
Orotic acid
35
CHAPTER-I
Thiophene derivatives
Thiophene was discovered as a contaminaent in benzene'^^ It was
observed that isatin forms a blue dye if it is mixed with sulfuric acid and crude
benzene. The formation of the blue indophenin was long believed to be a reaction
with benzene. Victor Meyer was able to isolate the substance responsible for this
reaction from benzene. This new heterocyclic compound was thiophene' "*.
Thiophene and its derivatives occur in petroleum, sometimes in
concentrations up to 1-3%. The thiophenic content of oil and coal is removed via
the hydrodesulfurization (HDS) process. In HDS, the liquid or gaseous feed is
passed over a form of molybdenum disulfide catalyst under a pressure of H2.
Thiophenes undergo hydrogenolysis to form hydrocarbons and hydrogen sulfide.
Thus, thiophene itself is converted to butane and H2S. More prevalent and more
problematic in petroleum are benzothiophene and dibenzothiophene.
Reflecting their high stabilities, thiophenes arise from many reactions
involving sulfur sources and hydrocarbons, especially unsaturated ones, e.g.
acetylenes and elemental sulfur, which was the first synthesis of thiophene by
Victor Meyer in the year of its discovery. Thiophenes are classically prepared by
the reaction of 1,4-diketones, diesters, or dicarboxylates with sulfiding reagents
such as P4S10. Specialized thiophenes can be synthesized similarly using
Lawesson's reagent as the sulfiding agent, via the Gewald reaction, which
involves the condensation of two esters in the presence of elemental sulfur.
Another method is the Volhard-Erdmann cyclization.
36
CHAPTER-I
Thiophene is produced on a scale of 2M kg per year worldwide.
Production involves the vapor phase reaction of a sulfur source, typically carbon
disulfide, and butanol. These reagents are contacted with an oxide catalyst'^^ at
500-550 °C.
At room temperature, thiophene is a colorless liquid with a mild pleasant
odour reminiscent of benzene, with which thiophene shares some similarities. The
high reactivity of thiophene toward sulfonation is the basis for the separation of
thiophene from benzene, which are difficult to separate by distillation due to their
similar boiling points (4 °C difference at ambient pressure). Like benzene,
thiophene forms an azeotrope with water.
The molecule is flat; the bond angle at the sulphur is around 93 degrees,
the C-C-S angle is around 109 degrees and the other two carbons have a bond
angle around 114 degrees. The C-C bonds to the carbons adjacent to the sulphur
are about 1.34 A°, the C-S bond length is around l.VOA" and the other C-C bond
is about 1.41A° (figures from the Cambridge Structural Database).
H
u H
Thiophene is considered aromatic, although theoretical calculations suggest
that the degree of aromaticity is less than that of benzene. The "electron pairs" on
sulfur are significantly delocalized in the 7i-system. As a consequence of its
aromaticity, thiophene does not exhibit the properties seen for conventional
thioethers. For example the sulfur atom resists alkylation and oxidation.
37
CHAPTER-I
E E
Although the sulfur atom is relatively unreactive, the flanking carbon
centers, the 2 and 5-positions, are highly susceptible to attack by electrophiles.
Halogens give initially 2-halo derivatives followed by 2,5-dihalothiophenes;
perhalogenation is easily accomplished to give C4X4S (X = CI, Br, I)'^^.
Thiophene brominates 10^ times faster than does benzene. Chloromethylation and
chloroethylation occur readily at the 2,5-positions. Reduction of the chloromethyl
product gives 2-methylthiophene. Hydrolysis followed by dehydration of the
chloroethyl species gives 2-vinylthiophene'^'"'^^.
Thiophenes are important heterocyclic compounds that are widely used as
building blocks in many agrochemicals and pharmaceuticals'^^. The benzene ring
of a biologically active compound may often be replaced by a thiophene without
loss of activity ^^^. This is seen in examples such as the NSAID's lomoxicam, the
thiophene analog of piroxicam. Lomoxicam (chlortenoxicam) is a NSAID's of the
oxicam class with analgesic, anti-inflammatory and antipyretic properties. It is
available in oral and parentral formulations.
OH O ^ ^ ^
Lomoxicam
Thiophene may have alkyl side chains or may be condensed with one or
more benzene ring(s) to form benzo[Z>]thiophenes, dibenzo[6]thiophenes,
38^
CHAPTER-I
naphthothiophenes or benzonaphthothiophenes. Indeed, sulfur is the third most
abundant element in crude oils'"*', and the condensed thiophenes are the most
common form in which sulfur is present. Alkyl dibenzo[A]thiophenes have been
shown to be quite persistent in petroleum contaminated environments''* '''*'' and
they concentrate in the tissues of aquatic species''*^"''* . Nonetheless, C-1 and C-
2 dibenzo[Z»]thiophenes are susceptible to biodegradation''*^"''' . Bressler'^° et al.,
have reviewed the literature on the ring cleavage of sulfur heterocycles. The type,
source and structure of various sulfur heterocycles have been examined and have
found the ring cleavage.
Compounds containing thiophene moiety 1 and 2 also have been isolated
from plants'^', bitumens, crude oils and in pyrolysates of kerogens and
asphaltenes 152
2-Hexadecyl-5-methylthiophene
2-Methyl-5-tridecylthiophene
2-Butyl-5-tridecylthiophene
CH32
39
CHAPTER-I
Thiophene analogs are also found in as a bithienyl derivative, it has been
isolated from the roots of Tagetes erecta Linn., commonly known as Marigold,
native of Mexico and other warmer parts of the America. An infusion of this plant
is used against rheumatism, cold and bronchitis. An extract of the root is credited
with laxative in action'^^.
The vitamin biotin is essential growth factor for a number of micro
organisms and for animals. It was first isolated from egg yolk and it is easily
obtained from milk concentrates.
HN NH
COOH
Tuberculosis is the leading infectious disease caused by Mycobacterium
tuberculosis}^'^'^^^. The situation is becoming alarming with the recent emergence
of multi-drug resistant (MDR) strains and its synergy with global human
immunodeficiency virus (HIV)'^^. The search for more effective agents against M
tuberculosis (MT) is ongoing in an attempt to enhance survival and reduce
morbidity, as proven by the high number of patents of new antitubercular agents
in the past decade.'^'
40
CHAPTER-1
A new series of thiophene containing triarylmethane derivatives'^* were
synthesized from the Friedel-Crafts alkylation of diarylcarbinols followed by
incorporation of amino alkyl chains. These were evaluated against
Mycobacterium tuberculosis H37RV and showed the activity in the range of 3.12-
12.5 Ig/ml in-vitro.
A large group of related benzo(b)thiophene derivatives'^^ have been
screened for antiviral activity in a simple cell culture system. Three viruses were
used; influenza A2, vaccinia and herpes simplex type 1.51% of the compounds
inhibited at least one virus by 75%, while 25 per cent were inhibitory by 90% per
cent. This high degree of antiviral activity is in agreement with the range of
biological properties possessed by benzo(b)thiophene derivatives as a whole.
Sets of tetrasubstituted thiophene esters'^° have been synthesized by reaction
of l-(a-carbomethoxy-P-aminothiocrotonoyl)-aryl/aroyl amines with 3-
(bromoacetyl)coumarin, 1,4-dibromodiacetyl and chloroacetone respectively. The
compounds were synthesized by nucleophilic addition of aryl/aroyl isothiocyanate
and enamine. The synthesized targeted compounds were evaluated for their in-
vivo anti-inflammatory, analgesic and nitric oxide radical scavenging activity
employed. Among all the targeted compounds showed maximum anti
inflammatory activity of 71% protection at lOmg/kg and 77% protection at
20 mg/kg to inflamed paw and analgesic activity of 56% inhibition and also
maximum in-vitro nitric oxide radical scavenging activity having IC50 value
31.59 ^g/ml.
41
CHAPTER-I
Ticlopidine'^' is a drug analog of thienopyridine, it is indicated in
cerebrovascular diseases such as transient ischemic attacks, reversible ischemic
neurological defects, stroke, coronary artery disease such as unstable angina,
coronary artery bypass-grafts and secondary prevention of myocardial infarction.
It acts by inhibition of ADP-induced aggregation, which is common pathway of
aggregation. Ticlopidine was synthesized by starting with thiophene-2-aldehyde.
Method of synthesis
01. Pall knorr synthesis'"
It is a most general method for the synthesis of substuited thiophenes from
1,4-diketone and phosphorous pentasulfide.
I I HEAT / ~ S 0 0 R
02. Gewald's synthesis'"
2-Amino-4-phenylpenta-l,3-diene-l,l,3-tricarbonitrile reacted with
elemental sulfur in the presence of triethylamine to give 2-amino-3-(b-amino-a-
cyanoacrylonitrilo-3-yl)-4-phenylthiophene.
42
CHAPTER-I
H,N CN
N C - ^ CN
NH4OAC HjN
H5C6
CN
CN -CH3
HjN CN
CN H,N CN
N C - ^ CN
* •
0
CH3
HjN
H5C6
CN
CN -CH3
dioxane (Z y>~~ EtjN S
-CH3
03. Ring closure methods**'*
This approach involves the use of methyl thioglycolate and its condensation
with dimethyl fumarate in the presence of a base. An acetylenic compound may
also be used to obtain a thiophene ring.
o s/''"^ > •
COOH
/ ^ ^ ^ C O O H 1
COOH
/ ^ ^ ^ C O O H
OCH3
H3COOC COOCH3
COOH
/ ^ ^ ^ C O O H
04.1,4-Dilithiobutadienes'*^ with CS2
This reaction pattern was novel. When the reaction mixture of CS2 with
monolithium compounds at low temperature was treated yields thiophene
compounds were obtained.
1.CS2
2. H
Recent Synthetic strategies in synthesis and biological activity of thiophenes
A series of 3,4,5-trisubstituted'^* derivatives have been synthesized and
investigation for HIV-1 reverse transcriptase inhibitor. An X-ray structure with
43
CHAPTER-I
HIV-IRT secured the binding mood and allowed the key interaction with enzyme
to be identified.
A novel 5,4-dialkyl substituted thiophene'^^ was discovered in silico
screening of the 3D polymerase crystal structure that demonstrated single digit
micromolar HCV inhibition activity in the replicon assay.
CONH,
4,5-Dihydroxypyrimidine carboxamidines'^*, which evolved from a related
series of HCV NS5b inhibitors, have been optimized to provide selective HIV
integrase stand transfer inhibitor. Similarly thiophene containing fused and
substituted pyrimidine derivative 2-methyl-3-substituted-5-(thiophen-2-
yl)thieno[2,3-^pyrimidin-4(3//)-ones was synthesized and these molecules have
been proved to be a good antitubercular agents'^^.
1 R = -NH2,=N=CHR
O 4-CI-C6H4
4-HO-C6H4
44
CHAPTER-I
The synthesis of thiophenes and fused derivatives as importance of such
compounds is based on their use as anti-inflammatory, anti-protozoal and
antitumor agents, for serine protease inhibition and alternate substrate inhibitors
of cholesterol esterase. In addition to this some fused thiophene with pyrimidine
and tetrahydrobenzen analogs have been reported as antidepressants, sedative and
analgesics activities'^°.
Y CONHPh
V-N
CJS-'"-Keeping in view of biological importance of pyrimidines and thiophene
derivatives and inspired by the scope of research in this field, we have carried out
the research work on the synthesis of pyrimidines and thiophene derivatives to
explore their biological profile.
In the present investigation, the starting materials were synthesized by the
condensation of ethylcynoacetate, thiourea with different substituted
arylaldehydes in the presence of potassium carbonate using dry alcohol as solvent
by conventional and microwave method "''^.
Syntheses of paracetamol and eugenol analogs were prepared by reacting
with ethylchloroacetate and hydrazine hydrate.
45
CHAPTER-I
HjN
O NC
OEt
NHj +
Scheme-I
Dry alcohol
,CHO K2CO3
O
H 6-Substituted-5-cyano-,3,4-
dihydrothiouracils
OCH,
OH Eugenol
1 CICH2COOC2H5
Acetone K2CO3
HjN-NH, H2O
C2H5OH
OCH,
H •. h—Q N-NH2
O 2-[2-Methoxy-4-(prop-2-en-l-yl)
phenoxyjacetohydrazide
CH3
N—(\ /)—OH
1 MW, 160 W, 4min
CICH2COOC2H5 Acetone
CH3
w N—(\ A—0 NHNI H ^ ^ J ^ 2 MW, 160 W, 4niin H \-J V_^
A'-(4-hydroxyphenyl)acetainide H2N-NH2
C2H5OH H2O 0
N-[4-(2-hydrazinyl-2-oxoethoxy)
phenyl] acetamide
CH3
H 5 C 2 0 0 C . , ^ ^ CH3
1 MW 4Min H2NHNOC. J \ , ^ ^ NH
^ 5 ^ ^ C H 0 - r NHj 2 H2N-NH2 ^ " ^ V ^ N ^ O
alcohol IT
4-Anisyl-6-methyl-2-oxo-l,23»4-tetrahydropyriinidine-5-carbohydrazide
COOH
J O H C - ^
CH3C00Na o ~ N
(CH3co)20* y \ _ p ~ ^
2-Phenyl-4-(thiophen-2-ylinethylidene)-l,3-oxazol-5(4ff)-one
46
CHAPTER-I
Employing sophisticated techniques such as IR, ' H N M R and Mass
spectroscopy, the structures of all the newly synthesized compounds were
elucidated. The reaction mechanism was also predicted for reactions and in
exploration of their biological investigation. We have screened for their
antibacterial, antifungal, antitubercular and cytotoxicity properties.
47
CHAPTER-I
ORGANIZATION OF THE WORK
The thesis consists of nine chapters and each chapter contains proper
classification of the work and discussion.
CHAPTER! Introduction
CHAPTER-II Synthesis of substituted pyrimidinopyrazoJes and pyriiTiidinotriazoles.
CHAPTER-III Synthesis of novel piperazine and morpholine linked pyrimidine derivatives.
CHAPTER-IV Synthesis of 6-(substituted)-5-cyano-2-(substituted)-3-N-methyl-3,4-dihydro pyrimidin-4-ones.
CHAPTER-V Synthesis of 4-(substituted)-6-methyl-5-[3-(substituted)prop-2-enoyl]-1,2,3,4-tetrahydropyriniidin-2-ones and 5-(5-(substituted)-4,5-dihydro-l//-pyrazol-3-yl)-4-anisyl-6-methyl-l,2,3,4-tetrahydropyrimidin-2-ones.
CHAPTER-VI Synthesis of 3-(substituted)-2-phenyl-5-(thiophen-2'-ylmethylidene)-3,5-dihydro-
4//-imidazol-4-ones.
CHAPTER-VII Synthesis of 6-(thiophen-2'-yl)- 5-cyano~2-(substituted)-3-N-methyl-3,4-dihydro pyrimidin-4-ones.
CHAPTER-VIII Pharmacological and biological activities.
48
CHAPTER-I
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49
CHAPTER-I
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