Chapter 2 Review of Literature
33 | Design, Synthesis and Biological Evaluation of Novel Anti-Fungal Agents
2. REVIEW OF LITERATURE
2.1. Benzamide
Priya BS and et al 1
reported, a compound with an amide-bond backbone have a wide
range of biological activities. Among the natural and synthetic substituted amide
derivatives, there are compounds possessing anti-proliferative, antiviral, antimalarial,
general anesthetics, anti-inflammatory, antimicrobials and in the treatment of
Alzheimer’s diseases
Amide moiety is versatile in organic compounds since all the three atoms in the O–C–
N chain are potentially reactive. Several efficient methods have been exploited for the
amidation using specific dehydrating reagents under mild liquid-phase condition. The
synthesis of substituted amides (3) began with the synthesis of various acid chlorides
(1), where the acid chloride undergoes condensation reaction with different amines (2)
in presence of triethylamine as acid scavenger in dichloroethane as solvent.
Nilo Zanatta et al., 2 synthesized furan-3-carboxamides (5) as antifungal agents,
reaction of 2,2,2-trichloro-1-(furan-3-yl)ethanone (4), with benzamidine, primary and
secondary amines, furnished a series of furan-3-carboxamides, in good yields. It is
interesting to note that, probably, due to the higher boiling point of the amines used in
these reactions, the use of a sealed tube was not necessary. For the reaction of 2, 2, 2-
trichloro-1-(furan-3-yl)ethanone, with benzamidine hydrochloride, the use of an
equivalent amount of sodium hydroxide solution was necessary to obtain the amidine
free base.
Esin Ak Sener et al., 3 reported, the synthesis and antimicrobial activity of some N-(o-
hydroxyphenyl)benzamides (8) synthesized by reacting suitable 2-aminophenols (7)
with appropriate carboxylic acid chlorides, (6) and their antimicrobial activity.
Chapter 2 Review of Literature
34 | Design, Synthesis and Biological Evaluation of Novel Anti-Fungal Agents
Ozlem Temiz-Arpaci et al., 4 had developed, a series of novel 2-[p-substituted-
phenyl]benzoxazole-5-yl-arylcarboxyamide (11), obtained by treating 5-amino-2-
phenyl-or 5-amino-2-(substituted-phenyl)benzoxazoles (10) with substituted benzoic
acids or furan-2-carboxylic acid or thiophene-2-carboxylic acid chlorides (9) and
examine their microbiological activity against various Gram-positive and Gram-
negative bacteria and against the yeast C. albicans in comparison.
Tugba Ertan et al., 5 reported, a series of N-(2-hydroxy-4(or 5)-nitrophenyl)
benzamides/ phenylacetamides (14) derivatives by reacting suitable 2-aminophenols
(13) with appropriate carboxylic acid chlorides, (12). The derivatives which have a
nitro group attached on position 4 or 5 of N-(2-hydroxyphenyl) binding them as a new
class of synthetic antimicrobial agents along with their in vitro antimicrobial activity.
Additionally, they also put an electron donating group such as amine instead of nitro
which is an electron withdrawing group for the same position in order to be able to
discuss the effect of substituent for biological activity. According to these studies they
conclude that benzamide structure played a noticeable role for increasing the activity.
When compared to the effect of nitro and amine group for this activity, it can be
concluded that compounds including a nitro group on the phenolic ring slightly
enhanced the activity.
Chapter 2 Review of Literature
35 | Design, Synthesis and Biological Evaluation of Novel Anti-Fungal Agents
Benzamide Scaffold incorporated with heterocyclic residue like thiazole, furan and
phenyl ring substituted with electron-donating and electron-withdrawing groups were
found to prove antifungal activity.
B. Narayana et al., 6 synthesized, new 2-hydroxy-5-(1,3-thiazol-5-yl) benzamide (18),
were prepared by reacting 5-(bromoacetyl) salicylamide (16) with thiourea,
thioformamide, thioalkylamide (17) and substituted thioureas in absolute ethanol and
investigate their antifungal activity.
Thiazoles and their derivatives have attracted continuing interest over the years
because of their varied biological activities.
Desai N.C. and et al.,7 synthesized N-(5-(2-(5-(arylidene)-4-oxo-3-phenylthiazolidin-
2-ylidene)hydrazinecarbonyl)-4-methylthiazol-2-yl)-4-fluorobenzamides (20)by con
densation of 4-fluoro-N-(4-methyl-5-(2-(4-oxo-3- phenylthiazolidin-2-ylidene) hy -
drazinecarbonyl)thiazol-2-yl)benzamide (19) and Knoevenagel condensation with
aromatic aldehydes through conventional and microwave methods and evaluated
for antifungal activity.
Anil Kumar et al, 8 had reported, a series of new substituted benzamides (23),
synthesized by were generated by the reaction of substituted benzoic acid (21) with 2-
aminophenol (22), using carbonyldiimidazole (CDI) in THF in one pot.
Chapter 2 Review of Literature
36 | Design, Synthesis and Biological Evaluation of Novel Anti-Fungal Agents
Furthermore the compounds comprising olefins shows good antifungal activity.
William F. Wood et al., 9 reported, long-chain (E)-3-alken-2-ones (24), synthesiz -ed
by condensation of an appropriate aldehyde with acetone using piperidine and acetic
acid as a catalyst and evaluated for antimicrobial activity.
Sarveswari S. et al., 10
had synthesized 1-(6-Chloro-2- methyl-4-phenyl quinolin-3-
yl)-(aryl) prop-2-en-1-ones (27), by stirring the mixture of 3-Acetyl-6-chloro-2-
methyl-4-phenyl quinoline (25) and arylaldehyde (26) into a KOH and evaluated for
atifungal activity.
Hasan Kucukbay et al., 11
reported, electron-rich olefins (29) derived benzimidazole
compound synthesized from appropriate benzimidazolium salts (28) and NaH and
screened for antifungal activity.
Chapter 2 Review of Literature
37 | Design, Synthesis and Biological Evaluation of Novel Anti-Fungal Agents
In the present study we synthesized N-subtituted benzamides and subjected them to
antifungal and molecular docking studies to examine their biological activities,
possible interactions and binding patterns with the proteins in relation to their activity.
2.1.1. Amide bond formation: methods and strategies
Carboxy components can be activated as acyl halides, acyl azides, acylimidazoles,
anhydrides, esters etc. There are different ways of coupling reactive carboxy
derivatives with
an amine:
an intermediate acylating agent is formed and isolated then subjected to
aminolysis.
a reactive acylating agent is formed from the acid in a separate step(s), followed
by immediate treatment with the amine.
the acylating agent is generated in situ from the acid in the presence of the amine,
by the addition of an activating or coupling agent.
In nature, protein synthesis involving a sequence of peptide coupling reactions (amide
bond formation between two α-amino acids or peptides), which is very complex,
supported by selective activation process catalyzed by enzymes.13
Laboratory
synthesis of amides historically involves condensation reaction between carboxylic
acids and amines. On mixing an amine with a carboxylic acid, an acid base reaction
occurs first to form a stable salt.The amide bond formation has to fight against
adverse thermodynamics as the equilibrium lies on the side of hydrolysis rather than
synthesis.14
Figure 8.Reaction of carboxylic acid with amine to form salt.
The direct condensation of the salt is reported to take place at high temperature (160-
180ºC),15
which is usually quite incompatible with the presence of other
Chapter 2 Review of Literature
38 | Design, Synthesis and Biological Evaluation of Novel Anti-Fungal Agents
functionalities. Therefore, activation of the acid, attachment of a leaving group to the
acyl carbon of the acid, to allow attack by the amino group is necessary.
Figure 9.Acid activation and aminolysis.
2.1.1.1. Acyl azides
The acyl azide route is one of the first developed for peptide coupling by Curtius.
16
Acyl azides can be prepared from the corresponding methyl esters via a two step
synthesis. The methoxy group is displaced with hydrazine to generate the acyl
hydrazide, which then undergoes a nitrosation reaction to yield the final acyl azide.
This is usually an efficient coupling method, but an occasional side reaction is a
Curtius rearrangement, leading to the formation of the unwanted corresponding
isocyanate.
The acyl azide route is one of the first developed for peptide coupling by Curtius.
Acyl azides can be prepared from the corresponding methyl esters via a two-step
synthesis. The methoxy group is displaced with hydrazine to generate the acyl
hydrazide, which then undergoes a nitrosation reaction to yield the final acyl azide
Figure 10. Amide synthesis via acyl azide
2.1.1.2. Acyl halides
Acyl chlorides (acid chlorides) are one of the easiest methods to activate an acid and
numerous acyl chlorides are commercially available. This is usually a two-step
process, involving first the conversion of the acid into the acyl halide followed by the
coupling itself.
Thionyl chloride SOCl2, 17
oxalyl chloride (COCl)2, 18
phosphorus trichloride PCl3 , 19
phosphorus oxychloride POCl3 20
and phosphorus pentachloride PCl5 21
are commonly
Chapter 2 Review of Literature
39 | Design, Synthesis and Biological Evaluation of Novel Anti-Fungal Agents
used to generate acyl chlorides from their corresponding acids. Phoshonium
pentachloride is generally used for aromatic acids, which contains electron
withdrawing substituents and which do not react readily with thionyl chloride.22
The
amide bond is formed by reacting the acyl chloride with the desired amine. An
additional base is usually required to trap the formed HCl and to avoid the conversion
of the amine into its unreactive HCl salt. Couplings are usually performed in inert dry
solvents.
Figure 11. Mechanism for acyl chloride formation using oxalyl chloride or thionyl
chloride
Nevertheless, acyl chlorides are moisture sensitive, hazardous and may pose danger of
hydrolysis, racemisation, cleavage of protecting groups and other side reactions
during coupling reaction.23
Use of acyl bromides and acyl fluorides to generate amide
bonds is also reported.24,25
2.1.1.3. Anhydrides
Anhydrides are species that readily react with a vast range of nucleophiles including
amines. Simple symmetric anhydrides and refined mixed anhydrides are utilized for
the preparation of amides.
2.1.1.3.1. Symmetric anhydrides The diversity of commercially available anhydrides
is rather limited and, quite often, the desired anhydride has to be prepared. Symmetric
anhydrides are formed either by heating the corresponding acid or, in milder
conditions, by reacting two molecules of acid in the presence of one equivalent of
dicyclohexyl carbodiimide (DCC).26
The anhydride is then reacted in a second step
with the selected amine (Fig.6). No additional base is required, as the addition
generates a carboxylate anion in situ. The main limitation is that only half of the acid
is effectively coupled and the other half is wasted.
Chapter 2 Review of Literature
40 | Design, Synthesis and Biological Evaluation of Novel Anti-Fungal Agents
Figure 12. Anhydride preparation and consecutive coupling with amines.
2.1.1.3.2. Mixed carboxylic anhydrides To overcome this waste problem, mixed
anhydride methods have been developed where the second carboxylic moiety is cheap
and easy to couple onto the acid. Mixed pivalic anhydrides 27
are one of the rare
examples. The desired aminolysis selectivity is believed to be due to the steric
hindrance of the t-Bu group.
Figure 13. Two step coupling procedure via pivalic anhydride.
Excellent selectivity is observed with mixed carbonic anhydrides. 28
The carbonate
electrophilic centre a is more reactive than the carboxylic site b as the reactive centre
a is less stabilized by resonance.
Figure 14. Two-step coupling via ethyl carbonic anhydride.
2.1.1.4. Acylimidazoles using CDICarbonyl diimidazole (CDI) is a useful coupling
reagent that allows one pot amide formation. 29
Acyl carboxy imidazole and imidazole
are initially formed but readily react together to yield the activated species as the
acylimidazole. Practically, the acylimidazole is preformed for 1 h and then the amine
is added. This reaction, which generates imidazole in situ, does not need an additional
base and is even compatible with HCl salts of the amine.30
Chapter 2 Review of Literature
41 | Design, Synthesis and Biological Evaluation of Novel Anti-Fungal Agents
Figure 15. One pot amide preparation using CDI
2.1.1.5. Acyloxyboron intermediates
Acyloxyboron species 31
generated from carboxylic acids and boron reagents often
react with amines to give amides. Boron reagents readily react with carboxylic acids
to yield acyloxyboron intermediates, which are coupled to amines in moderate yields.
The main drawback of this procedure is the low conversion rate usually observed
during the aminolysis step.
Figure 16. Acylboronate formation and aminolysis
2.1.1.6. Esters
Alkyl esters (e.g., methyl, ethyl, benzyl esters) cannot be considered as activated
species and are commonly used as protecting groups in peptide synthesis. Alkyl esters
can, however, be displaced occasionally by amines under forcing conditions such as
the use of high temperatures or the addition of a Lewis acid (e.g., TiCl4).32
Activated
esters such as aromatic esters are usually easier to hydrolyze than alkyl esters and are
prone to react with a wide range of nucleophiles. More importantly, they cleanly react
with amines under mild conditions. 33
Chapter 2 Review of Literature
42 | Design, Synthesis and Biological Evaluation of Novel Anti-Fungal Agents
Figure 17. Conversion of activated esters to amide
2.1.1.7. Phosphonium salts
Benzotriazol-1-yl-oxytris(dimethylamino)phosphonium hexafluorophosphate (Fig.
14), also called Castro’s reagent, 34
is the first published example of these HOBt-based
onium salt reagents. The one-pot coupling is performed mixing the desired acid and
amine in the presence of BOP 60 and triethylamine or Hu¨nig’s base. The
deprotonated acid first reacts with BOP 60 to generate both an activated
acylphosphonium species and HOBt. HOBt readily reacts with the activated acid to
produce a reactive Bt ester, which finally undergoes aminolysis. The driving force of
this phosphonium-based reaction is to generate the correspondingoxide
Figure 18. One-pot coupling procedure using BOP
2.1.1.8. Microwave activation
In several cases, microwave irradiation has been a successful alternative to
conventional high temperatures to perform direct condensation of amines to
carboxylic acids without prior activation. The use of direct microwave heating is
reported to reduce the chemical reaction time, reduce side reactions, increase yields
and improve reproducibility. 35
The microwave irradiation may be run with or without
catalyst.
Chapter 2 Review of Literature
43 | Design, Synthesis and Biological Evaluation of Novel Anti-Fungal Agents
2.2. Thienopyrimidin-4(3H)-thiones
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.
Thieno[2,3-d]pyrimidines are considered to be bioisosteres of quinazolines. The
concept of bioisosterism has been exploited by medicinal chemists as an approach to
the drug design. This has lead to the synthesis of various types of condensed
pyrimidines, which show a wide range of biological activities.
Following are the few examples of various biological activities exhibited by the
thienopyrimidines.
Richard Luke et al.,36
reported the improvement in potency against Tie2 of novel
thieno pyrimidine (30) and thiazolopyrimidine kinase inhibitors. These compounds
have moderate potency in cellular assays of Tie-2 inhibition, good physical properties,
DMPK, and show evidence of in vivo inhibition of Tie-2.
Jeroen C. et al., 37
synthesized 2-Aryl-4-morpholinothieno[3,2-d]pyrimidines (31)
which are known as PI3K inhibitors. This class of compounds also potently inhibited
the homologous enzyme mTOR. Replacement of the morpholine group in these
compounds with 8-oxa-3-azabicyclo [3.2.1] octane group led to mTOR inhibitors with
selectivity over PI3K. Optimization of the 2-aryl substituent led to the discovery of 2-
(4-ureidophenyl)-thienopyrimidines as highly potent (IC50<1nM) mTOR inhibitors
with excellent selectivity (upto >1,000-fold) over PI3K and good potency in a cellular
proliferation assay (IC50 <50 nM).
Chapter 2 Review of Literature
44 | Design, Synthesis and Biological Evaluation of Novel Anti-Fungal Agents
Hans-Georg Häcker et al., 38
synthesized a series of 2-alkylthio-4-amino thieno[2,3-d]
pyrimidines (32) and tested in a daunorubicin accumulation assay.
Chen Yu Lu et al., 39
synthesized 5,6-Dihydrothieno[3,2:4,5]thieno[2,3-d]pyrimidin-
4(3H)-ones (33) in yields of 71–87% by a consecutive method, which includes aza-
Wittig reaction of iminophosphorane with aromatic isocynate to give carbodiimide
and subsequent reaction with various amines, phenols or alcohols in the presence of
catalytic amount of sodium ethoxide or solid potassium carbonate.
Lakshmi N. et al., 40
reported the diazotization of 3-amino-2-sulfanyl-2,3,5,6,7,8-
hexahydro[1] benzothieno[2,3-d]pyrimidin-4(1H)-one (34) to give the diazonium salt
of 3-amino-2-sulfanyl-2,3,5,6,7,8-hexahydro[1]benzothieno[2,3-d]pyrimidin-4(1H)-
one. Various Schiff bases are then treated with the above to give 3(phenylhydrazono)
(substitutedphenyl) ethyl]-2-sulfanyl-2,3,5,6,7,8-hexahydro[1] benzothieno [2,3-d]
pyrimidin-4-(1H)-ones. All the compounds have shown promising antibacterial and
antifungal activities.
Chapter 2 Review of Literature
45 | Design, Synthesis and Biological Evaluation of Novel Anti-Fungal Agents
Salahuddin et al., 41
carried out the synthesis of some novel benzothienopyrimidines
(35) by using Gewald reaction and further cyclization and chlorination of 2-amino-5-
benzyl-4,5,6,7-tetrahydrothieno-pyridine-3-carboxamide. All the synthesized compo -
unds were tested against bacterial strains (Gram +ve and Gram–ve).
Ahmeda et al., 42
synthesized a series of fused pyrimidopyrazolo theinopyrimidine
derivatives using 2-(1-methyl-1H-indol-ylmethyl)-4-methyl-5-ethoxycarbonyl-6-
mercapto pyrimidine (36) as a starting material. The pharmacological screening
showed that many of these compounds have good anti-inflammatory and analgesic
activities comparable to Prednisolone and valdecoxib as reference drugs.
Salahuddin et al., 43
carried out the synthesis of novel thieno[2,3-d]pyrimidines (37)
by using Gewald reaction and further bromination of intermediate 1-[4-(6,7-dihydro-
5Hcyclopenta[4,5]thieno[2,3-d]pyrimidin-4-yl-amino)phenyl]ethanone. Which upon
reaction with different substituted benzothiazoles give a novel series of thieno -
pyrimidines. All the synthesized compounds were tested against Gram +ve and Gram
-ve bacterial strains.
Chapter 2 Review of Literature
46 | Design, Synthesis and Biological Evaluation of Novel Anti-Fungal Agents
Nitinkumar et al., 44
reported the synthesis of novel tricyclic thienopyrimidines and
triazole (38) fused tetracyclic thienopyrimidines from 2-amino-6-methyl-4,5,6,7-tetra
-hydro-1-benzothiophene-3-carbonitrile and 2-amino-7-oxo-4,5,6,7-tetrahydro-1-ben -
zothio-phene-3-carbonitrile respectively. The corresponding precursors were prepared
by employing the Gewald reaction. The compounds displayed promising antibacterial
and antifungal activities.
Ahmed M.M. et al., 45
reported the synthesis of 3-amino-2-(4-bromo benzoyl)-4-
cyano-5-phenyl-aminothiophene (39) and 2-acetyl-3-amino-4-cyano-5-phenylamino-
thiophene with a variety of active methylene compounds, such as ethyl cyanoacetate,
ethylacetoacetate, ethylbenzoylacetate and diethylmalonate, yielded the corresponding
thieno[3,2-b]pyridine-2-one derivatives. Also the reaction with formamide and formic
acid, afforded the corresponding thieno[3,2-d]pyrimidine derivatives. While the
reaction of compound with phenyl-isothiocyanate, yielded thieno[3,2-b]pyrimidin-2-
thione derivative.
Robert D Hubbard et al., 46
synthesized a novel class of substituted pyrrolidinyl
acetylenic thieno[3,2-d]pyrimidines (40) that are potent and selective inhibitors of
both EGFR/ErbB-2 receptor tyrosine kinases. Selected molecules, including
compound, were found to be potent in enzymatic and cellular assays while also
demonstrating exposure in the mouse from an oral dose
Chapter 2 Review of Literature
47 | Design, Synthesis and Biological Evaluation of Novel Anti-Fungal Agents
Manisha S. Phoujdar et al., 47
reported a series of novel 2-unsubstituted 4-(sub -
stituted)anilinothieno[2,3-d]pyrimidines, which are synthesized through the
chlorination of the corresponding 2-unsubstituted-thieno[2,3-d]pyrimidin-4-ones ( 41)
followed by the nucleophilic displacement of the 4-Cl group, with a variety of
Anilines. All four steps of this synthesis involved microwave irradiation (MWI).
Ming-Guo Liu et al., 48
the mono (iminophosphorane) was selectively prepared from
the reaction of 3,4-diaminothieno[2,3-b]thiophene (42) with excess triphenyl
phosphine, and Et3N due to intramolecular double hydrogen bond formation.
mono(iminophosphorane) reacted with aromatic isocyanates to give stable
carbodiimides, which were further treated with aliphatic secondary or primary amines
to give 2-amino substituted thieno[3,2:4,5]thieno[3,2-d]pyrimidin-4(3H)-ones in the
presence of a catalytic amounts of EtO-Naþ. The reaction of carbodiimides with
phenols in the presence of a catalytic amounts of potassium carbonate gave a mixture
of 2-aryloxy substituted thieno[30,20:4,5]thieno[3,2-d]pyrimidin-4(3H)-ones.
Chapter 2 Review of Literature
48 | Design, Synthesis and Biological Evaluation of Novel Anti-Fungal Agents
Roger J. Gillespie et al., 49
reported that the (-)-(11R, 2S)-enantiomer of the
antimalarial drug mefloquine has been found to be a reasonably potent and
moderately selective adenosine A2A receptor antagonist. Further investigation of this
compound has led to the discovery of a series of keto-aryl thieno [3,2-d]pyrimidine
(43) derivatives, which are potent and selective antagonists of the adenosine A2A
receptor. These derivatives show selectivity against the A1 receptor.
Agathe Begouin et al.,50
has employed DDQ as a dehydrogenation reagent synthesize
polyaromatic compounds benzothieno pyrido pyrimidinones and benzothieno
pyrimido isoquinolinone (44) by microwave-assisted process which allows shorter
reaction times and easier purification as fewer degradation products were formed.
Sachin et al., 51
reported the synthesis of novel 1,2,9,11-tetrasubstituted-7Hthieno
[2,3:4,5]pyrimido[6,1-b]quinazolin-7-ones starting from 5,6-disubstituted-3Hthieno
[2,3-d]pyrimidin-4-ones (45) which could be reached in two steps through a von
Niementowski reaction, which involves condensation of substituted anthranilic acids
with a 4-chloro-5,6-disubstituted-3H-thieno[2,3-d]pyrimidines.
Chapter 2 Review of Literature
49 | Design, Synthesis and Biological Evaluation of Novel Anti-Fungal Agents
Alagarsamya et al.,52
designed and synthesized some of 2-methylthio-3-substituted-
5,6-dimethylthieno[2,3-d]Pyrimidin-4(3H)-ones (46). The synthesized compounds
were investigated for analgesic, anti-inflammatory and antibacterial activities.
Veerachamy et al., 53
synthesised a new series of 2-mercapto-3-substituted-5,6-di -
methylthieno[2,3-d]pyrimidin-4(3H)-ones by reacting 3-amino-2-mercapto-5,6-dimet
-hylthieno[2,3-d]pyrimidin-4(3H)-one with different aldehydes and ketones. The
starting material 3-amino-2-mercapto-5,6-dimethylthieno[2,3-d]pyrimidin-4(3H)-one
(47) was synthesised from 2-amino-3-carbethoxy-4,5-dimethyl thiophene by a novel
innovative route. The title compounds were investigated for analgesic, anti-
inflammatory and ulcerogenic index activities.
Ashalatha et al., 54
synthesized nine new 2-(substituted phenyl) /alky [1,3,4]
thiadiazolo[2,3-b]6,7,8,9-tetrahydrobenzo(b)thieno[3,2-e]pyrimidin-5(4H)-ones(48).
Six new 3-amino-2-[(2-oxo-2-(aryl)ethyl)thio]-5,6,7,8-tetrahydro [1] benzothieno[2,3-
d]pyrimidin-4(3H)-ones, one 2-mercapto[1,3,4]thiadiazolo[2,3-b]-6,7,8,9-tetrahydro -
benzo(b) thieno[3,2-e]pyrimidin-5(4H)-one and one 2-chloromethyl [1,3,4] thiadi -
azolo[2,3-b]-6,7,8,9-tetrahydrobenzo(b)thieno[3,2-e]pyrimidin-5(4H)-one.
Compounds were screened for anti-inflammatory and antimicrobial activities.
Chapter 2 Review of Literature
50 | Design, Synthesis and Biological Evaluation of Novel Anti-Fungal Agents
Davoodnia A. et al., 55 has carried out a one-pot synthesis of new 3-arylthieno[2,3-d]
pyrimidine-2,4(1H,3H)-diones (49)viabase-catalyzed cyclocondensation of ethyl 2-
amino-4,5-dimethylthiophene-3-carboxylate with aryl isocyanates is described.
Abdel-Rahman et al.,56
has reacted 5-Methyl-6-phenyl-2-thioxo thieno[2,3-d]
pyrimidone derivative with hydrazonoyl chloride derivatives to afford triazolo
thienopyrimidines(50). Also, acetone-1-(2-amino-5-isopropyl-thiophene-3-carbonitr-
ile) which was reacted with functional and bifunctional groups to yield the correspond
-ing compounds. The new products showed anti-inflammatory, analgesic and
ulcerogenic activities comparable to that of Indomethacin and acetylsalicylic acid.
Gerardo Blanco et al.,57
described a simple one-pot and efficient method for the
synthesis of pyrazino[2,3,4,5]thieno[3,2-d]pyrimidinone (51) derivatives via a tandem
aza-Wittig/heterocumulene-mediated annulation process. The effects of the nucleo phi
-les and isocyanates on the regioselectivity of the cyclization have been investigated.
Chapter 2 Review of Literature
51 | Design, Synthesis and Biological Evaluation of Novel Anti-Fungal Agents
Alagarsamy et al.,58
reported a variety of novel 2-methylthio-3-substituted-5,6,7,8-
tetrahydrobenzo(b)thieno[2,3-d]pyrimidin-4(3H)-ones (52) which have been synthesiz
-ed by reacting (2-methylthio-4-oxo-3H-5,6,7,8-etrahydrobenzo(b)thieno[2,3-d] pyri -
midin-3-yl)dithiocarbamic acid methyl ester with a variety of amines. The starting
material dithiocarbamate was synthesized from 2-amino-3-carbethoxy-4,5,6,7 tetrahy
-drobenzo(b)thiophene by a novel innovative route. The title compounds were
investigated for analgesic, anti-inflammatory, ulcerogenicity index and antibacterial
activities.
Riyadh et al.,59 reported two convenient methods for synthesis of novel pyrido
[3,2:4,5] thieno[3,2-d][1,2,4] triazolo[5,4-a] pyrimidin-5-ones were developed. The
first route involved the reaction between 2,3-dihydro-7,9-dimethyl-2-thioxopyrido
[3,2:4,5]thieno[3,2-d] pyrimidin-4(1H)-one ( 53) or its 2-methylthio derivative with
hydrazonoyl halides in dioxane under reflux in presence of triethylamine. The
alternative route proceeded via reaction of the appropriate active chloromethylene
compounds followed by coupling the products with benzene diazonium chloride
which afforded the azo coupling products and then was converted in situ to.
Abdullah G. M. et al.,
60 reported the reaction of naproxanoyl chloride with some
nucleophilic reagents as ammonium thiocyanate and sodium azide to produce the
novel isothiocyanate derivatives. Interaction of isothiocyanate with 1,2-
phenylenediamine and anthranilic acid has produced the corresponding benzimidazole
derivatives and 3,1-benzoxazine derivatives respectively. In a similar manner ethyl 4,
5- disubstituted-aminothiophene-3-carboxylate were reacted with naproxenoyl
chloride in benzene to furnish corresponding amide derivatives which on treatment
Chapter 2 Review of Literature
52 | Design, Synthesis and Biological Evaluation of Novel Anti-Fungal Agents
with hydrazine hydrate yielded 3-amino[2,3-d]pyrimidines (54).
Narayana B. et al.,61
has converted ethyl-2-amino-4,5,6,7-tetrahydro-benzothio-
phene-3-carboxylate into 2-(acetyl amino)-5,6,7-tetrahydro-1-benzo thiophene-3-
carboxylate and ethyl 2-(propionyl amino)-4,5,6,7-tetrahydro-1-benzothiophene-3-
carboxylate. The above compounds on treatment with hydrazine hydrate give 3-
amino-2-methyl-5,6,7,8-tetrahydrobenzothieno[2,3-d]pyrimidine-4-(3H)-one and 3-
amino-2-ethyl-5,6, 7,8-tetrahydro (55) benzothieno[2,3-d]pyrimidine-4-(3H)-one
respectively. The comp -ounds screened for antibacterial and antifungal activity.
Mosharef Hossain Bhuiyan MD et al.,
62 reported the reaction of o-aminonitrile with
ethyl N-bis
thieno[3,2-e]imidazole[1,2-c]pyrimidine moiety in a one process.[1,2,4]triazolo[4,3-c]
thieno-[3,2-e]pyrimidine derivatives were prepared by initial treatment of o-amino -
nitrile with carbon disulfide, followed by methylation with methyl iodide and
subsequent reaction with benzhydrazide and thiosemicarbazide, respectively.
Hydrazino thieno(2,3-d)pyrimidine was prepared by cyclization of heteroaromatic
oaminoester with formamide, followed by chlorination and subsequent displacement
with hydrazine. Treatment of the hydrazino derivative with acetylacetone,
benzaldehyde and acetic anhydride afforded pyrazolylpyrimidine, benzylidene
hydrazonopyrimidine and triazolopyrimidine derivatives (56). Some of these
derivatives exhibited pronounced antimicrobial activity.
Chapter 2 Review of Literature
53 | Design, Synthesis and Biological Evaluation of Novel Anti-Fungal Agents
Fatma EM El-Baih et al.,63
prepared thioxo thienopyrimidinones, alkyl thio and aryl
alkyl thio thieno pyrimidinones, thienopyrimidinones, thienopyrimidines a thieno
pyrimidinedione and a thieno triazolo pyrimidinone (57) from 2-amino-3-carboethoxy
-4,5-disubstituted thiophenes and 2-amino-3-cyano-4,5-disubstituted thiophenes via
reactions with different reagents.
Alagarsamy et al.,64
synthesized a variety of novel 2-mercapto-3-(substituted amino)-
5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-ones(58) by reacting 3-
Amino-2-mercapto-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyramidine-4-one
with different aldehydes and ketones; the starting material 3-amino-2-mercapto-5,6,7,
8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one was synthesized from 2-
amino-3-carbethoxy-4,5,6,7-tetrahydrobenzo thiophene by a novel innovative route.
The title compounds were investigated for analgesic, anti-inflammatory and
ulcerogenic index activities.
Ming Wu Ding et al.,
65 synthesized 2-Alkylamino-5,6,7,8-tetrahydro benzo
thieno[2,3-d] pyrimidin-4(3H)-ones (59) by a new selective synthetic method, which
includes aza-wittig reaction of iminophosphorane with aromatic isocynate to give
Chapter 2 Review of Literature
54 | Design, Synthesis and Biological Evaluation of Novel Anti-Fungal Agents
carbodi-imide and subsequent reaction with various aliphatic primary amine in the
presence of EtO-Na+.
Sheng Zhen XU et al.,66
reported the 2,7-diaminothieno[2,3-d:5,4-d]dipyrimidine-
4,5(3H,6H) diones (60) synthesis by a facile synthetic method, which includes bisaza-
Wittig reaction of bis-iminophosphorane with aromatic isocyanate to give bis-
carbodiimide and subsequent reaction with various dialkylamine in the presence
ofsolid K2CO3 or EtONa.
Abu Zieda Hassanien et al.,67
reported the reaction of 2-acetylbenzoimidazole with
some arylaldehydes under different conditions gave chalcones, 1,5-pentanediones and
pyridines. Treatment of chalcones with various types of reagents gave the
corresponding new pyridines, thienopyridines (61) pyrido [2,3:4',5], thieno[3',2'-d]-
pyrimidin-8-ones via initial addition of active methylene or amino group to the double
bond followed by cyclization.
Chapter 2 Review of Literature
55 | Design, Synthesis and Biological Evaluation of Novel Anti-Fungal Agents
Michael et al., 68
synthesized new classes of thienopyrimidines and thienopyridines
(62) as potent inhibitors of VEGFR-2 kinase.
David Vazquez Vilarelle et al.,
69 reported one-pot synthesis of the hitherto unrepor
tedpyrido[5,6:4,5;3,2:4,5]dithieno[3,2-d:3,2-d]dipyrimidine-4,8(3H,9H)-dione (63)
and pyrazino[5,6:4,5;3,2:4,5]dithieno[3,2-d:3,2-d]dipyrimidine-4,8 (3H, 9H)-dione
pentaheterocyclic systems, based on the tandem aza-Wittig hetero cumulenemediated
annulations strategy is described.
Mohamed Amal Abdel Haleem Eissa et al.,
70 reported the reaction of 2-substituted or
unsubstituted-4-(4-acetylanilino)-5,6,7,8-terahydrobenzo[b]thieno [2,3-d] pyrimidines
(64) derivatives with the hydrazine derivatives, and thiosemicarbazides, provided the
corresponding hydrazones and thiosemicarbazones. Representative compounds were
tested for their antimicrobial activity against Candida Albicans and certain gram-
positive and gram-negative bacteria.
Chapter 2 Review of Literature
56 | Design, Synthesis and Biological Evaluation of Novel Anti-Fungal Agents
Melissa L.P. et al.,71 designed and synthesized N-(2,4-dioxo-1,2,3,4-tetrahydro-
thieno[3,2-d]pyrimidin-7-yl)-guanidines (65) as a novel class of thymidine phosphory
-lase (TP)inhibitors.
Kidwai et al.,
72 synthesized novel 5-methyl-6-ethylcarboxylate-2-thioxo-thieno[3,2-d]
pyrimidine-4(1H)-ones (66) from 2-amino-3,5-diethyl carboxylate-4-methyl
thiophene and mono substituted thioureas using microwave technology under the
solid support of K2CO3.
Ammar Y. A. et al.,
73 Carried out the reactivity of quinoxaline-2,3-dicarboxylic
anhydride towards some heterocyclic amines as nitrogen nucleophiles. Thieno[2,3-d]
pyrimidine (67) is obtained by refluxing the compound with hydrazine hydrate.
Condensation of compound with aromatic aldehydes furnishes the corresponding
Schiff bases. Finally, refluxing of compound with acetic anhydride yields the
acetamido derivative
Annamaria Panico et al.,
74 reported the effects of a series of thienopyrimidine
derivatives on the prevention of cartilage destruction in articular disease. Some
thienopyrimidine derivatives (68) in the presence of IL-1, blocked the cartilage
Chapter 2 Review of Literature
57 | Design, Synthesis and Biological Evaluation of Novel Anti-Fungal Agents
breakdown by inhibiting both the NO production and GAGs release in a
dosedependent manner.
Magda A. Abdallah et al.,75 synthesized 1,4,7,8,9,10-Hexahydro-6H[1]benzothieno
[2,3;4,5]pyrimido[1,2-b][1,2,4,5]tetrazin-6-ones (69) via reaction of 2,3,5,6,7,8-
hexahydro-3-amino-2-thioxo[1]benzothieno[2,3-d]-pyrimidin-4(1H)-one or its 2-
methylthio derivative with hydrazonoyl halides in ethanol in the presence of
triethylamine. Some of the products were screened for their biological activity.
Ogawva K. et al.,
76 synthesized a series of 2,4-dioxo-thieno[2,3-6], [3,2-d] and [3,4-d]
pyrimidin-l-acetic acids (70) with a benzyl moiety at the N-3 position and tested in
vitro for aldose reductase inhibitory activity against partially purified enzyme from rat
lens. Some of these compounds were also evaluated for inhibition of sorbitol
accumulation in the sciatic nerve or lens of streptozotocin-induced diabetic rats in
vivo. Among the synthesized compounds, several showed potent aldose reductase
inhibitory activity.
The thieno[2,3-d]pyrimidine and fused heterocycles containing this ring system might
be expected to show close resemblance in properties to the quinazoline structure
because of the similarity between benzene and thiophene.
Chapter 2 Review of Literature
58 | Design, Synthesis and Biological Evaluation of Novel Anti-Fungal Agents
In view of the close association of pyrimidines with important biodynamic agents,
numerous compounds containing such a ring system have been extensively
investigated. Most of the work reported in the literature often involves fusion of
pyrimidine nucleus with thiophene heterocyclic system.
2.2.1. Synthesis of thienopyrimidines
Synthetic approaches to the construction of thienopyrimidines are sufficiently well
developed. Three possible types of annelation of thiophene to the pyrimidine ring and,
correspondingly, three isomeric thienopyrimidines are known:
(a) thieno [2,3d] pyrimidine
(b) thieno[3,2d]pyrimidine and
(c) thieno[3,4d]pyrimidine
The structures and the conventional numbering of these heterocyclic systems are
shown below.
The known approaches to the synthesis of thienopyrimidines can be divided into two
main groups:
a. The construction of the pyrimidine ring by intramolecular cyclization of
thiophene derivatives and
b. The thiophene ring closure in pyrimidine derivatives
2.2.1.1. Synthesis of thienopyrimidines by pyrimidine ring closure
Appropriately substituted aminothiophenes, which are accessible by various methods,
serve as the main starting compounds for the preparation of thienopyrimidines with
the use of this approach. 77-80
Syntheses involving the pyrimidine ring closure starting
from both 2 and 3 aminothiophenes proceed under similar conditions and in virtually
the same reaction sequences, due to which all three types of thienopyrimidi -nes
become accessible.
Hence, it is reasonable to classify the reactions leading to these compounds according
to the type of substitution in the pyrimidine rings formed.
One of the most popular approaches to the synthesis of thienopyrimidinediones (75) is
based on the pyrimidine ring closure in thienylureas (74).
Chapter 2 Review of Literature
59 | Design, Synthesis and Biological Evaluation of Novel Anti-Fungal Agents
Hereinafter, A is the thiophene ring bearing substituents at positions 2 and 3 or 3 and
4; thienopyrimidine structure (75) is thiophene analogously annelated to the
pyrimidine ring; the ester group is most widely used as the COX group.
The starting thienylureas are synthesized according to the known procedures based on
reactions of aminothiophenes with isocyanates, 81-85
KOCN—HCl,46 ClSO2NCO,
and some other reagents. The substituent R in thienylureas can be replaced with other
hydrocarbon groups using reactions with amines.81
Pyrimidine ring closure from thienylureas occurs easily upon treatment with bases
(generally, with ethanolic or aqueous solutions of alkalis).81-88
An example of the use
of potassium tertbutoxide as a cyclizing agent was documented. Cyclization of ureas
with a —CONH2 group in an acidic medium was also described. 86
Thienopyrimidinediones containing the hydrogenated thiophene ring were
synthesized starting from the corresponding tetrahydrothienylureas. 82, 88-90
Thienopyrimidinediones (75) unsubstituted at the nitrogen atom (R = H) were
prepared starting from aminothiophenes (76), whose successive treatment with
chloroformates (or phosgene) and primary amines 91-95
afforded the target products
(77).
Although intermediate thienylureas were not isolated,their transient formation is quite
probable. 96, 97
Substituted thienopyrimidinedione (79) was prepared in 91% yield by
heating N-N-diethyl-N-methoxycarbonyl-N-´(3-methylamino-5-phenyl-2-thenoyl )
thiourea (78) in methanol. 98
Chapter 2 Review of Literature
60 | Design, Synthesis and Biological Evaluation of Novel Anti-Fungal Agents
Thienylthioureas (80) prepared by reactions of vicamino (ethoxycarbonyl) thiophenes
(74) with isothiocyanates 98-101,
or by reactions of thiophenes succesively with
thiophosgene and amines 100,101
undergo, like thienylureas , the pyrimidine ring
closure upon treatment with an ethanoholic solution of HCl 100
or ethanolic alkali
followed by acidification of the reaction mixture with hydrochloric acid. 98-103
Earlier,
104,105 it has been demonstrated that for R = Acyl, the latter reactions resulted in
hydrolysis to give unsubstituted thioxopyrimidinone (81)
The reactions of aminocarbonyl derivatives of thiophene (82) with potassium
thiocyanate afforded (4-oxo3, 4dihydrothieno[2,3d]pyrimidin-2-ylthio)acetic acid
derivatives (83) in yields up to 51%. Analogously, the isomeric aminocarbonyl
derivative (84) gave ethyl (7-cyano-6-methylthio-4-oxo-3,4-dihydrothieno [3,2d]
pyrimidin-2-ylthio)acetate (85) in 85% yield. 106, 111
Thioxothienopyrimidinones (86) were prepared 107,112
by recyclization of thiazines in
an acidic medium.
Chapter 2 Review of Literature
61 | Design, Synthesis and Biological Evaluation of Novel Anti-Fungal Agents
A procedure was developed 108-111
, for the synthesis of thienopyrimidinedithiones (89)
involving thermal recyclization of thiazines (88), which, in turn, are prepared by the
reactions of substituted 2-amino-3-cyanothiophenes (87) with carbon disulfide in the
presence of bases.
1-Aminothieno[2,3d]pyrimidine-3(4H)-thiones (92) were prepared by cyclization of
vic cyano(thioureido)thiophenes (90) followed by the Dimroth rearrangement of
intermediates (91) under the action of bases112-116,
or by heating of 2-amino-3-
cyanothiophenes with thiourea.117
Thienopyrimidinones (94) were prepared1 118-123,
by the reactions of thiophenes (93)
containing the ethoxycarbonyl and amide groups with amines. It was postulated that
these reactions proceed via intermediate diamides 94
The third general procedure for the synthesis of thienopyrimidines (98) is based on
recyclization of thienooxazinones (96), which are generated by the reactions of amino
-carboxylic acids (95) or esters with acylating agents (Ac2O, HC(OEt)3, or PhCOCl)
in the presence of bases,under the action of amines.86, 124-136
This recyclization
proceeds through the intermediate formation of diamides (97). The reactions with
secondary amines give these diamides as the only reaction products. 135, 137
Chapter 2 Review of Literature
62 | Design, Synthesis and Biological Evaluation of Novel Anti-Fungal Agents
Successive treatment of 2-amino-3-cyanothiophenes (99) with carbon disulfide in the
presence of sodium methoxide and then with methyl iodide gave rise to vic-bis
(methylthio) methyl deneamino(cyano)thiophenes (100), which were transformed into
alkylthiothienopyrimidineimines (101) under the action of amines.138
It was
emphasized that it is necessary to thoroughly control the reaction conditions to
prevent the possible Dimroth rearrangement.
2.2.1.2. Synthesis of thienopyrimidines by thiophene ring closure
As earlier, procedures for the synthesis of thienopyrimidines by the thiophene ring
closure starting from the available pyrimidine system are used much more rarely than
the pyrimidine ring closure. This is attributable to the fact that the starting
appropriately substituted pyrimidines are less readily accessible. In this section, the
data are systematized according to the types of reactions giving rise to the thiophene
ring formation. Generally, the synthesis of thienopyrimidines using the Claisen,
Thorpe—Ziegler and Friedläender condensations can be represented by the following
scheme:
Another procedure for the synthesis of pyrimidines (103) involves alkylation of 5-
ethoxy carbonylpyrimidine-4(3H)thiones (102) with chloroacetic acid derivatives. In
Chapter 2 Review of Literature
63 | Design, Synthesis and Biological Evaluation of Novel Anti-Fungal Agents
this case, thienopyrimidines (104) were prepared without isolation of intermediate
pyrimidines. 139-142
Alternative approaches to the synthesis of thienopyrimidines by the thiophene ring
closure are also documented. For example, the thioClaisen rearrangement of proparg -
yl sulfide (104) (X = S) affords thienopyrimidinediones (105); the rearrange -ment of
sulfoxide 143
, (X = SO) gives rise to the corresponding formyl derivative 144
(R2 =
CHO).
Another approach to the construction of the thiophene ring based on functionalized
pyrimidines involves thiolation of the methyl group in vic-methylpyrimidine -
carbonitriles (106) with elemental sulfur followed by cyclization of intermediate
thiols (107) to give thienopyrimidines (108). The reactions were carried out with
pyrimidinethiones 145
and pyrimidinediones. 146
Chapter 2 Review of Literature
64 | Design, Synthesis and Biological Evaluation of Novel Anti-Fungal Agents
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