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CHAPTER 3
Synthetic Routes of Thiazole and Thiophene Derivatives and Their Therapeutic
Importance
Introduction:
The ideal goal of drug-discovery is to create a chemical substance that acts
specifically and optimally at appropriate specific targets to perturb in ill vivo biochemistry,
in order to eliminate the biochemical challenges that have taken place due to diseased
condition. [I) From the medicinal chemistry point of view the gamut of options available to
design the chemical substance are a) Macromolecular structure based drug discovery and b)
chemical leads used as models or templates by the designed chemical synthesis approach.
In both these approaches, the crux of the factors involved; i) The binding's epitope
(the pharmacophore) in the candidate and ii) an ideal molecular scaffolding tethered to it
which helps in conferring optimal physiochemical properties to the designed drug candidate.
Literature is replete with instances where five member heterocyclic rings have turned
out to be optimal molecular scaffolding thiazole and thiophene moieties, due to 7f excessive
and 7f deficient features in the former and 7f excessive features in the latter have been widely
incorporated in drug like candidates as useful templates. An amino feature attached to both
there scaffolding have been adopted extensively in the design of new chemical entities.[2)
It is of interest to note that thiophene is a bioisoster of benzene. Thiazole can be
considered as bioisosteres of oxazole, imidazole, and pyridine.
In literature there are reports giving various synthetic routes and therapeutic
importance of thiazole and thiophene derivatives. Here we discuss in brief about the
synthetic routes and their therapeutic importance.
3.1 Synthetic Routes of Thiazole Derivatives
Literature survey of synthesis of 5-substituted thiazole derivatives has revealed the
synthetic methods with wide possibility of molecular diversity.
The first thiazole derivative 2,4-dihydroxythiazole was prepared in 1895. However,
the history of thiazole series begins in 1879 with the work of Hoffmann, who synthesized
a number of benzothiazole derivatives. [3) Compounds containing simple thiazole nucleus
were first reported by Hantzsch et al.[4) in a series of papers beginning in 1887. After this 59
Chapter 3 Synthetic Routes of Thiazole and Thiophene
pioneering work, knowledge of the thiazole nng system developed steadily and many
different routes of its synthesis were disclosed.
Reaction of chloroacetaldehyde with thioformamide yields thiazole while
thioformamide and bromoethylamine condenses to give 2-thiazoline.[S]
H~S + HyO
CI
() S
H~S + f NH
2
Be
--. (J S
l,4-dicarbonyl compounds containing nitrogen atom between two carbonyl groups
make a synthon for thiazole formation according to Gabriel synthesis of 1910. He showed
the cyclization of a-acylaminoacetophenone in the presence of P2S5 at 170°C. He made the
acylaminoacetophenone from acyl chloride and aminoacetophenone in quantitative yield.[6]
Tosylmethyl isocyanide (TOSMIC) has also been used for the synthesis of thiazoles.
It reacts with carbon disulfide to form tetrabutylammonium salt of 2-mercapto-1,3-thiazole
which on reaction with alkyl halide produces 4-tosyl-S-alkylthio thiazoles as shown in the
following scheme.[7]
60
Chapter 3
TOS~NC +
TOSMIC
Synthetic Routes of Thiazole and Thiophene
2-aminothiazoles can be synthesized cleanly and in high yields from a a
bromoketone and a thiourea vIa the Hantzsch thiazole synthesis.[8] A modification of
Hantzsch synthesis was reported by Moriarty et al. in 1992. They avoided the lise of general
a-halocarbonyl compounds, instead, they made the tosyloxylated ketone by a reaction of
ketone with (Hydroxy[tosyloxy]iodo) benzene which reacted with thioamide to produce
thiazole derivative. They also utilized the same method for 1,3-dicarbonyl compounds to
synthesize 5-acyl thiazoles.[9]
+
f lyLh IX y[(lsyiox yil I<.I! )~n,-,.:nl!
5-substituted ketone derivatives were synthesized by the reaction of thioacetamide
with 3-bromo-2,4-pentanedione.[10] Formamide reacts with POCI3 in chloroform and then
treated with thioamide to produce N-thiocarbamyl formamidines which reacts with a
halocarbonyl compounds to yield 5-acyl thiazole derivatives.[II] I-aminothioenolether
reacts with thionyl chloride and intramolecularly cyclizes to 5-acyl thiazole derivatives[12].
PYRIDINE
61
'-- - ------
Chapter 3 Synthetic Routes of Thiazole and Thiophene
In 1986, Rajasekharan et al. reported the synthesis of 2,4-diamino-5-thiazolyl
carbonyl compounds using l-amidino-3-arylthioureas and reacting it with a-halocarbonyl
compounds such as phenacyl bromide.[ 13] The use of thiourea as the sulfur component with
2-chloroacetamides as the second unit gives rise to 2,4-diaminothiazoles.[14]
Be Ethanol
Acetone. r.1.
-NH z
o o Intermediate
5-thiazolyl carboxylate derivatives were obtained from the reaction of secondary a
halocarbonyl compounds with thioacetamides.[15] In another method, isothiourea derivative
was reacted with methyl thioglycolate to yield 5-thiazolyl carboxylate derivatives.[16]
Recently, Dridi, K. et al. reported that N-thiocarbamoylimidates reacted with methyl
thioglycolate in sodium methoxide solution in methanol to afford 4-amino-5-thiazolyl
carboxylate derivative. It was hypothesized that the reaction consists of two steps :
formation of the N-thiocarbamoylthioimidate intermediate which cyclized after liberation of
hydrogen sulfide as a neutral molecule. [17]
N-thiocarbamoylthioimidatc imenTIediate
HS~O'---CH' o
Methyl thioglycolate
MeGNa
62
Chapter 3 Synthetic Routes of Thiazole and Thiophene
Monosubstituted thiourea derivatives were reacted with a-halocarbonyl compounds
to yield 4-thiazolines.[18-20] 4-Thiazoline-2-thione was prepared from phenacylmercaptan
derivatives in the presence of sulphuric acid.[21]
<O~'"' o
•
Starting from 1970, from the first report of the novel synthesis of thiazole
ring, a series of paper were published by Rajappa, S. et al.[22] In the first paper, they
reacted isothiocyanate with acetamidine yielding an adduct which was further
reacted with phenacyl bromide t·J afford 5-acyl thiazole.[23] The first step in the
cyclization is the S-alkylation followed by attack of active methylene group on
amidine carbon eliminating an amino group. In the next paper, they reacted the
similar adduct with bromonitromethane to yield thiazole substituted by nitro group at
5th position of the thiazole ring.[24] In the third publication they evaluated the role of
arylamino as a leaving group.[25] In the fourth paper, tetramethylguanidine was used
instead of acetamidine.[26] They found that with this also the reaction proceeded
well. In all the above reactions, phenacyl bromide or chloroacetone or
bromonitromethane was used as a-halocarbonyllnitro compound. They also reacted
heterocyclic derivatives instead of a-halocarbonyl compounds such as 2-
chloromethyl pyridine, 2-chloromethyl quinoline etc.[27] They also studied the
reaction of monosubstituted thiourea derivatives with a-halocarbonyl compound to
give thiazolines.
63
Chapter 3 Synthetic Routes of Thiazole and Thiophene
+
Isoth ioe ya fla te Acetm idille
Adduct o
Phenacyl Bromide o
S-alkylated intermediate
CH,
o
From all these reported synthesis of different 5-substituted thiazole derivatives, the
most efficient method which can give rise to a wide variety of substituents at 2od, 4th and 5th
position of the thiazole ring and can provide the necessary structural features needed for the
target molecules is of Rajappa, S. et al.[24] This method was adopted for synthesis of target
molecules which is mentioned in above figure.
3.2 Synthetic Routes of Thiophene Derivatives
There are several methods available for the synthesis of the thiophenes. One of the
oldest methods reported for the synthesis of thiophenes was by Gewald.
Gewald reaction:
Ketones and aldehydes [28] with free methylene group at a position condense with
nitrile [29] and elemental sulfur in presence of a secondary amine (diethyl amine, piperidine,
morpho line) to yield 2- amino-3- substituted thiophene (II). The condensation of carbonyl
compounds, S and malononitrile derivatives in presence of secondary amine catalyst, which
involves the formation of alkylidene nitrile, thiolation and finally intramolecular cyclisation
to substituted thiophene system proceeds smoothly and uniformly around 45°C. This one pot
modified Wilgerodt-Kindler (13) type reaction has become known as Gewald reaction[30].
64
Chapter 3 Synthetic Routes of Thiazole and Thiophene
"10
R X
1-\ .. f ~ eN
R, NH2 R, ( (0) S (ll )
Willgerodt- Kindler reaction:
I-Phenyl butanones when reacted with 2 molecules of morpholine and 2 gram atom
of sulfur at 130°C yield an intermediate thiomorpholide, which when subjected to similar
treatment [31] affords thiophene.
The synthesis of thiophenes has been reviewed excessively [32, 33]. The synthesis of
2,5 disubstituted thiophenes has been described by Smutny, where he utilized amino dithio
acrylates and (X- halo carbonyl compounds as synthetic equivalents in the presence of a base.
A polar aprotic solvent like acetone was utilized [34].
S SCH3
O/\N~SCH3 I II alpha halllketone H3C~ LI H S •
H H
Amino dithio acrylates o 2,5 disubstituted thiophene
Tetra substituted thiophenes were synthesized by Gompper using dithiolates and
alpha halogen derivatives in the presence of a base [35].
C6HsOC CN , X ~·"'''w .~" H3COOCH2CS SCH2COOCH3
Alkylated dithiolates Tetra substituted thiophene
Rajappa described a two-step synthetic process for the synthesis of tetra-substituted
thiophenes [36].
65
Chapter 3 Synthetic Routes of Thiazole and Thiophene
~I-h ~ + R-NC~"" --H3~a'C~ A. H3hCON::
~~a'C~ "H~NHR Ar-CO-CJiBr Yl--AMINO ESTER STEP 2 • °
ADDUCT TETRA SUBSTITlITIill TIlIOPHENE
3.3 Bio-isosteres: Concept for Drug Design
Bioisosterism is a strategy of used for the rational design of new drugs, based on
chemical lead [37]. The chemical lead should possess well-known mechanism of action, if
possible at the level of topographic interaction with the receptor, including knowledge of all
of its pharmacophoric groups. Furthermore, the pathways of metabolic inactivation [38], as
well as the main determining structural factors of the physicochemical properties which
regulate the bioavailability, and its side effects, whether directly or not, should be known so
as to allow for a broad prediction of the definition of the bioisosteric relation to be used.
The success of this strategy in developing new substances, which are therapeutically
attractive, has achieved significant growth in distinct therapeutic classes, being amply used
by the pharmaceutical industry to discover new analogs of therapeutic innovations
commercially attractive, and also as a tool useful in the molecular modification.
There may be numerous reasons for the use of bioisosterism to design new drugs,
including the necessity to improve pharmacological activity, gain selectivity for a
determined receptor or enzymatic isoform SUbtype with simultaneous reduction of certain
adverse effects, or even optimize the pharmacokinetics the LC might present. In this part of
the chapter, we will discuss bioisosterism as a strategy of molecular modification, showing
its importance in building a new series of congeners compounds designed as candidate of
new drugs, giving examples of successful cases in distinct therapeutic classes.
3.3.1 Background
The bioisosteric rationale for the modification of lead compounds is traced back to
the observation by Langmuir in 1919 regarding the similarities of various physicochemical
properties of atoms, groups, radicals, and molecules. Langmuir compared the physical
properties of various molecules such as N2 and CO, N02 and CO2, and N3 - and NCO- and
found them to be similar. On the basis of these similarities he identified 21 groups of
66
Chapter 3 Synthetic Routes of Thiazole and Thiophene
isosleres. Some of these groups are listed in Table I. He further deduced from the octet
theory that the number and arrangement of electrons in these molecules are the same. Thus,
isosteres were initially defined as those compounds or groups of atoms that have the same
number and arrangement of electrons. He further defined other relationships in a similar
manner. Argon was viewed as an isostere of K+ ion and methane as an isostere of NH4 +
ion. He deduced, therefore, that K+ ions and NH4 + ions must be similar because argon and
methane are very similar in physical properties. The biological similarity of molecules such
as C02 and N20 was later coincidentally acknowledged as both compounds were capable of
acting as reversible anesthetics to the slime mold Physarum polycephalum. [39]
Table 1. Groups of Isosteres as Identified by Langmuir
groups isosteres
1 H-, He, Li+ 2 0 2-, F-, Ne, Na+, Mg2+, A13+ 3 SZ-, Cl-, Ar, K+, Ca2+ 4 Cu2- Zn2+ , I I
8 N 2 , CO, CN-g CH4, NH4+
10 CO2 , NzO, N3-, CNO-I I
20 Mn04-, Cr042-21 Se04z-, AS043-
A further extension to this concept of isosteres came about in 1925 with Grimm's
Hydride Displacement Law. This law states: "Atoms anywhere up to four places in the
periodic system before an inert gas change their properties by uniting with one to four
hydrogen atoms, in such a manner that the resulting combinations behave like pseudoatoms,
which are similar to elements in the groups one to four places respectively, to their right."
Each vertical column as illustrated in Table 2, according to Grimm, would represent a group
of isosteres. [40]
67
Chapter 3 Synthetic Routes of Thiazole and Thiophene
Table 2. Grimm's Hydride Displacement Law
C N 0 F Ne Na CH NH OH FH -
CH2 NHz OHz FHz+ CH3 NH3 OH3+
CH4 NH4+
Erlenmeyer further broadened Grimm's classification and redefined isosteres as
atoms, ions, and molecules in which the peripheral layers of electrons can be considered
identical (Table 3), [41]
Table 3. Isosteres Eased on the Number of Peripheral Electrons
no. of peripheral electrons
4 5 6 7 N+ P S CI P+ As Se Br S+ Sb Te I As+ PH SH Sb+ PHz
8
CIH B,-H IH SHz PH3
Over the years, innumerous bioisosteric relations have been identified in compounds
both natural and synthetic. In nature, people have identified many examples of isosterism as
a form of broadening chemodiversity (Scheme 1), striking among which are the classic
bioisosteric relation existing between the essential amino acids serine (I) and cysteine (2),
tyrosine (3) and histidine (4) among the pyrimidine and purine bases cytosine (5) and uracil
(6), adenine (7) and guanine (8); among the xanthines caffeine (9) and theophyline (10); and
among the salicylic (II) and anthranilic (12) acids, which originated two important classes
of non-steroid anti-inflammatory drugs, e.g. acetylsalicylic acid and mefenamic acids,
respectively. Furthermore, examples of the application of non-classic bioisosterism are also
found in nature - such as the bioisosteric relationship existing between y-aminobutyric acid
(GABA) (13) and muscimol (14), between the neurotransmittors glutamate (15) and AMPA
( 16).
68
Chapter 3 Synthetic Routes of Thiazole and Thiophene
0 0 0
~m ~0I1 OH ~OH Nlll \;:0 N :-.H,
~H2 :"11, HO
2 J 4
~ ~ 0 :-.H,
~ N" II,) x,.. N H. N N N I oJ.-. N oJ.-. N oJ.-. N ~ ~ N I '.,
N N H~h~ ~ I I . H H H H H
5 6 7 R
1jp 0 0
H3C, ~ ~' «;,j' N ' J.- I I. o :-.; N OH ,
GI, 9
CHj 10 II 12
I\fl NH ~2
m
8 0 0
I h- Nfl, " HO N flO Ofl ,
HO 0 :-':H2 fi,e
13 14 15 16
Scheme 1
3.3.2 CLASSIFICATION OF BIOISOSTERISM: CLASSIC AND NON-CLASSIC
Bioisosteres have been classified as either classical or nonclassicaL Grimm's
Hydride Displacement Law and Erlenmeyer's definition of isosteres outline a series of
replacements which have been referred to as classical bioisosteres. Classical bioisosteres
have been traditionally divided into several distinct categories: (A) monovalent atoms or
groups; (B) divalent atoms or groups; (C) trivalent atoms or groups; (D) tetrasubstituted
atoms; and (E) ring equivalents. (see table I)
Nonclassical isosteres do not obey the steric and electronic definition of classical
isosteres. A second notable characteristic of nonclassical bioisosteres is that they do not
have the same number of atoms as the substituent or moiety for which they are used as a
replacement. Nonclassical bioisosteres can be further divided into groups: (A) rings vs
noncyclic structures; and (B) exchangeable groups. (see table 2)
69
Chapter 3 Synthetic Routes of Thiazole and Thiophene
Table 1 Classic Bioisostere Groups and Atoms
'\'[lmO\'Ulelll Dil'(l/nlt Tr;Wllell'
,-011. -:'i1l 2• -cn,. -OR -c 11,- ~CII-
-F -CI. -Dr. - I. -SII. -PII,. -0- =N-
-SiJ.-SR -s- =1--
-Se- =As-
-Tc- ~Sb-
Table 2 Non-Classic Bioisosteres
·co ..
-so~- -Ielrazule
.SOl:"liIiR
.SOl="'U1
-CO:"- -3-hydrOl)iso,,:uole
-CII(C.'i)- -2-hydro\)'Chromont";
R-S-R
t.R-U-H')
-hal ilk<;
-eN
-{"(C:"Ii).1
.1'OIOJI)'liIl!
-II
-f
-011 -(,11"011
.. " II-C(=C1I,\O l)- "II ~ -." 11-('(=(, I !C.'" )-:"i tl2
·:-.ouc()..
TelrUl"alelll
~c~
=Si=
=:"1'+=
=1>+=
=.-\s+=
=Sb+=
..COOR
·ROCO·
3.3.3 BIOISOSTERISM AS A STRATEGY OF MOLECULAR MODIFICATION
Among the most recent numerous examples used in the strategy of bioisosterism for
designing new pharmacotherapeutically attractive substances [42J. there is a significant
predominance on non-classic bioisosterism. distributed in distinct therapeutic categories, be
they selective receptor antagonist or agonist drugs, enzymatic inhibitors or anti-metabolites.
The use of classic bioisosterism for the structural design of new drugs, while less numerous.
has also been carried out successfully [43J.
70
Chapter 3 Synthetic Routes of Thiazole and Thiophene
The correct use of bioisosterism demands physical, chemical, electronic and
conformational parameters involved in the planned bioisosteric substitution, carefully
analyzed so as to predict, although theoretically, any eventual alterations in terms of the
pharmacodynamic and pharmacokinetic properties which the new bioisosteric substance
presents. Thus being, any bioisosteric replacement should be rigorously preceded by careful
analysis of the following parameters:
a) size, volume and electronic distribution of the atoms or the considerations on the
degree of hybridization, polarizability, bonding angles and inductive and mesomeric
effects when fitting;
b) degree of lipidic and aqueous solubility, so as to allow prediction of alteration of the
physicochemical properties such as 10gP and pKa;
c) chemical reactivity of the functional groups or bioisosteric structural subunits, mainly to
predict significant alterations in the processes of biotransformation, including for the
eventual alteration of the toxicity profile relative to the main metabolites;
d) conformational factors, including the differential capacity formation of inter- or
intramolecular hydrogen bonds.
3.3.4 BIOISOSTERISM AND ALTERATIONS OF PHYSICOCHEMICAL
PROPERTIES
Some bioisosteric groups dramatically alter the physicochemical properties of
substances and, therefore, their activities. This can be easily understood by comparing
classic isosteres resulting from bioisosteric replacement between hydroxyl (-OH) and amine
(-NH2), an example of classic bioisosterism of monovalent groups according to Grimm's
Rule. In this case, considering the bioisosteric replacement of aromatic amine present in
aniline by hydroxyl, we have phenol resulting in a significant change in the acid-base
properties of isosteres, with dramatic modification of the pKa of the compounds, which is
responsible for the distinct pharmacokinetic profiles among the isosteres in question. Thus,
in this example, we may predict that the use of bioisosterism, even the classic type, can
promote severe alterations of molecular properties, as much in terms of lipidic-aqueous
solubility as well as chemical reactivity, among others, which, broadly speaking, is not
observed in the same homologue carbonic series.
71
Chapter 3 Synthetic Routes of Thiazole and Thiophene
Here we have discussed the basics and the importance of the bioisosteric
replacement. Here in this thesis several bioisosterisom will be exemplified.
3.4 Therapeutic Importance of Thiazole and Thiophene Derivatives
3.4.1 Therapeutic Importance of Thiazole Derivatives:
One of the most important azoles is thiazole having nitrogen and sulfur as two
heteroatoms with an aromatic character. [44] In nature, thiazole moiety, unlike oxazole
present in experiment candidate Romazarit, has been found to be present in Vitamin-B 1•
Thiazole nucleus is reported to be important for various therapeutic activities, and
there are briefly summarised below.
Neurologic Disorders
Jaen, J.c. et a1. demonstrated the dopaminergic activity of 4-(1 ,2,5,6-tetrahydro-l-alkyl-
3-pyridinyl)-2-thiazole derivative (22) and proposed it to be effective in parkinson's disease.
Thiazole scaffold (23) has also been proved to be beneficial for the treatment of
Schizophrenia.(34) Thiazoles condensed with itself giving rise to thiazolothiazole
compounds (24, Ibazane) were found to be CNS depressant. [45]
;-{\ NH .2HCI
H2W---""'_~ I S ~CH3
(23)
(24)
72
Chapter 3 Synthetic Routes of Thiazole and Thiophene
Migraine and Pain
Replacement of the amide/ester linkage in the ICS-205-930 (25; Ki : 2.7 nM) series and
ketone functionality in the Ondansetron (26; Ki : 16.2 nM) series with thiazole moiety (27;
Ki : 0.42 nM) improved the 5-HT] receptor antagonistic activity. In this publication, authors
established that thiazole is a carbonyl bioisostere.[46]
o
N
I CH ,
H~N "w N~N;;
~~ )/'-NH
~ ~ H3 C
I ~ (27)
OCH 3
0& (25) N"
CH ,
o
Anticancer
Thiazole-4-carboxamide moiety In 28 (TAD, Thiazole-4-carboxamide adenine
dinucleotide) mimicks the nicotinamide nng in binding with cofactor site to inhibit
dehydrogenases (GDH, ADH, LDH and MDH) exhibiting antitumor activity. Thiazolyl
purine derivatives (29) were reported to be potent antitumor agents. Some of the
phthalimidothiazole derivatives (30) showed considerable activity in the screen against
Lewis lung carcinoma.[47]
N~ JLNH
,
N N 0 0 s~ --.
~O~jl~O~jl~O~N
I I 0 OH OH
o
OH OH ,.,
RJ-~~~N H L»
[2'/1 s
73
Chapter 3 Synthetic Routes of Thiazole and Thiophene
Anti-inflammatory
Thiazole attached with quinoline by amide linkage as exemplified by RU43526 (31)
produced anti-arthritic and analgesic compound showing the importance of thiazole
moiety.[40] Bisaryl thiazoles (32) have been found to have platelet aggregation inhibitory
activity as reported by Rynbrandt et al.(41) Thiazoles fused with another heterocycle,
imidazole, named imidazothiazole (33) derivatives have shown anti-inflammatory
activity.[42] A variety of novel 2,4-diaryl thiazole-5-acetic acids (34) were evaluated as
anti-inflammatory agents as shown in carrageenan induced edema assay in the rat.[48]
OH
CF , (31)
eN ~ N~S
(.B\
0 s:-) N~N H
CH ,
°n----CH 3 0
H 3eo
=--~ /;
S
)--CF'
N -=
~ # (32)
H 3eo
o
OH
It is worth mentioning that the replacement of isoxazole moiety as in Isoxicam and
pyridine moiety as in Piroxicam by a thiazole moiety as in Meloxicam gave rise to
significant COX-2 selectivity.[49]
74
Chapter 3 Synthetic Routes of Thiazole and Thiophene
OH o
Piroxicam Isoxicam
OH o
MeJoxicam
The introduction of thiazole motif in the benzothiazine dioxide carboxamide (36) in
place of aryl or alkyl group as in (35) resulted in the lower pKa value and very much
improved potency as anti-inflammatory agents. [SO]
OH 0
~ OH 0 s:) -:? ~ N N~N H
~ /N"
-:? ~ H
§s~ CH3 ~ /N" 07' ":::0
§s~ CH3
07' ":::0 (35) (36)
ED : 3.3 mglkg ED : 0.3 mglkg
Sudoxicam
When the thiazole ring (37) was replaced with cyclopentathiazole ring (38), anti
inflammatory activity of the compound completely vanished showing the importance of
conformationally non-restricted thiazole in the potency.[SI]
75
--------- ------
Chapter 3 Synthetic Routes of Thiazole and Thiophene
o OH
INACTIVE
Steroidal [3,2-d] thiazoles (39) were found to be better anti-inflammatory compounds as
compared to simple steroids.[52]
OH
,OH HO
< N #-(9)
Selectivity of drugs towards 5-lipoxygenase enzyme in comparison to cyc100xygenase
enzyme was achieved by a novel (methoxyalkyl) thiazole (40) [53] derivatives as 5-
lipoxygenase inhibitors and in another study, Kerdesky et al. found that 4-hydroxythiazoles
were potent and selective inhibitors of 5-lipoxygenase enzyme in-vitro [54].
o
(40)
OH N
H3C-Z ~ s
(41)
76
Chapter 3 Synthetic Routes of Thiazole and Thiophene
Cardiovascular
Thiazolyl derivatives (42) having ~-adrenergic blocking activity has been published by
Baldwin et al. in 1980. They were useful as anti-hypertensive drugs.(50) 2-Acetylamino
thiazole derivatives (43) have shown hypotensive activity.[55)
Antiinrectives
Parasites were also not barred from the terror of thiazoles. 2-(5-Nitro-2-thienyl) thiazole
derivatives (44) are reported to be antiprotozoal drugs. [56)
Thiazolines (45) were found to be active against heterakids, ascarids and capillarids
type of worms, useful as anthelmintic. From 49 analogs, tetramisole (46) (2,3,5,6-
tetrahydro-6-phenylimidazo-[2,I-b) thiazole hydrochloride) has been discovered a~ a novel
broad spectrum anthelmintic.[57)
.H C I
77
Chapter 3 Synthetic Routes of Thiazole and Thiophene
Some 2-heteroylimino-5-nitro-4-thiazoline-3-acetamides (47) and l-(carbamoylmethyl)-
1-(5-nitro-2-thiazolyl) ureas (48) were reported by Islip et al. as antiparasitic agents.(55)
Various 2-acyl and 2-(alkoxycarbonylimino)-5-nitro-4-thiazoline-3-acetamides (49) were
reported to have potent schistosomicidal activity. In another example, l-alkyl-3-(3-alkyl-5-
nitro-4-thiazolin-2-yl) ureas (SO) was published as schistosomicides. [58]
Thiazolyl imidazopyridines (51) were evaluated as anthelmintic and anti-fungal agents
and found to be very potent lead candidates.[59]
Anti-diabetic
New class of 4-(and 5-)-thiazolyl pyridazinium salts (52) as oral hypoglycemic agents
were reported.[60]
Thiazolidinedione derivatives are reported to be very potent hypoglycemic and
hypolipidemic agents. Recently, Sohda et al. reported that thaizolylalkoxylbenzylidene
78
Chapter 3 Synthetic Routes of Thiazole and Thiophene
thiazolidinedione (54) were more potent than Pioglitazone (53) which has recently been
launched as an anti-diabetic drug in the market.[61]
"::.::: ~ NH H,C s-\ # ~
N 0 0
(53) 0
~ NH
<) (~o s-\ ~ 0
(54)
Antihistamine
5-(2-aminoethyl)-thiazole derivatives elicited the histamine H2 receptor agonistic
activity. It was hypothesized that the acceptance of a proton by a thiazole nucleus from a
receptor site stimulates the histamine H2 receptor. Amthamine (55) is the most potent of this
series.[62] Hargrave et al. reported that N-(4-substituted thiazolyl) oxamic acid derivatives
(56) are potent anti allergy agents.[63]
.Elhallolaminc sail
f \\ 0
~~OH 5 N
(56) H 0
Anti HIV(Human Immunodeficiency Virus)
N-(2-phenethyl)-N' -(2-thiazolyl) thiourea (L Y 73497) (57) inhibits HIV -I reverse
trascriptase enzyme useful as anti AIDS molecule. [64]
79
Chapter 3 Synthetic Routes of Thiazole and Thiophene
(57)
All these reports have suggested the potential of thiazole moiety as a useful
molecular scaffold in drug design.
3.4.2 Therapeutic Importance of Thiophene Derivatives:
Thiophene derivatives have been used in different therapeutic areas. We have identified the
thiophene molecular scaffolding as being useful for the design of new analogs for anti
inflammatory evaluation. Some of the compounds of interest are shown in (fig 24). [65]
PYRAl'IiTEL ANTHEI}'llN1K He , \
0--0)
STEPRO~IN
MUCOLYTIC
O--CO',,"'''"iJCONHCH,COOH ,
H,NOC--f\ /
'''FENT.''''. ~\I NAR('OTIC A~ALGE.<;IC \
s CHp·~
",/\~, AROTINOLOL Nd ANTIliYI'ERTI,NSIVE \
~CH,N 1- NH
N~/ N
METIIAPIIENIU;:-'-E ANTlHI~"TMlINIC
SCHlCH(OH1CHzNHC(C~J
CI
AZOSEMIDE DIURETIC
(Fig 24)
I
9H,OC~ N(~!ilCOCI-I:,.GI-\..l
CARllCANE (LOCAL ANESTlIETlC)
PHETHENYLATE ANTICONVUI..5ANT
, :>----1-3=0 N
\ No
80
Chapter 3 Synthetic Routes of Thiazole and Thiophene
The thiophene derivative tiaprofenic acid (fig 25) has been reported to have good
efficacy as an anti-inflammatory drug. [66]
HO
(Fig 25)
The initial reports of 2,3 diaryl thiophenes (fig 26) as a non-ulcerogenic anti
inflammatory agent has led to much activity in this area.[67]
H3C0 2S
H
Br
F
(Fig 26)
Several laboratories have subsequently investigated 2, 3-diaryl thiophenes (fig 27)
such as methyl sulphones and sulfonamides and found them to be selective COX-2 inhibitor.
[68]
R=CH3 A, R=NH2
R=NH2. R 1 =F. R2=R3=H
R,
(Fig 27)
The thiophene analog had displayed a selective COX-2 inhibition (COX-l=O%,
COX-2=69% inhibition at 0.0 I microM, and it was found to be orally active (ED 30 = 1.4 81
Chapter 3 Synthetic Routes of Thiazole and Thiophene
mpk, P. 0) in rat carrageenan induced foot paw edema (CFE).(67). The isomeric 3, 4- diaryl
thiophene methyl sulphones and sulfonamides (fig 28) have also been reported as selective
COX-2 inhibitors.[69, 70]
R, SO,R
j f" ~ ~
RoCH 3 R=NH 2
( R3 R,
(Fig 28)
The lack of cyclooxygenase selectivity observed with 3,4 bis-(4-methoxy phenyl)
analog (COX-1 ID 50= 0.3 micron, COX-2 ID 50 = 0.8 micron) suggests that the presence
of a methyl sulphone or sulfonamide moiety is required for good selectivity. Replacement of
one of the benzene rings in the scaffohl of clozapine (which has the side effect of possible
agranulocytosis.) by thiophene has lead to olanzapine a drug which has superior efficacy and
good safety profile and also a blockbuster drug as antipsychotic agent. These examples
illustrate the utility of thiophene moiety as scaffolding in drug candidates. [7 I]
Clozapine
N_
CI~ V'N
H
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