Inshodhganga.inflibnet.ac.in/bitstream/10603/91116/10/10chapter 3.pdf · oldest methods reported for the synthesis of thiophenes was by Gewald. ... to substituted thiophene system

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

'-- - ------


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


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


+

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


"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


~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


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


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


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


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


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


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


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


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


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

--------- ------


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


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


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


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


(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


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


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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Inshodhganga.inflibnet.ac.in/bitstream/10603/91116/10/10chapter 3.pdf · oldest methods reported for the synthesis of thiophenes was by Gewald. ... to substituted thiophene system