Shah 

and Verma Chemistry Central Journal

https://doi.org/10.1186/s13065-018-0511-5
(2018) 12:137
Chemistry Central Journal

REVIEW Open Access

Therapeutic importance of synthetic

thiophene
Rashmi Shah and Prabhakar Kumar Verma*

Abstract 
Thiophene and its substituted derivatives are very important class of heterocyclic compounds which shows interest-
ing applications in the field of medicinal chemistry. It has made an indispensable anchor for medicinal chemists to
produce combinatorial library and carry out exhaustive efforts in the search of lead molecules. It has been reported to
possess a wide range of therapeutic properties with diverse applications in medicinal chemistry and material science,
attracting great interest in industry as well as academia. It has been proven to be effectual drugs in present respective
disease scenario. They are remarkably effective compounds both with respect to their biological and physiological
functions such as anti-inflammatory, anti-psychotic, anti-arrhythmic, anti-anxiety, anti-fungal, antioxidant, estrogen
receptor modulating, anti-mitotic, anti-microbial, kinases inhibiting and anti-cancer. Thus the synthesis and characteri-
zation of novel thiophene moieties with wider therapeutic activity is a topic of interest for the medicinal chemist to
synthesize and investigate new structural prototypes with more effective pharmacological activity. However, several
commercially available drugs such as Tipepidine, Tiquizium Bromides, Timepidium Bromide, Dorzolamide, Tiocona-
zole, Citizolam, Sertaconazole Nitrate and Benocyclidine also contain thiophene nucleus. Therefore, it seems to be
a requirement to collect recent information in order to understand the current status of the thiophene nucleus in
medicinal chemistry research.
Keywords:  Thiophene, Heterocyclic compounds, Combinatorial library, Antimicrobial

Introduction considered to be a structural alert with formula C ­ 4H4S,

As the world’s population is increasing at an alarming chemical name is thiacyclopentadiene [3].
rate, health problems have also become a very serious Thiophene was discovered as a contaminant in benzene
clinical problem. Therefore, it is an urgent requirement [4]. It has the molecular mass of 84.14  g/mol, density is
for the scientist to design and discover new drug mol- 1.051  g/ml and Melting Point is − 38  °C. It is soluble in
ecules which possibly offers some of the greatest hopes most organic solvents like alcohol and ether but insolu-
for success in present and future epoch. However, there ble in water. The “electron pairs” on sulfur are signifi-
are still enormous numbers of pharmacologically active cantly delocalized in the π electron system and behaves
heterocyclic compounds which are in regular clinical use extremely reactive like benzene derivative. Thiophene
[1]. Heterocyclic compounds are extensively distributed forms a azeotrope with ethanol like benzene. The simi-
in nature and have versatile synthetic applicability and larity between the physicochemical properties of ben-
biological activity which helped the medicinal chemist to zene and thiophene is remarkable. For example, the
plan, organize and implement new approaches towards boiling point of benzene is 81.1 °C and that of thiophene
the discovery of novel drugs [2]. is 84.4 °C (at 760 mmHg) and therefore, both are a well
Thiophene (Fig.  1) is a five membered heteroaromatic known example of bioisosterism [5]. It can be easily sul-
compound containing a sulfur atom at 1 position. It is fonated, nitrated, halogenated, acylated but cannot be
alkylated and oxidized [3].
In medicinal chemistry, thiophene derivatives
*Correspondence: vermapk422@rediffmail.com are very important heterocycles exhibiting remark-
Department of Pharmaceutical Sciences, Maharshi Dayanand University,
able applications in different disciplines. In medicine,
Rohtak, Haryana 124001, India

© The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License
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Shah and Verma Chemistry Central Journal (2018) 12:137 Page 2 of 22

fabrication of light-emitting diodes in material science

[11].
S
Fig. 1 Thiophene
Biological activities of thiophene derivatives
Thiophene nucleus containing compounds show various
thiophene derivatives shows antimicrobial [6], anal- activities like for example 1-[1-(2,5-dimethylthiophen-
gesic and anti-inflammatory [7], antihypertensive [8], 3-yl)ethyl]-1-hydroxyurea (1) act as an anti-inflammatory
and antitumor activity [9] while they are also used agent; the maleate salt of 1-(2,5-dimethylthiophen-3-yl)-
as inhibitors of corrosion of metals [10] or in the 3-(5-methyl-1H-imidazol-4-yl)propan-1-one (2) work as
serotonin antagonists and is used in the treatment of Alz-
heimer’s disease.

S OH
N NH2 S

O N
1-(1-(2,5-Dimethylthiophen-3-yl) O
HN
ethyl)-1-hydroxyurea
1
1-(2,5-Dimethylthiophen-3-yl)-3-
(5-methyl-1H-imidazol-4-yl)propan-1-one
2

O F O Cl
Cl O
O Pyridine / EtOH
S O
N S
N F S Cl reflux for 12 hr N Urea
F
O stirred for 3 hr
O
H
1H-indole-3- 3-Chloro-6-fluorobenzo O Cl
carbaldehyde [b]thiophene-2-carbonyl HN
chloride 3
1 N O
2 H
4-(1-(3-Chloro-6-fluoro-1-benzo[b]thiophene
-2carbonyl)-1H-indol-3-yl)7, 7-dimethyl-3, 4,
7, 8-tetrahydroquinazoline-2,5(1H,6H) dione
4
Scheme 1  Synthesis of 4-(1-(3-chloro-6-fluoro-1-benzo[b]thiophene-2-carbonyl)-1H-indol-3-yl)-7,7-dimethyl-3,4,7,8-tetrahydroquinazoline
2,5(1H,6H)dione

Table 1  Biological activity of synthesized compounds

S. no. Antibacterial strains Antifungal strains

Gram negative Gram positive

E. coli P. aeruginosa S. Aureus C. albicans A. niger A. clavatus

4 500 100 250 250 100 100

SD 100 100 50 100 100 100
Minimum inhibitory concentrations was expressed as (µg/ml)
SD =  Ampicillin for antibacterial drug; SD = Griseofulvin for antifungal drug
Shah and Verma Chemistry Central Journal (2018) 12:137 Page 3 of 22

O
S O O O
NaOH NH2NH2
S S
Grinding AcOH, reflux
R
(Substituted-3-phenyl-1- R N N
(thiophen-2-yl)prop-2-en-1-one 6 (5-(4-Substituted-phenyl)-3-
5 (thiophen-2-yl)-5,5a,6,7,8,9-
hexahydro-4H-
benzo[c][1,2]diazepine

7a R = H
7b R = OMe
Scheme 2  Synthesis of diazepines (7a, 7b)

Table 2 Antimicrobial activity of  thiophen-2-yl-chalcone as (5). It also act as metal complexing agents and in the
derived heterocyclic compounds development of insecticides.
S. no. S. aureus E. coli B. subtilis P. C. albicans
aeruginosa

7a 0.313 0.625 0.625 0.313 0.313 S

7b 0.313 0.625 0.625 0.313 0.313 S
Ciprofloxa- 0.625 0.625 0.625 0.625 – 2-Octylthiophene
2-Butylthiophene
cin
Fluconazole – – – – 0.625 3 4
Minimum inhibitory concentration (MIC; µg/ml)

The higher alkylated thiophenes (6) has been used

2-Butylthiophene (3) is used as a raw material in the extensively as a raw material in patents relating to liquid
synthesis of anticancer agents and 2-octylthiophene (4) is crystals [12].
used in the synthesis of anti-atherosclerotic agents such

S
R1 O O S S Base,450-550c NH2
N S S Stirring
O S S OC2H5
R2 S S O
Ethyl-2-cyanoacetate
1,4-Substituted
-ethane-2-one 9 Sulphur 11
8 10 OH
ArCHO

S
NH

OC2H5
O
Ethyl 2-(4-hydroxyphenylamino)-4-
phenylthiophene-3-carboxylate
12
Scheme 3  Synthesis of ethyl 2-(4-hydroxyphenylamino)-4-phenylthiophene-3-carboxylate
Shah and Verma Chemistry Central Journal (2018) 12:137 Page 4 of 22

HN S NH
S R
OH
R= C2H5-C 6 H13
C8H11
C2H5OOC OH
Ethyl 3-(3-((5-octylthiophen-2-yl)methyl Alkylated derivatives of thiophene
amino)phenyl)propanoate 6
5

Table 3 Antimicrobial activity of  2-aminothiophene Antimicrobial activity

derivatives Thiophene derivatives show high antimicrobial activ-
ity against various microbial infections. Different
S. no. P. vulgaris B. subtilis E. coli S. aureus
approaches were made to prove thiophene as antimicro-
12 25 50 12.5 50 bial agent by different scientist for the discovery of most
Ampicillin 25 50 12.5 50 active thiophene derivatives to the present scenario [13].
Streptomycin 12.5 50 12.5 25 Mehta et  al. [14] developed a new class of
Minimum inhibitory concentration (µg/ml) 4-(1-(3-chlorobenzo[b]thiophene-2-carbonyl)-1H-in-
dol-3-yl)-7, 7-dimethyl-3,4,7,8-tetrahydroquinazoline

H H
N SH NaNO /HCl S N SH N
S N R HN
2
H H
N N S N SH N
NH2 0-5oC N NCl
O O N N
N
3-Amino-2-sulfanyl- 14
2,3,5,6,7,8-hexahydro O
[1]benzothieno[2,3-d] R
3-{[(Phenyl hydrazono)(substituted phenyl)
pyrimidin-4(1H)-one
methyl] diazenyl}-2-sulfanyl-2,3,5,6,7,8-hexa
13 hydro[1]benzothieno[2,3-d]pyrimidin-4(1H)-one
15a-i
Compound code R
15a H
15b 2-Cl
15c 4-NO
2
15d 3,4,5-OCH
3
15e 2-NO
2
15f 4-N(CH )
3 2
15g 3,4-OCH
3
15h 4-OCH
3
15i 4-CH
3

Scheme 4  Synthesis of 3-{[(phenylhydrazono)(substitutedphenyl)methyl]diazenyl}-2-sulfanyl-2,3,5,6,7,8-hexahydro [1] benzothieno[2,3-d]

pyrimidin-4(1H)-one (15a–i)
Shah and Verma Chemistry Central Journal (2018) 12:137 Page 5 of 22

Table 
4 Antimicrobial activity of  benzothieno[2,3-c] 2,5(1H,6H)dione thiophene derivatives (Scheme 1). These
chromen-6-one derivatives synthesized compounds were screened for their antibac-
Compound Antibacterial Antifungal terial activity against three bacterial strains viz. E. coli,
P. aeruginosa, S. aureus and three fungal strains viz. C.
B. subtilis E. coli P. aureginosa C. albicans
albicans, A. niger, A. Clavatus using serial broth dilution
15a 11 00 15 10 method. The standard drug used in this study was ‘Ampi-
15b 00 10 00 14 cillin’ for evaluating antibacterial activity which showed
15c 12 00 12 12 (50, 100, and 50 μg/ml) MIC against E. coli, P. aeruginosa
15d 00 14 13 00 and S. aureus, respectively. For antifungal activity ‘Gri-
15e 00 10 11 00 seofulvin’ was used as a standard drug, which showed
15f 00 00 00 12 (100, 100, and 100  μg/ml) MIC against C. albicans, A.
15 g 14 00 14 11 niger, and A. clavatus, respectively. Among the synthe-
15 h 12 10 12 13 sized derivatives, Compound 4 was found to be good
15i 14 11 12 12 active against P. aeruginosa. For the antifungal activity
Ampicillin 15 18 20 – compounds 4 was considered as good active against A.
Fluconazole – – – 15 niger and A. clavatus. The results of synthesized com-
Minimum inhibitory concentrations was expressed as (µg/ml)
pounds presented in Table 1.

NO2 H3CO
O O pyridine COOH
HO OH
OHC OCH3 NO2
Malonic acid
3-Methoxy-5-nitrobenzaldehyde 17 18
16
SOCl2
R1 pyridine
R R2
O2N R2
H3CO Cl
NO2 HO R1 H3CO Cl
O R
S S O
NO2 O
NO2
10-Methoxy-4,8-dinitro-6H-benzothieno
[2,3-c]chromen-6-one derivatives 19
20a-c
Compound R R1 R2
20a –H –NO2 –H
20b –H –CH3 –H
20c –OCH3 –H –H
Scheme 5  Synthesis of 10-methoxy-4,8-dinitro-6H-benzothieno[2,3-c]chromen-6-one derivatives (20a–c)

Table 5  Antimicrobial activity of benzothienopyrimidinone derivatives

Compd S. aureus E. coli B. Subtilis S. typhosa
2 µg/ml 5 µg/ml 2 µg/ml 5 µg/ml 2 µg/ml 5 µg/ml 2 µg/ml 5 µg/ml

20a – + + ++ – + + ++
20b + + + + + ++ + +
20c – + + + – + + +
Inhibition zone diameter: (–) < 11 mm [inactive]; (+) 11–14 mm [weakly active]; (++) 15–18 mm [moderately active]
Shah and Verma Chemistry Central Journal (2018) 12:137 Page 6 of 22

NC CN
KOH, dioxane
NC CN PhNCS CH3
PhHN S
O
1-Isothio O
Malononitrile cyanatobenzene X
CH3 23
21 X= Cl, Br
22
NaOEt EtOH
N
N
H2N
NH
S CH3COCH2COOEt S
O
O
N N K2CO3/DMF
H 24
O
CH2(COOEt)2
3-Acetyl-4-methyl-2-oxo-5-(phenylamino)
-2,4-dihydrothieno[3,2-b]pyridine-7-carbonitrile K2CO3/DMF

25a
O
O
H
N N
O
S

N
Ethyl 7-cyano-4-methyl-2-oxo-5-(phenylamino)
-2,4-dihydrothieno[3,2-b]pyridine-3-carboxylate
25b
Scheme 6  Synthesis of Ethyl 7-cyano-4-methyl-2-oxo-5-(phenylamino)-1,2-dihydrothieno[3,2-b]pyridine

Table 6  The in  vitro antibacterial activity (7a, b) exhibited excellent antibacterial (S. aureus and P.
of the synthesized thienopyridines derivatives aeruginosa) and antifungal (C. albicans) activities. The
Compound Gram-positive species Gram-negative results showed the importance of the carbon–nitrogen
species bond in biological systems because of which antimicro-
B. Subtilis S. aureus E. coli S. typhosa
bial activities for these N-containing compounds were
reported. The results of synthesized compounds showed
25a 12.5 12.5 25 50 in Table 2.
25b 6.3 12.5 25 50 Prasad et  al. [16] synthesized newly ethyl 2-amino-
Minimum Inhibitory Concentrations was expressed as (µg/ml) 4-phenylthiophene-3-carboxylate derivatives using
Scheme  3. The synthesized compounds were screened
Mazimba [15] synthesized thiophene analogues of for their antibacterial activity by using minimum inhibi-
chalcones in good yields by condensation of 2-acetylth- tory concentration (MIC) method by taking ampicil-
iophene and salicylaldehydes using Scheme  2. 1,5-Dik- lin and streptomycin as standard drug. Among all the
etones were formed by solvent-free michael addition synthesized derivatives, compound 12 showed greater
of cyclohexanone and 2-thienylchalcones devoid of inhibitory effect against the organisms used, particu-
hydroxyl groups which were used as synthons for syn- larly against B. subtilis, E. coli, P. vulgaris and S. aureus
thesis of diazepines. The synthesized compounds were with MIC. The present study has given deep insight as
screened for in  vitro antimicrobial activities against the 2-aminothiophene bearing 4-hydroxy benzaldehyde
S. aureus, E. coli, B. subtilis, P. Aeruginosa and C. Albi- shown significant anti-microbial activity. The compound
cans using dilution method. The compounds were found 12 showed the significant anti-microbial activity among
to show moderate to good antibacterial and antifun- all the synthesized 2-aminothiophene derivatives because
gal activities. Among the tested compounds, diazepines of the presence of 4-hydroxy benzaldehyde at second
Shah and Verma Chemistry Central Journal (2018) 12:137 Page 7 of 22

N
N
CN N
SMe
MeS CO2Et CH3COOH N
NH2 SMe S
S
2-Amino-4,5,6,7-tetrahydro Ethyl 2-(bis(methylthio) 5-Methylthio-8,9,10,11-tetrahydro
benzo[b]thiophene-3-carbonitrile methyleneamino)acetate benzothieno[3,2-e]-imidazo[1,2-c]
pyrimidin-2(3H)-one
26 27 28
Cl
O NH
CO2Et
NH
HCONH2 SOCl2
NH2 N
S N S
S
Ethyl 2-amino-4,5,6,7-tetrahydro 31
benzo[b]thiophene-3-carboxylate 30
29
CH3
NH2NH2.H2O
N dioxane
N
NH NHNH2
H3C CH3COCH2COCH3
NH
N EtOH
S S N
4-(3,5-Dimethylpyrazolyl)-5,6,7,8-tetra
hydrobenzothieno[2,3-d]pyrimidine 32

33
Scheme 7  Synthesis of thienopyrimidine derivatives

Table 
7 Antibacterial activity of  some synthesized position. The results of synthesized compounds pre-
compounds sented in Table 3.
Compound Zone of inhibition (mm)
Lakshmi et  al. [17] synthesized 3-{[(phenylhydra-
zono) (substituted phenyl)methyl]diazenyl}-2-sul-
B. cereus S. dysenteriae S. typhi fanyl-2,3,5,6,7,8-hexahydro [1] benzothieno[2,3-d]
28 20 13 26 pyrimidin-4(1H)-one derivatives by using Scheme  4.
33 31 28 29 All the synthesized compounds were screened for their
Ampicillin 21 30 24 antibacterial and antifungal activities against various
microbes such as B. subtilis, E. coli, P. aeruginosa and C.
1 mg/ml per disc
albicans by the cup-plate agar diffusion method. From
all the series, compounds 15a, 15c, 15g, 15h, 15i were
active against B. subtilis, compounds 15b, 15d, 15e, 15h,
Table 
8 
Antifungal activity of  some synthesized
compounds 15i were active against E. coli, compounds 15a, 15c, 15d,
15e, 15g, 15h, 15i showed activity against P. aeruginosa
Compound Inhibition of mycelial growth (%)a and compounds 15a, 15b, 15c, 15f, 15g, 15h, 15i were
M. phaseolina F. equiseti A. alternate C. corchori found active against C. albicans. The results of synthe-
sized compounds showed in Table 4.
28 34.5 37.5 54 50
Havaldar et  al. [18] synthesized 10-methoxy-4,8-dini-
33 48.3 65.6 65.4 54.5
tro-6H-benzothieno[2,3-c]chromen-6-one derivatives
Nystatin 71.8 44.7 51.6 40.5
by using Scheme 5. All the synthesized compounds were
a
  1 mg/ml per disc tested for their antibacterial activity against S. aureus,
Shah and Verma Chemistry Central Journal (2018) 12:137 Page 8 of 22

S NH2 S N
HCONH2
N
N H2N
2-Amino-6-methyl-4,5,6,7 7-Methyl-5,6,7,8-tetrahydro[1]benzothieno
-tetrahydro-benzo-[b] [2,3-d]pyrimidin-4-amine
thiophene-3-carbonitrile 35
34 NH
H2N S O H2N
N
Triethylorthoformate, reflux
N S O
N
2-Amino-7-oxo-4,5,6,7-tetr 3-Amino-4-imino-5,6,7,8-tetrahydro-5H-benzo
ahydro-1-benzothiophene- [4,5]thieno[2,3-d]pyrimidin-8-one
3-carbonitrile 37
36 NH2NH2·H2O
anhydrous ethanolic NH3 RC(OEt)3
NH
N S O
H2N
N
N
N S O N
N
6,7-Dihydro-[1]benzothieno[2,3-d]pyrimidin- 8,9,10,11-Tetrahydro[1]benzothieno[3,2-e]
4,8(3H,5H)-dione [1,2,4]triazolo[1,5-c]pyrimidine-8-one
38 39a-c
a = H, b = CH3, c = C2H5
Scheme 8  Synthesis of thienopyrimidines and triazolothienopyrimidines derivatives

Table 9  Antibacterial and antifungal activities of the compounds as MIC values (μg/ml)

Compounds S. aureus B. subtilis E. coli P. aeruginosa C. albicans C. parapsilosis

35 256 11 128 256 128 64

37 512 256 256 256 16 128
38 512 11 256 256 128 256
39a 128 11 128 256 128 128
39b 256 11 128 256 256 64
39c 128 11 256 128 128 64
Ampicillin 4 8 4 – – –
Fluconazole – – – – 8 0.25

E. coli, B. subtilis and S. typhosa using concentrations of disk) as reference antibiotic. The compounds 25a and
2 and 5  µg/ml by the ditch plate technique. Among all 25b showed remarkable biological activity because of
the series, the compounds 20b showed a much higher the substitution of the CN (at C3) either by acetyl (as
inhibitory effect on the growth of bacteria because of the in 25a) and/or ethoxycarbonyl (as in 25b). However,
presence of C ­ H3 group. The results of synthesized com- the antibacterial activity was slightly hampered by the
pounds presented in Table 5. existence of the electron withdrawing p-bromophenyl
Ahmed et  al. [19] synthesized thieno[3,2-b]pyridine- group at fourth position of carbon. The results of syn-
2-one derivatives by using Scheme  6. The synthesized thesized compounds presented in Table 6.
thienopyridines derivatives were evaluated for their Bhuiyan et al. [20] synthesized a novel class of [1,2,4]
in  vitro antibacterial activity against two gramposi- triazolo[4,3-c]thieno-[3,2-e] pyrimidine derivatives
tive (B. subtilis and S. aureus) and two Gram-negative using Scheme 7 and assayed for the antibacterial activ-
(E. coli and S. typhi) strains using paper disk diffusion ity against B. cereus, S. dysenteriae and S. typhi and for
assay method by comparing with amoxicillin (30  μg/ antifungal activity against M. phaseolina, F. equiseti, A.
Shah and Verma Chemistry Central Journal (2018) 12:137 Page 9 of 22

O O Cl
EtOH N
COOEt NH POCl3
S HCONH2
N 43
CN S N
HN O S
Cyclohexanone 42
Ethyl-2-cyano R secondary
40 acetate amines
41 N
DMF
S N NH2NH2·H2O
4-(Substituted amino)-5,6,7,8-tetrahydro-
[1]benzothieno[2,3-d]pyrimidines
44a-b
H2NHN
H
S N S
N ArCHO, N
C
N N H EtOH
4-[2-(Thiophen-3-ylmethylidene)hydrazino] S N
-5,6,7,8-tetrahydro[1]benzothieno[2,3- 45
d]pyrimidine
CS2 / NaOH
46 Cl HN CH3 anhyd. K2CO3 /
dry Acetone
O

N N
S HN CH3
N
O
S N
N-(4-methylphenyl)-2-(8,9,10,11-tetrahydro
[1]benzothieno[3,2-e][1,2,4]triazolo[4,3-c]-
pyrimidin-3-ylsulfanyl)acetamide
47
Scheme 9  Synthesis of tetrahydrobenzothieno[2,3-d]pyrimidine and tetrahydrobenzothienotri azolopyrimidine

Table 10 Antibacterial and  antifungal activities might be responsible for enhancement of antimicrobial

of synthesized compounds activity of these compounds. The results of synthesized
Compound The inhibition zones (IZ) in mm diameter compounds are presented in Tables 7 and 8.
Khazi et al. [21] developed some novel tricyclic thieno-
S. aureus E. coli P. aeruginosa C. albicans
pyrimidines and triazole fused tetracyclic thienopyri-
44a – 15 16 22 midines derivatives by employing the Gewald reaction
44b – 16 19 16 (Scheme 8). The synthesized compounds were evaluated
46 21 17 20 20 against two Gram positive bacteria (S. aureus, B. subti-
47 – 17 – 22 lis), two Gram negative bacteria (P. aeruginosa, E. coli)
Ampicillin 25 28 32 – and two yeast-like fungi C. albicans and C. parapsilosis
Clotrimazole – – – 35 using the broth micro dilution method. The result indi-
(–) no inhibition zone, Minimum Inhibitory Concentrations was expressed as
cated that the compounds 35, 37, 39a, 39b and 39c have
(µg/ml) exhibited good antibacterial activity against B. subtilis
comparable to the standard ampicillin, while compound
38 displayed better antifungal activity against C. albicans
alternate and C. corchori. The disc diffusion method
comparable to the standard fluconazole. The results of
and poisoned-food techniques were used for antibacte-
synthesized compounds are presented in Table 9.
rial and antifungal activities, respectively. Among the
Tombary et  al. [22] synthesized series of
synthesized compounds 28 and 33 resulted in wide
tetrahydrobenzothieno[2,3-d]pyrimidine and tet-
spectrum antimicrobial activity against all the test bac-
rahydrobenzothienotriazolopyrimidine derivatives as
teria and fungi using ampicillin and nystatin as a stand-
presented in Scheme  9 and evaluated for their anti-
ard drug, respectively. Introduction of imidazo (28)
microbial activity using the cup diffusion technique
or pyrazolo (33) moiety to the pyrimidine derivatives
against S. aureus as Gram-positive bacteria, E. coli and
Shah and Verma Chemistry Central Journal (2018) 12:137 Page 10 of 22

piperidine
S DMF, 70oC for 75 min X DMF, 70oC for 75 min H2N CN
S
Na2S.9H2O Y Na2S.9H2O
NC O S
chloroacetonitrile chloroacetonitrile NC N
S
K2CO3 S
H2N O K2CO3
3-Amino-5-(1-piperidinyl)-2,4-
Ethyl 4-amino-5-cyano-2- 48a X=Y= CN
48b X = COEt Y = CN thiophenedicarbonitrile
(methylthio)thiophene-3-
carboxylate 49a
49b
Scheme 10  Synthesis of tetrasubstituted thiophenes derivatives

P. aeruginosa as Gram-negative bacteria in addition to C. method. Antibacterial activity result indicated that
albicans as fungi. The minimum inhibitory concentration among the synthesized derivatives, compounds 51, 54
(MIC) and minimum bactericidal concentration (MBC) and 56 showed promising broad spectrum antibacte-
for the active compounds were studied and compared rial activities against E. coli. The results of synthesized
with ampicillin and clotrimazole as reference antibiotics. compounds presented in Table 12.
Antimicrobial testing revealed that compounds 44a and
47 were the most active among the tested compounds Anticancer activity
against C. albicans while compounds 44b and 46 showed Cancer is among the most challenging health prob-
the highest antibacterial potency against P. aeruginosa lems worldwide which has become a major problem for
among the tested compounds. The significant results of increasing mortality rate globally. Currently available
these compounds are presented in Table 10. treatments such as chemotherapy and radiotherapy can
Adiwish et al. [23] synthesized tetra substituted thio- only provide temporary therapeutic benefits as well as
phenes from ketene dithioacetals as represented in being limited by a narrow therapeutic index, remark-
Scheme  10. The synthesized compounds 49a and 49b able toxicity, and acquired resistance for most of the type
were evaluated in  vitro for their antibacterial activity of cancer. However, the research of anticancer drugs in
against Gram-positive bacteria (S. aureus and B. subti- the past several decades has shown extensive progress
lis) and Gram-negative bacteria (E. coli and K. pneumo- and has cured considerable number of patients. Still it
nia) by using agar disc-diffusion technique. The result is the extreme area of investigation due to the complex
revealed that compound 49a exhibited bigger inhibi- physiological changes in the cell functionality, metasta-
tion zones compared to 49b. The results of synthesized sis and apoptotic mechanisms. Lots of compounds were
compounds presented in Table 11. screened for anticancer activity in the past few years
Reheim et al. [24] synthesized some novel substituted because of the presence of various cell lines and screen-
thieno[3,2-c]pyrazole and pyrazolo[3′,4′:4,5]thieno[2,3- ing methods. Most of the scientist has synthesized and
d]pyrimidine derivatives as represented in Scheme  11. investigated some of novel thiophene derivatives for the
The antimicrobial activity of the target synthesized anticancer activity carrying the biologically active sulfon-
compounds were screened against various microorgan- amide, isoxazole, benzothiazole, quinoline and anthra-
isms such as E. coli, B. megaterium, B. subtilis, F. pro- cene moieties [25–27].
liferatum, T. harzianum, A. niger by the disc diffusion Ghorab et al. [28] developed a novel series of thiophenes
derivatives having biologically active sulfonamide, isoxa-
zole, benzothiazole, quinoline and anthracene moieties
as presented in Scheme 12. The synthesized compounds
Table 
11 Antibacterial activities of  newly synthesized
were evaluated for in  vitro anticancer activity against
compounds
human breast cancer cell line (MCF7). Many of them
Bacteria Inhibition zones (mm) showed cytotoxic activities compared to doxorubicin as
49a 49b DMSO Streptomycin a positive control. Among this series, (Z)-4-(3-oxo-3-
(thiophen-2-yl)prop-1-enylamino)-N-(thiazol-2-yl)ben-
B. subtilis – – – 25 zenesulfonamide (59), (Z)-4-(3-oxo-3-(thio-phen-2-yl)
S. aureus 9 7 – 13 prop-1-enylamino)-N-(1-phenyl-1H-pyrazol-5-yl)benze-
E. coli 7 – – 25 nesulfonamide (60), (Z)-4-(3-oxo-3-(thiophen-2-yl)prop-
K. pneumonia – – – 25 1-enylamino)-N-(pyrimidin-2-yl)benzenesulfonamide
Minimum inhibitory concentrations was expressed as (µg/ml)
Shah and Verma Chemistry Central Journal (2018) 12:137 Page 11 of 22

Ph O
N Ph O O
N AcOH/NaNO2 Ar
N Ph ArCHO
Ph N N N Ph N Ph
O Ph EtOH/Pip. N
Ph
1,3-Diphenyl-1H- 52
4-(5-Oxo-1,3-diphenyl-1H- pyrazol-5(4H)-one
pyrazol-4(5H)-ylidene)-1,3- KOH
50 reflux, 20h (NH2)2CS
diphenyl-1H-pyrazol-5-one
51
Ph Ar
Ph X O
ClCH2COOH NH
N N
X = C6H4Cl-p N
N N S
N N S AcONa/AcOH H
reflux, 3h Ph
Ph
Pyrazolo[3,4-d]thiazolo[3,2-a]pyrimidine 53
54
Ph Ph
S malononitrile, reflux S
NH2
N NH2 ethanol N
N N CN
NH2 piperidine
Ph N Ph
O H HN
N NH2
5-Amino-1,3-diphenyl-1H-thieno 3-Amino-5-(5-amino-1,3-diphenyl-
[3,2-c]pyrazole-6-carbohydrazide 1H-thieno[3,2-c]pyrazol-6-yl)-1H-
55 pyrazole-4-carbonitrile
56
Scheme 11  Synthesis of substituted thieno[3,2-c]pyrazole and pyrazolo[3′,4′:4,5]thieno[2,3-d]pyrimidine derivatives

Table 12  Antibacterial and antifungal activities of compound as MIC values (μg/ml)

Compounds Bacterial species Fungal species
E. coli B. megaterium B. subtilis F. proliferatum T. harzianum A. niger

54 15 10 20 12 12 10
51 20 12 20 12 15 12
56 15 10 15 20 10 15
Ampicillin 23 23 23 – – –
Clotrimazole – – – 22 22 22
Inhibition zone diameter (mm)

(61) and (Z)-3-(4 methoxybenzo[d]thiazol-2-ylamino)- 61, or benzothiazole 62 moieties. The results of synthe-
1-(thiophen-2-yl)prop-2-en-1-one (62) having I­ C50 sized compounds showed in Table 13.
values 10.25, 9.70, 9.55 and 9.39  μmol/l, respectively Gaunda et al. [29] synthesized some new derivatives of
revealed a promising anti-breast cancer activity than that 3-[(2-substituted-6,7,8,9-tetrahydro-5H-cyclohepta[b]
of doxorubicin with I­C50 = 32.00  μmol/l. It was mainly thieno[2,3-d]pyrimidin-4-yl)amino]propan-1-ol deriva-
due to the thiophene nucleus containing biologically tives (Scheme  13). The in  vitro cytotoxicity activity of
active sulfathiazole 59, sulfaphenazole 60, sulfadiazine synthesized compounds were screened against both the
cell lines (HC 29-Colorectal adenoma cell line and MDA
Shah and Verma Chemistry Central Journal (2018) 12:137 Page 12 of 22

H O R
S O N S NH S O
S O H O
DMF-DMA
O R
xylene
N EtOH, AcOH N S NH
1-(Thiophen-2-yl)ethanone H O
57 58 (Z)-4-(3-oxo-3-(thiophen-2-yl)prop-1-
enylamino)-N-(substituted)benzene
O sulfonamide
59-61
N
H2N N
S 59 = R =
O S
S O H N N
60 = R = N
N Ph
S N
(Z)-3-(4-methoxybenzo[d]thiazol-2-ylamino) 61 = R =
N
-1-(thiophen-2-yl)prop-2-en-1-one
62
Scheme 12  Synthesis of thiophenes having the biologically active sulfonamide (59–61) and 3-methylisoxazole 12,4-methoxybenzo[d]thiazole (62)

Table 13  In vitro anticancer screening of  the  newly synthesized compounds against  the  human breast cancer cell line
MCF7
Compound Compound concentration (μmol/l)

Surviving ­fractiona
10 25 50 100 IC50 (μmol/l)

Doxorubicin 0.551 ± 0.026 0.480 ± 0.003 0.139 ± 0.005 0.130 ± 0.016 32.00

59 0.541 ± 0.003 0.323 ± 0.020 0.360 ± 0.018 0.460 ± 0.015 10.25
60 0.480 ± 0.010 0.327 ± 0.016 0.313 ± 0.005 0.381 ± 0.007 9.70
61 0.443 ± 0.017 0.251 ± 0.012 0.355 ± 0.020 0.290 ± 0.009 9.55
62 0.435 ± 0.009 0.233 ± 0.006 0.371 ± 0.018 0.309 ± 0.011 9.39
a
 Mean ± S.E, n = 3

O S O
S S benzene,
O- DEA NH2 RCN/HCl NH
O S S
R
S S 4 - 6hr
S S O N
N O S
Cycloheptanoe 64
2-Cyanobutanoate
63 66 67
65
12 hr, POCl3
100oC
dioxane Cl
HN OH
R = a = CH3 12 hr
R = b = C2H5 N
N 100oC
R = c = C6H5
NH2
S N R
S N R OH
68
3-[(2-Substituted-6,7,8,9-tetrahydro-5H-cyclohepta
[b]thieno[2,3-d] pyrimidin-4-yl)amino]propan-1-ol
69a-c
Scheme 13  Synthesis of 3-[(2-substituted-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[2,3-d]pyrimidin-4-yl)amino]propan-1-ol

231-adenocarcinoma breast cancer cell line) by MTT at all concentrations on both the cell lines followed by
assay and analyzed statistically. Among this series, the compound 69a, 69b. It was due to the phenyl substitu-
compound 69c had shown better anticancer activity tion (69c) which has shown better anticancer activity.
Shah and Verma Chemistry Central Journal (2018) 12:137 Page 13 of 22

Table 14  Anticancer activity of the title compounds (69a– against three tumor cell lines–MCF-7 (breast adenocar-
69c) cinoma), NCI-H460 (non-small cell lung cancer) and
Compound Concentration Percentage inhibition of cell growth SF-268 (CNS cancer) and a normal fibroblast human cell
code (μmol) line (WI-38) compared to the anti-proliferative effects
HC MDA 231-
29-colorectal adenocarcinoma
of the reference control doxorubicin. Among the series,
adenoma cell breast cancer cell ethyl-5-amino-3-(4-chlorostyryl)-4-cyanothiophene-
line (%) line (%) 2-carboxylate (74), ethyl 5-amino-4-[(4-methoxyphenyl)
69a 0.03 32.39 31.18
carbamoyl]-3-methylthiophene-2-carboxylate (76b)
0.07 31.43 29.35
and ethyl 5-(3-ethoxy-3-oxopropanamido)-3-methyl-4-
0.17 27.96 24.47
(phenylcarbamoyl)thiophene-2-carboxylate (77) were
69b 0.03 30.73 24.94
found to be the most active compounds against the three
0.07 27.94 25.79
tumor cell lines such as MCF-7, NCI-H460 and SF-268
0.17 25.27 26.41
where as they showed low potency against the normal
fibroblasts human cell line (WI-38). It was revealed that
69c 0.03 34.52 33.68
higher cytotoxicity activity of compound 74 was due to
0.07 32.83 30.72
the presence of the chloro group, O­ CH3 group in com-
0.17 28.45 25.35
pound 76b and the presence of two ethoxy groups in
compound 77. Thus it has been shown that, in most
cases, the electronegative Cl, ­OCH3 and ­OC2H5 hydro-
However, all the synthesized compounds showed consid-
phobic groups in the thiophene derivatives might play a
erable anticancer activity as compared to cyclophospha-
very important role in enhancing the cytotoxic effect. The
mide. The results of synthesized compounds presented in
results of synthesized compounds presented in Table 15.
Table 14.
Sharkawy et  al. [31] synthesized a series of thio-
Mohareb et  al. [30] developed a convenient synthetic
phene incorporating pyrazolone moieties via diazo
approach for novel thiophene and benzothiophene deriv-
coupling of diazonium salt of 3-substituted-2-amino-
atives (Scheme 14). The in vitro cytotoxicity was screened

NC
NH2
O O O
X H2N S piperidine
EtOH S
N S8 Cl
O Et3N O H
Ethyl-3-oxobutanoate NC Cl O
71 72 O O
70 73 (E)-ethyl 3-(4-chlorostyryl)-5-amino-4-
cyanothiophene-2-carboxylate
74
a Synthesis of various derivatives of thiophene
H2N
O
O S
EtOH O
X NH CN 72 X NH
70
Et3N O
2-Cyano-N-substituted Ethyl 5-amino-4-(substituted
phenylacetamide phenylcarbamoyl)thiophene-2-carboxylate
75 O O 76a X = H
76b X= OCH3
O HN O
CH2(COOC2H5)2
76a S
N
DMF H
O
O
Ethyl 5-(3-ethoxy-3-oxopropanamido)-3-methyl-4-
(phenylcarbamoyl)thiophene-2-carboxylate
77

b Synthesis of various benzothiophene derivatives

Scheme 14  a Synthesis of various derivatives of thiophene, b Synthesis of various benzothiophene derivatives
Shah and Verma Chemistry Central Journal (2018) 12:137 Page 14 of 22

Table 15  Anticancer activity of the title compounds

Compound IC50 (μmol/l)a
MCF-7 NCI-H460 SF-268 WI-38

74 0.03 ± 0.007 0.02 ± 0.008 0.01 ± 0.004 > 100

76b 0.01 ± 0.006 0.03 ± 0.002 0.06 ± 0.005 > 100
77 0.01 ± 0.003 0.02 ± 0.001 0.01 ± 0.001 66.5 ± 12.7
DSMO 94.3 ± 6.4 96.4 ± 10.2 98.6 ± 12.2 > 100
Doxorubicin 0.0428 ± 0.0082 0.0940 ± 0.0087 0.0940 ± 0.0070 > 100
a
  Drug concentration required to inhibit tumor cell proliferation by 50% after continuous exposure of 48 h; data are expressed as mean ± SEM of three independent
experiments performed in duplicates

N
H2N NH
X X X
N O
NaNO2/HCl pyridine
NH2 N2Cl NH
S H S
S N N
3-Substituted-4,5,6,7-tetrahydro O 3-Amino-4-(2-(3-substituted-4,5,6,7-
79
benzo[b]thiophen-2-amine NH2 tetrahydrobenzo[b]thiophen-2-yl)
hydrazono)-1H-pyrazol-5(4H)-one
78
80a, X= COOEt
80b, X= CONH2
80c, X= CN
Scheme 15  Synthesis of substituted-4-{2-[(or 3-phenyl-)4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl]hydrazono}-1H-pyrazol-5(4H)-one derivatives

Table 16  Antitumor activity of synthesized compounds synthesized derivatives were tested for cytotoxic-
Compound no % Dead
ity against the well known established model ehrlich
ascites carcinoma cells (EAC) in  vitro. The results
100 µg/ml (%) 500 µg/ml (%) 25 µg/ml (%) showed clearly that compounds 80a–c exhibited high
5-Fluorouracil 97.3 68 38.6 cytotoxic activity than 5-fluorouracil which may be
80a 100 98.6 94 due to the presence of amino group in position 3 of the
80b 98.4 81 65 pyrazol-5-one moiety. Further, the order of antitumor
80c 98.1 79 60 activity of this series of synthesized compounds fol-
The % dead refers to the % of the dead tumor cells
lows 80c < 80b < 80a which may be due to replacement
of ­CONH2 by CN or ­COOC2H5 groups of benzothio-
phene ring in position 3. The results of synthesized
compounds showed in Table 16.
4,5,6,7-tetrahydrobenzo[b]thiophenes with 3-methyl-
Seley et  al. [32] synthesized tricyclic thieno-sepa-
1H-pyrazol-5(4H)-one, 3-methyl-1-phenyl-1H-pyra-
rated purine analogues using Scheme  16. These syn-
zol-5(4H)-one or 3-amino-1H-pyrazol-5(4H)-one,
thesized derivatives were screened for their cytotoxic
respectively as represented in Scheme  15. Newly
activity against HCT116 colorectal cancer cell lines.

N H P2S5 N N H
anhydrous pyridine H
HN N N K2CO3 HN N
HN
N reflux N MeOH, NH3 N
O S S S H 2N S
1600C, 90h
Imidazo[4',5':4,5]thieno 82
6-Aminoimidazo[4',5' :4,5]
[3,2-d]pyrimidin-5(6H)-one thieno[3,2-d]pyrimidine
81
83
Scheme 16  Synthesis of 6-Aminoimidazo[4′,5′:4,5]thieno[3,2-d]pyrimidine
Shah and Verma Chemistry Central Journal (2018) 12:137 Page 15 of 22

Table 
17 Tricyclic compound-induced inhibition thieno-separated nucleosides may increase the growth
of HCT116 growth inhibitory properties of these analogues. The results of
Time (h) Compd 0.1 µM 1 µM 10 µM 100 µM synthesized compounds presented in Table 17.
Mohareb et  al. [33] synthesized novel heterocy-
24 83 96.1 ± 3.8 106.6 ± 4.8 104.8 ± 3.8 82.0 ± 7.8 clic compounds from 2-cyano-N-(3-cyano-4,5,6,7-
48 83 105.1 ± 3.3 98.3 ± 4.3 105.0 ± 2.1 71.5 ± 3.8b tetrahydrobenzo[b]thiophen-2-yl)-acetamide as
72 83 101.3 ± 7.3 96.1 ± 6.6 93.8 ± 12.1 51.5 ± 10.7a presented in Scheme 17. The tumor cell growth inhibi-
HCT116 cells were treated and growth was assessed. Data represent the average tion activities of the newly synthesized thiophene sys-
(SEM as a % of control-treated (DMSO) cells (n = 3–5)
a
tems were assessed in vitro on three human tumor cell
  p < 0.05
b
lines, namely, MCF-7 (breast adenocarcinoma), NCI-
  p < 0.005 when compared to control-treated cells
H460 (non-small cell lung cancer), and SF-268 (CNS
cancer) after a continuous exposure of 48 h. The results
were compared to the antiproliferative effects of the ref-
In this series, compound 83 showed potent cytotoxic
erence control doxorubicin. In this series, compounds
activity against cancer cell lines. It was due to the cou-
89, 86, 88, 85, and 87 showed significant activity on the
pling of compound 83 to a ribo-sugar to create the

H CN CHO O
S
NC N C
OH N
O S H O
CN O

2-Cyano-N-(3-cyano-4,5,6,7-tetrahydro N-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)
benzo[b]thiophen-2-yl)-acetamide -2-oxo-2H-chromen-3-il-carboxamide
84 85
NH2NH2
(i) 1,5-dipolar cyclization
H2N NC (ii) -2H
NC NC
C H2N N
H2
S S O
NC O
4,6-Diamino-1-(3-cyano-4,5,6,7-tetra N NH
NC H
hydrobenzo[b]thiophen-2-yl)-2-oxo-1,2- N
dihydropyridine-3-carbonitrile H2N
87 3-Amino-N-(3-cyano-4,5,6,7-tetrahydrobenzo
[b]thiophen-2-yl)-5-phenyl-1H-pyrazol-4-yl-carboxamide
NC
O 86
Br O NH2 O
Ph C
H2 S
NH
S
NH
NC NC PhN NCl
C NaOH
H2
3-Amino-2-benzoyl-4-[(3-cyano-4,5,6,7-tetrahydrobenzo-
CN [b]thiophene-2-carbonyl)-amino]-5-phenylaminothiophene
H2N NH2 88

S N N
N
O
CN

5-(2-phenyldiazenyl)-2,4-diamino-1-(3-cyano-
4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-1,6-
dihydro-6-oxopyridine-3-carbonitrile
89
Scheme 17  Synthesis ofsubstituted-1-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl) derivatives
Shah and Verma Chemistry Central Journal (2018) 12:137 Page 16 of 22

Table 18  Antiproliferative activity GI50 (μM) Table 19 Reduction of  DPPH by  substituted
of the synthesized compounds 2-(2-cyanoacetamido) thiophenes
Compound GI50 (μM)a Compound R1, ­R2 R3 %
Inhibition
MCF-7 NCI-H460 SF-268 at 100 μM
85 10.8 ± 0.6 16.5 ± 0.8 16.7 ± 1.6 92a –CH3 –CONH2 52.4
86 2.5 ± 0.5 10.4 ± 0.6 8.0 ± 0.4 Ascorbic acid 64.7
87 16.7 ± 1.6 10.8 ± 0.6 16.5 ± 0.8
88 11.8 ± 0.6 14.5 ± 0.8 16.7 ± 1.6
89 2.0 ± 0.4 8.3 ± 0.8 4.0 ± 0.8 Table 
20 Effect of  substituted 2-(2-cyanoacetamido)
Doxorubicin 0.0428 ± 0.0082 0.0940 ± 0.0087 0.0940 ± 0.0070 thiophenes on scavenging of nitric oxide
a
  Drug concentration required to inhibit tumor cell proliferation by 50% after Compound R1, ­R2 R3 %
continuous exposure of 48 h. Doxorubicin was used as positive control
Inhibition
at 100 μM

three tumor cell lines tested. The results of synthesized 92a –CH3 –CONH2 56.9
compounds showed in Table 18. 92b –(CH2)4– –CONH2 55.5

Antioxidant activities
Madhavi et  al. [34] developed a novel class of substi- Anti‑inflammatory activity
tuted 2-(2-cyanoacetamido)thiophenes by cyanoa- Bahashwan et  al. [35] synthesized new series of
cetylation of substituted 2-aminothiophene by using fused triazolo- and tetrazolopyrimidine derivatives
an effective cyanoacetylating agent, 1-cyanoacetyl- (Scheme  19) and their anti-inflammatory activity was
3,5-dimethylpyrazole as presented in Scheme  18. All evaluated. Newly synthesized thienopyrimidine deriva-
the synthesized compounds were evaluated for in vitro tives were screened for anti-inflammatory activity (per-
antioxidant activity by scavenging 1,1-diphenyl-2-pic- cent inhibition of edema obtained by the reference drug
rylhydrazyl (DPPH) and nitric oxide free radicals at and tested compounds, respectively) in comparison to
100  μM concentration. Among these evaluated com- that of indomethacin. Among the series, compounds
pounds, 2-(2-cyanoacetamido)-4,5-dimethylthio- 94, 95, 96, 97 and 98 possess strong anti-inflamma-
phene-3-carboxamide (Compound 92a) was found to tory activity. The high anti-inflammatory activity was
possess highest anti-oxidant activity in both models of mainly due to the presence of electron-donating moi-
free radical scavenging. However in case of assay with eties which increase the pharmacological activity. The
nitric oxide free radical scavenging, the highest activity order of anti-inflammatory properties with the sub-
was exhibited by 2-(2-cyanoacetamido)-4,5-dimeth- stitution of electron–donating group in pyrimidine
ylthiophene-3-carboxamide (Compound 92a, 56.9%) derivatives follows as: hydrazine > methyl > cyanome-
and 2-(2-cyanoacetamido)-4,5,6,7-tetrahydrobenzo[b] thyl > tetrazine > amide as exhibited in compounds
thiophene-3-carboxamide (Compound 92b, 55.5%). 94 > 98 > 95 > 96 > 97, respectively. The results of syn-
The greater activity of these compounds were attrib- thesized compounds presented in Table 21.
uted due to the polar nature of carboxamide or nitrile Ouf et  al. [36] synthesized hydrazones derivatives
group at 3rd position on thiophene ring. The results of which shows significant anti-inflammatory activities as
synthesized compounds presented in Tables 19 and 20. presented in Scheme  20. The synthesized compounds

CH3 R1
R1 R3
CN N R3 toluene
N R2 R2
refluxed at 110ºC HN S
H2N S
O CH3 CN
91 O
Substituted 2-(2-cyano
3-(3,5-Dimethyl-1H-pyrazol- acetamido)thiophene
1-yl)-3-oxopropanenitrile
92a-b
90
Scheme 18  Synthesis of substituted 2-aminothiophene
Shah and Verma Chemistry Central Journal (2018) 12:137 Page 17 of 22

NH2
HN
N
NH2NH2 OCH3
N
S
2-(4-Methoxyphenyl)-4-hydrazinocyclo
octeno[4.5]thieno[2.3-d]pyrimidine
Cl
N 94
CN
OCH3 N
N N
S CNCH2CONHNH2 N
2-(4-Methoxypheyl)-4-chlorocycloocteno OCH3
[4,5]thieno[2,3-e]pyrimidine N
93 S
5-(4-Methoxyphenyl)-3-cyanomethylcyclo
octeno[4.5]thieno[2.3-d]triazolo[1,2,4]
-[4,5-a]pyrimidine
95

N
N N
NaN3 N
OCH3
N
S
5-(4-Methoxyphenyl)-cycloocteno[4.5]
94 thieno[2.3-d]tetrazolo[4.5-e]pyrimidine
96
ClCOOEt
Ac2O
ethyl chloroformate

H N CH3
N N
N O
N
N OCH3
OCH3 N
N S
S 5-(4-Methoxyphenyl)-3-methyl-2H-cycloocteno
6-(4-Methoxyphenyl)-3,4-dioxo-2H-cycloocteno
[4.5]thieno[2,3-d]triazino[1,2.4]-[3,4-a]pyrimidine [4,5]thieno[2,3-d][1,2,4]triazolo-[4,5-a] pyrimidine
98
97
Scheme 19  Synthesis of thienotriazolopyrimidine derivatives

Table 21 Anti-inflammatory activity of  the  synthesized were screened against the standard drug flurbiprofen.
compounds Among the synthesized hydrazones, the substituted
Compounds Edema inhibition (means ± E.M)a,b (%) 4-methoxy- 100a, 4-chloro- 100b and 4-nitro-deriv-
atives 100c have anti-inflammatory activities higher
1 h 2 h 3 h
than that of hydrazone with an unsubstituted benzal-
94 42.3 ± 1.1 49.2 ± 1.2 57.1 ± 1.4 dehyde group against the standard drug flurbiprofen.
95 37.2 ± 1.3 46.3 ± 1.5 54.4 ± 1.1 Thus, the lipophilicity plays an important role for the
96 34.5 ± 1.2 35.1 ± 1.5 48.2 ± 1.2 potent anti-inflammatory activity. The results of syn-
97 31.2 ± 1.2 35.1 ± 1.5 40.2 ± 1.6 thesized compounds presented in Table 22.
98 39.1 ± 1.5 48.4 ± 1.2 55.6 ± 1.1 Hafez et  al. [37] synthesized some of the novel ben-
Indomethacin 44.7 ± 1.2 52.4 ± 1.2 61.2 ± 1.3 zothino-pyrimidine derivatives (Scheme  21) which
a
  Dose 5 mg/kg b.m (p.o.)
showed considerable potent anti-inflammatory activity.
b
  n = 6
The anti-inflammatory activity of the newly synthesized
Shah and Verma Chemistry Central Journal (2018) 12:137 Page 18 of 22

CH3 CH3 CH3

CH3 R
NHNH2 N NHN
N RCHO
S O Ar N S O
Ar N
2-((Benzo[d][1,3]dioxol-5-yl)vinyl) 2-((Benzo[d][1,3]dioxol-5-yl)vinyl)-4,5-
dimethylthieno[2,3-d]-pyrimidine-6-
-4,5-dimethylthieno[2,3-d]-
carbo-substituted-hydrazones
pyrimidine-6-carbo-hydrazide
99 100a = R= MeOC6H4
100b = R = ClC6H4
100c = R = NO2C6H4
Scheme 20  Synthesis of 2-((Benzo[d] [1, 3] dioxol-5-yl)vinyl)-4,5-dimethylthieno[2,3-d]-pyrimidine-6-carbohydrazones derivatives

Table 22  Anti-inflammatory activity of  some synthesized compounds were evaluated by applying carrageenan-
compounds (% reduction in edema induced by yeast) induced paw edema bioassay in rats using indometha-
Compound Post treatment 3 h = % Post treatment 6 h = % cin as a reference standard. Compounds 105, 106, 107,
108 and 109 caused significant decreases in paw edema
100a 26.6 34.4 after 2, 3, 4 h after drug administration. Thus, it can be
100b 17.2 30.0 concluded that spirobenzothienopyrimidine moiety,
100c 24.2 34.2 phenylpyrazolothinopyrimidine, morphonyl and piper-
azinylthinopyrimidine ring systems are important for

O COOC2H5 O O
O O
NH2NH2
NH2 CH3I NH2
NH2 N
CS2 N
S CH3
S S N S
N S H
Ethyl 2-amino-6,6-dimethyl-4- H
oxo-4,5, 6,7-tetrahydro-1- 3-Amino-7,7-dimethyl-2-(methylthio)-
102 3,6,7,8-tetrahydro[1]benzothieno
benzothiophene-3-carboxylate
101 NH2NH2 [2,3-d]pyrimidine-4,5-dione
103
O NH2 O O
O O O
N 3-chloropentane
NH2 NH2 -2,4-dione NH2
N chloroacetone N
N
N
S S S N
C6H5 N NHNH2 N N CH3
H H
3,4-Diamino-8,8-dimethyl-2-phenyl-3a,4,8, H3C
104 Cl
9-tetrahydro[1]benzothieno[3,2-e]imidazo 3-Amino-2-(4-chloro-3,5-dimethyl-1H-
[1,2-a] pyrimidine-5,6-(3H,7H)-dione pyrazol-1-yl)-7,7-dimethyl-3,6,7,8-
105 tetrahydro[1]benzothieno[2,3-d]
pyrimidine-4,5-dione
103 106

O NH H3C N NH HN NH

O O
O O O
O
NH2 NH2
NH2 N N
N
S S N N S N N
N N H H
H N NH
O CH3
3-amino-7,7-dimethyl-2-piperazin-1-yl)
3-amino-7,7-dimethyl-2-morpholin-4- yl- 3-amino-7,7-dimethyl-2-(4-methyl -3,6,7,8-tetraahydro[1]benzothieno
3,6,7,8-tetrahydro[1]benzothieno[2,3-d] piperazin-1-yl)-3,6,7,8-tetrahydro [2,3-d]pyrimi-dine-4,5-dione
pyrimidine-4,5-dione [1]benzo-thieno[2,3-d]pyrimidine
-4,5-dione 109
107 108
Scheme 21  Synthesis of phenylpyrazolothinopyrimidine, morphonyl and piperazinylthinopyrimidine derivatives
Shah and Verma Chemistry Central Journal (2018) 12:137 Page 19 of 22

Table 
23 
Anti-inflammatory effect of  synthesized effects of functional groups. The results of synthesized
compounds compounds are presented in Table 24.
Compd. no. Oedema volume
Anticonvulsant activity
1 h 2 h 3 h 4 h
Dashyan et  al. [39] synthesized 2,4-disubstituted pyr
105 49.4 ± 7.1 71.8 ± 6.7a
76.4 ± 4.8 a
82.2 ± 5.2 ano[4′′,3′′:4′,5′]pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidines
106 44.2 ± 5.1 59.6 ± 4.7a 67.8 ± 3.3a 81.9 ± 3.2 derivatives by using Scheme  23. The synthesized com-
107 61.0 ± 6.6 66.6 ± 5.9a 68.6 ± 7.0a 72.4 ± 7.4 pounds were screened for the anticonvulsant activity of
108 66.4 ± 7.5 78.2 ± 3.5a 81.3 ± 3.3 87.1 ± 2.1 by taking the comparator drug, diazepam which was per-
109 56.2 ± 9.9 65.1 ± 7.5a 55.9 ± 10.6a 54.7 ± 7.2a formed using male albino mice weighing 18–24  g (200
Indomethacin 49.8 ± 5.3 42.9 ± 5.1a 45.9 ± 4.6a 46.9 ± 5.8a animals) and rats (Wistar) weighing 120–140  g (40 ani-
a
  p < 0.05: Statistically significant from the control using one way ANOVA (Two-
mals of both sexes).
sided Dunnett as Post Hoc test) The anticonvulsant activity of the compounds was
assessed by the prevention of clonic twitches and the
clonic component of convulsions caused by subcutane-
anti-inflammatory activity. The results of synthesized
ous administration of 90 mg/kg metrazol in mice. When
compounds presented in Table 23.
studying anticonvulsant activity, it was found that the
compounds (114a, b, c) and (115a, b, c, d, e) caused a
Antiurease activity marked protective anticonvulsive effect, which developed
Rasool et  al. [38] synthesized variety of novel 5-aryl in mice starting with a dose of 25  mg/kg, while statisti-
thiophenes derivatives containing sulphonylacetamide cally calculated dose ­(ED50) ranged from 23 to 56 mg/kg
(sulfacetamide) using Scheme  22. The synthesized com- (Table 25).
pounds were screened for their anti-urease activities by
taking thiourea as standard drug. Among all the synthe-
sized derivatives, compound 112, N-((5′-methyl-[2,2′- Antithrombotic activity
bithiophen]-5-yl)sulfonyl)acetamide, showed excellent Jubair et  al. [40] synthesized novel series of
urease inhibition activity at 40 µg/ml and 80 µg/ml con- 2-(bromomethyl)-5-aryl-thiophenes derivatives via
centrations where the percentage inhibition values were Suzuki cross-coupling reactions of various aryl boronic
found to be 92.12 ± 0.21 and 94.66 ± 0.11, respectively acids with 2-bromo-5 (bromomethyl)thiophene as given
with an I­C50 value ~ 17.1 ± 0.15  µg/ml. It is further con- in Scheme 24. The synthesized compounds were screened
cluded that the urease inhibitory activity of compound for their antithrombolytic activity. All the Compounds
might be due to the presence of the electronic and steric (100 μL) having concentration of 1 mg/ml were added to

H
O H
O
O (CH3CO)2O N Aryl boronic acids N
H2N S
S S CH3CN, H2O S esters, K3PO4 S S
O Br O O Br O O
60OC, 40 min S CH3
5-Bromothiophene- 111 N-(5-(5-methylthiophen-2-yl)
2-sulfonamide thiophen-2-ylsulfonyl)acetamide
110 112
Scheme 22  Synthesis of N-(5-(5-methylthiophen-2-yl)thiophen-2 ylsulfonyl)acetamide

Table 24  Urease inhibition studies of 5-arylthiophene-2-sulfonylacetamides

Compound Percentage activity at 15 µg/ml Percentage activity at 40 µg/ml Percentage activity at 80 µg/ml IC50 µg/ml

112 42.44 ± 0.11 92.12 ± 0.21 94.66 ± 0.11 17.1 ± 0.15

Standard 47.1 ± 0.31 65 ± 0.01 – 23.3 ± 0.21
Standard = Thiourea
Shah and Verma Chemistry Central Journal (2018) 12:137 Page 20 of 22

SCH3 SCH3
O N O N
NHR1R2
N N

N N S Cl N N S N R2
R1
O O
8-Chloro-2,2-dimethyl-10-methylthio-5-(morpholin- (115à–e)
4-yl)-1,4-dihydro-2H-pyrano[4'',3'':4',5']pyrido-
[3',2':4,5]thieno[3,2-d]pyrimidine (a), R1 = H, R2 = (CH2)2CH(CH3)2
113 (b), R1 = H, R2 = (CH2)2N(C2H5)2
H2NC(S)NH2 (c), R1 = H, R2 = (CH2)-tetrahydrofuran
RHal (d), R1 = H, R2 = CH2-furan
SCH3 (e), R1 = R2 = 4-ethanolpiperazin
O N
N

N N S SR
O
(114a-c)
(a), R = (CH2)2CH(CH3)2
(b), R = (CH2)3COCH3
(c), R = (CH2)3COOC2H5
Scheme 23  Synthesis of 2,4-Disubstituted pyrano[4′,3′:4,5]pyrido[2,3-b]thieno[3,2-d]pyrimidine derivatives

Table 25  Activity against  metrazol convulsions

Table 26 Percentage efficiency of  Clot lysis of  synthetic
for  the  compounds (114a, b, c), (115a, b, c, d, e),
compounds
and diazepam
Compounds Clot lysis %
Compound Activity against metrazol
convulsions* (ED50, mg/kg) 118 31.5 ± 0.45
114a 56.0 (36.0–100.8) Water 0.43 ± 0.005
114b 40.0 (23.5–68.0) Streptokinase 87.2 ± 0.95
114c 23.0 (15.9–33.1) The results are average ± S.D of triplicate experiments p < 0.05
115a 40.0 (23.5–68.0)
115b 56.0 (36.0–100.8)
115c 34.0 (25.3–45.7) the micro-centrifuge tubes containing venous blood, and
115d 40.0 (23.5–68.0) incubated at 37 °C for 45 min. Streptokinase was used as
115e 56.0 (36.0–100.8) standard clot lysis agent and water as negative control for
Diazepam 0.51 (0.39–0.69) this assay. Among all the synthesized compounds, 118
showed potent clot lysis (31.5%). However, the results
* Probability levels at p = 0.05 are indicated in brackets
were significant p < 0.05, when compared with streptoki-
nase. Clot lysis activity results are presented in Table 26.

Me
ArB(OH)2
NBS Br
Me
reflux in CCl4 for S Br 1,4-dioxane/H2O (4:1) Br
S S
4–5 hour
Me
2-Methylthiophene 117
2-(Bromomethyl)-5-(3,5-
116 dimethylphenyl)thiophene
118
Scheme 24  Synthesis of 2-(Bromomethyl)-5-(3,5-dimethylphenyl)thiophene
Shah and Verma Chemistry Central Journal (2018) 12:137 Page 21 of 22

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