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  • Review
  • Open Access

Therapeutic importance of synthetic thiophene

Chemistry Central Journal201812:137

https://doi.org/10.1186/s13065-018-0511-5

  • Received: 4 March 2018
  • Accepted: 4 December 2018
  • Published:

Abstract

Thiophene and its substituted derivatives are very important class of heterocyclic compounds which shows interesting 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 characterization 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, Tioconazole, 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

As the world’s population is increasing at an alarming rate, health problems have also become a very serious clinical problem. Therefore, it is an urgent requirement for the scientist to design and discover new drug molecules which possibly offers some of the greatest hopes for success in present and future epoch. However, there are still enormous numbers of pharmacologically active heterocyclic compounds which are in regular clinical use [1]. Heterocyclic compounds are extensively distributed in nature and have versatile synthetic applicability and biological activity which helped the medicinal chemist to plan, organize and implement new approaches towards the discovery of novel drugs [2].

Thiophene (Fig. 1) is a five membered heteroaromatic compound containing a sulfur atom at 1 position. It is considered to be a structural alert with formula C4H4S, chemical name is thiacyclopentadiene [3].
Fig. 1
Fig. 1

Thiophene

Thiophene was discovered as a contaminant in benzene [4]. It has the molecular mass of 84.14 g/mol, density is 1.051 g/ml and Melting Point is − 38 °C. It is soluble in most organic solvents like alcohol and ether but insoluble in water. The “electron pairs” on sulfur are significantly delocalized in the π electron system and behaves extremely reactive like benzene derivative. Thiophene forms a azeotrope with ethanol like benzene. The similarity between the physicochemical properties of benzene and thiophene is remarkable. For example, the boiling point of benzene is 81.1 °C and that of thiophene is 84.4 °C (at 760 mmHg) and therefore, both are a well known example of bioisosterism [5]. It can be easily sulfonated, nitrated, halogenated, acylated but cannot be alkylated and oxidized [3].

In medicinal chemistry, thiophene derivatives are very important heterocycles exhibiting remarkable applications in different disciplines. In medicine, thiophene derivatives shows antimicrobial [6], analgesic and anti-inflammatory [7], antihypertensive [8], and antitumor activity [9] while they are also used as inhibitors of corrosion of metals [10] or in the fabrication of light-emitting diodes in material science [11].

Biological activities of thiophene derivatives

Thiophene nucleus containing compounds show various activities like for example 1-[1-(2,5-dimethylthiophen-3-yl)ethyl]-1-hydroxyurea (1) act as an anti-inflammatory agent; the maleate salt of 1-(2,5-dimethylthiophen-3-yl)-3-(5-methyl-1H-imidazol-4-yl)propan-1-one (2) work as serotonin antagonists and is used in the treatment of Alzheimer’s disease.

2-Butylthiophene (3) is used as a raw material in the synthesis of anticancer agents and 2-octylthiophene (4) is used in the synthesis of anti-atherosclerotic agents such as (5). It also act as metal complexing agents and in the development of insecticides.

The higher alkylated thiophenes (6) has been used extensively as a raw material in patents relating to liquid crystals [12].

Antimicrobial activity

Thiophene derivatives show high antimicrobial activity against various microbial infections. Different approaches were made to prove thiophene as antimicrobial agent by different scientist for the discovery of most active thiophene derivatives to the present scenario [13].

Mehta et al. [14] developed a new class of 4-(1-(3-chlorobenzo[b]thiophene-2-carbonyl)-1H-indol-3-yl)-7, 7-dimethyl-3,4,7,8-tetrahydroquinazoline 2,5(1H,6H)dione thiophene derivatives (Scheme 1). These synthesized compounds were screened for their antibacterial activity against three bacterial strains viz. E. coli, P. aeruginosa, S. aureus and three fungal strains viz. C. albicans, A. niger, A. Clavatus using serial broth dilution method. The standard drug used in this study was ‘Ampicillin’ for evaluating antibacterial activity which showed (50, 100, and 50 μg/ml) MIC against E. coli, P. aeruginosa and S. aureus, respectively. For antifungal activity ‘Griseofulvin’ was used as a standard drug, which showed (100, 100, and 100 μg/ml) MIC against C. albicans, A. niger, and A. clavatus, respectively. Among the synthesized derivatives, Compound 4 was found to be good active against P. aeruginosa. For the antifungal activity compounds 4 was considered as good active against A. niger and A. clavatus. The results of synthesized compounds presented in Table 1.
Scheme 1
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

Mazimba [15] synthesized thiophene analogues of chalcones in good yields by condensation of 2-acetylthiophene and salicylaldehydes using Scheme 2. 1,5-Diketones were formed by solvent-free michael addition of cyclohexanone and 2-thienylchalcones devoid of hydroxyl groups which were used as synthons for synthesis of diazepines. The synthesized compounds were screened for in vitro antimicrobial activities against S. aureus, E. coli, B. subtilis, P. Aeruginosa and C. Albicans using dilution method. The compounds were found to show moderate to good antibacterial and antifungal activities. Among the tested compounds, diazepines (7a, b) exhibited excellent antibacterial (S. aureus and P. aeruginosa) and antifungal (C. albicans) activities. The results showed the importance of the carbon–nitrogen bond in biological systems because of which antimicrobial activities for these N-containing compounds were reported. The results of synthesized compounds showed in Table 2.
Scheme 2
Scheme 2

Synthesis of diazepines (7a, 7b)

Table 2

Antimicrobial activity of thiophen-2-yl-chalcone derived heterocyclic compounds

S. no.

S. aureus

E. coli

B. subtilis

P. aeruginosa

C. albicans

7a

0.313

0.625

0.625

0.313

0.313

7b

0.313

0.625

0.625

0.313

0.313

Ciprofloxacin

0.625

0.625

0.625

0.625

Fluconazole

0.625

Minimum inhibitory concentration (MIC; µg/ml)

Prasad et al. [16] synthesized newly ethyl 2-amino-4-phenylthiophene-3-carboxylate derivatives using Scheme 3. The synthesized compounds were screened for their antibacterial activity by using minimum inhibitory concentration (MIC) method by taking ampicillin and streptomycin as standard drug. Among all the synthesized derivatives, compound 12 showed greater inhibitory effect against the organisms used, particularly against B. subtilis, E. coli, P. vulgaris and S. aureus with MIC. The present study has given deep insight as the 2-aminothiophene bearing 4-hydroxy benzaldehyde shown significant anti-microbial activity. The compound 12 showed the significant anti-microbial activity among all the synthesized 2-aminothiophene derivatives because of the presence of 4-hydroxy benzaldehyde at second position. The results of synthesized compounds presented in Table 3.
Scheme 3
Scheme 3

Synthesis of ethyl 2-(4-hydroxyphenylamino)-4-phenylthiophene-3-carboxylate

Table 3

Antimicrobial activity of 2-aminothiophene derivatives

S. no.

P. vulgaris

B. subtilis

E. coli

S. aureus

12

25

50

12.5

50

Ampicillin

25

50

12.5

50

Streptomycin

12.5

50

12.5

25

Minimum inhibitory concentration (µg/ml)

Lakshmi et al. [17] synthesized 3-{[(phenylhydrazono) (substituted phenyl)methyl]diazenyl}-2-sulfanyl-2,3,5,6,7,8-hexahydro [1] benzothieno[2,3-d]pyrimidin-4(1H)-one derivatives by using Scheme 4. All the synthesized compounds were screened for their antibacterial and antifungal activities against various microbes such as B. subtilis, E. coli, P. aeruginosa and C. 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, 15i were active against E. coli, compounds 15a, 15c, 15d, 15e, 15g, 15h, 15i showed activity against P. aeruginosa and compounds 15a, 15b, 15c, 15f, 15g, 15h, 15i were found active against C. albicans. The results of synthesized compounds showed in Table 4.
Scheme 4
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 (15ai)

Table 4

Antimicrobial activity of benzothieno[2,3-c]chromen-6-one derivatives

Compound

Antibacterial

Antifungal

B. subtilis

E. coli

P. aureginosa

C. albicans

15a

11

00

15

10

15b

00

10

00

14

15c

12

00

12

12

15d

00

14

13

00

15e

00

10

11

00

15f

00

00

00

12

15 g

14

00

14

11

15 h

12

10

12

13

15i

14

11

12

12

Ampicillin

15

18

20

Fluconazole

15

Minimum inhibitory concentrations was expressed as (µg/ml)

Havaldar et al. [18] synthesized 10-methoxy-4,8-dinitro-6H-benzothieno[2,3-c]chromen-6-one derivatives by using Scheme 5. All the synthesized compounds were tested for their antibacterial activity against S. aureus, E. coli, B. subtilis and S. typhosa using concentrations of 2 and 5 µg/ml by the ditch plate technique. Among all the series, the compounds 20b showed a much higher inhibitory effect on the growth of bacteria because of the presence of CH3 group. The results of synthesized compounds presented in Table 5.
Scheme 5
Scheme 5

Synthesis of 10-methoxy-4,8-dinitro-6H-benzothieno[2,3-c]chromen-6-one derivatives (20ac)

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]

Ahmed et al. [19] synthesized thieno[3,2-b]pyridine-2-one derivatives by using Scheme 6. The synthesized thienopyridines derivatives were evaluated for their in vitro antibacterial activity against two grampositive (B. subtilis and S. aureus) and two Gram-negative (E. coli and S. typhi) strains using paper disk diffusion assay method by comparing with amoxicillin (30 μg/disk) as reference antibiotic. The compounds 25a and 25b showed remarkable biological activity because of the substitution of the CN (at C3) either by acetyl (as in 25a) and/or ethoxycarbonyl (as in 25b). However, the antibacterial activity was slightly hampered by the existence of the electron withdrawing p-bromophenyl group at fourth position of carbon. The results of synthesized compounds presented in Table 6.
Scheme 6
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 of the synthesized thienopyridines derivatives

Compound

Gram-positive species

Gram-negative species

B. Subtilis

S. aureus

E. coli

S. typhosa

25a

12.5

12.5

25

50

25b

6.3

12.5

25

50

Minimum Inhibitory Concentrations was expressed as (µg/ml)

Bhuiyan et al. [20] synthesized a novel class of [1,2,4]triazolo[4,3-c]thieno-[3,2-e] pyrimidine derivatives using Scheme 7 and assayed for the antibacterial activity against B. cereus, S. dysenteriae and S. typhi and for antifungal activity against M. phaseolina, F. equiseti, A. alternate and C. corchori. The disc diffusion method and poisoned-food techniques were used for antibacterial and antifungal activities, respectively. Among the synthesized compounds 28 and 33 resulted in wide spectrum antimicrobial activity against all the test bacteria and fungi using ampicillin and nystatin as a standard drug, respectively. Introduction of imidazo (28) or pyrazolo (33) moiety to the pyrimidine derivatives might be responsible for enhancement of antimicrobial activity of these compounds. The results of synthesized compounds are presented in Tables 7 and 8.
Scheme 7
Scheme 7

Synthesis of thienopyrimidine derivatives

Table 7

Antibacterial activity of some synthesized compounds

Compound

Zone of inhibition (mm)

B. cereus

S. dysenteriae

S. typhi

28

20

13

26

33

31

28

29

Ampicillin

21

30

24

1 mg/ml per disc

Table 8

Antifungal activity of some synthesized compounds

Compound

Inhibition of mycelial growth (%)a

M. phaseolina

F. equiseti

A. alternate

C. corchori

28

34.5

37.5

54

50

33

48.3

65.6

65.4

54.5

Nystatin

71.8

44.7

51.6

40.5

a1 mg/ml per disc

Khazi et al. [21] developed some novel tricyclic thienopyrimidines and triazole fused tetracyclic thienopyrimidines derivatives by employing the Gewald reaction (Scheme 8). The synthesized compounds were evaluated against two Gram positive bacteria (S. aureus, B. subtilis), two Gram negative bacteria (P. aeruginosa, E. coli) and two yeast-like fungi C. albicans and C. parapsilosis using the broth micro dilution method. The result indicated that the compounds 35, 37, 39a, 39b and 39c have exhibited good antibacterial activity against B. subtilis comparable to the standard ampicillin, while compound 38 displayed better antifungal activity against C. albicans comparable to the standard fluconazole. The results of synthesized compounds are presented in Table 9.
Scheme 8
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

Tombary et al. [22] synthesized series of tetrahydrobenzothieno[2,3-d]pyrimidine and tetrahydrobenzothienotriazolopyrimidine derivatives as presented in Scheme 9 and evaluated for their antimicrobial activity using the cup diffusion technique against S. aureus as Gram-positive bacteria, E. coli and P. aeruginosa as Gram-negative bacteria in addition to C. albicans as fungi. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) for the active compounds were studied and compared with ampicillin and clotrimazole as reference antibiotics. Antimicrobial testing revealed that compounds 44a and 47 were the most active among the tested compounds against C. albicans while compounds 44b and 46 showed the highest antibacterial potency against P. aeruginosa among the tested compounds. The significant results of these compounds are presented in Table 10.
Scheme 9
Scheme 9

Synthesis of tetrahydrobenzothieno[2,3-d]pyrimidine and tetrahydrobenzothienotri azolopyrimidine

Table 10

Antibacterial and antifungal activities of synthesized compounds

Compound

The inhibition zones (IZ) in mm diameter

S. aureus

E. coli

P. aeruginosa

C. albicans

44a

15

16

22

44b

16

19

16

46

21

17

20

20

47

17

22

Ampicillin

25

28

32

Clotrimazole

35

(–) no inhibition zone, Minimum Inhibitory Concentrations was expressed as (µg/ml)

Adiwish et al. [23] synthesized tetra substituted thiophenes from ketene dithioacetals as represented in Scheme 10. The synthesized compounds 49a and 49b were evaluated in vitro for their antibacterial activity against Gram-positive bacteria (S. aureus and B. subtilis) and Gram-negative bacteria (E. coli and K. pneumonia) by using agar disc-diffusion technique. The result revealed that compound 49a exhibited bigger inhibition zones compared to 49b. The results of synthesized compounds presented in Table 11.
Scheme 10
Scheme 10

Synthesis of tetrasubstituted thiophenes derivatives

Table 11

Antibacterial activities of newly synthesized compounds

Bacteria

Inhibition zones (mm)

49a

49b

DMSO

Streptomycin

B. subtilis

25

S. aureus

9

7

13

E. coli

7

25

K. pneumonia

25

Minimum inhibitory concentrations was expressed as (µg/ml)

Reheim et al. [24] synthesized some novel substituted thieno[3,2-c]pyrazole and pyrazolo[3′,4′:4,5]thieno[2,3-d]pyrimidine derivatives as represented in Scheme 11. The antimicrobial activity of the target synthesized compounds were screened against various microorganisms such as E. coli, B. megaterium, B. subtilis, F. proliferatum, T. harzianum, A. niger by the disc diffusion method. Antibacterial activity result indicated that among the synthesized derivatives, compounds 51, 54 and 56 showed promising broad spectrum antibacterial activities against E. coli. The results of synthesized compounds presented in Table 12.
Scheme 11
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)

Anticancer activity

Cancer is among the most challenging health problems worldwide which has become a major problem for increasing mortality rate globally. Currently available treatments such as chemotherapy and radiotherapy can only provide temporary therapeutic benefits as well as being limited by a narrow therapeutic index, remarkable toxicity, and acquired resistance for most of the type of cancer. However, the research of anticancer drugs in the past several decades has shown extensive progress and has cured considerable number of patients. Still it is the extreme area of investigation due to the complex physiological changes in the cell functionality, metastasis and apoptotic mechanisms. Lots of compounds were screened for anticancer activity in the past few years because of the presence of various cell lines and screening methods. Most of the scientist has synthesized and investigated some of novel thiophene derivatives for the anticancer activity carrying the biologically active sulfonamide, isoxazole, benzothiazole, quinoline and anthracene moieties [2527].

Ghorab et al. [28] developed a novel series of thiophenes derivatives having biologically active sulfonamide, isoxazole, benzothiazole, quinoline and anthracene moieties as presented in Scheme 12. The synthesized compounds were evaluated for in vitro anticancer activity against human breast cancer cell line (MCF7). Many of them showed cytotoxic activities compared to doxorubicin as a positive control. Among this series, (Z)-4-(3-oxo-3-(thiophen-2-yl)prop-1-enylamino)-N-(thiazol-2-yl)benzenesulfonamide (59), (Z)-4-(3-oxo-3-(thio-phen-2-yl)prop-1-enylamino)-N-(1-phenyl-1H-pyrazol-5-yl)benzenesulfonamide (60), (Z)-4-(3-oxo-3-(thiophen-2-yl)prop-1-enylamino)-N-(pyrimidin-2-yl)benzenesulfonamide (61) and (Z)-3-(4 methoxybenzo[d]thiazol-2-ylamino)-1-(thiophen-2-yl)prop-2-en-1-one (62) having IC50 values 10.25, 9.70, 9.55 and 9.39 μmol/l, respectively revealed a promising anti-breast cancer activity than that of doxorubicin with IC50 = 32.00 μmol/l. It was mainly due to the thiophene nucleus containing biologically active sulfathiazole 59, sulfaphenazole 60, sulfadiazine 61, or benzothiazole 62 moieties. The results of synthesized compounds showed in Table 13.
Scheme 12
Scheme 12

Synthesis of thiophenes having the biologically active sulfonamide (5961) 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

aMean ± S.E, n = 3

Gaunda et al. [29] synthesized some new derivatives of 3-[(2-substituted-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[2,3-d]pyrimidin-4-yl)amino]propan-1-ol derivatives (Scheme 13). The in vitro cytotoxicity activity of synthesized compounds were screened against both the cell lines (HC 29-Colorectal adenoma cell line and MDA 231-adenocarcinoma breast cancer cell line) by MTT assay and analyzed statistically. Among this series, the compound 69c had shown better anticancer activity at all concentrations on both the cell lines followed by compound 69a, 69b. It was due to the phenyl substitution (69c) which has shown better anticancer activity. However, all the synthesized compounds showed considerable anticancer activity as compared to cyclophosphamide. The results of synthesized compounds presented in Table 14.
Scheme 13
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

Table 14

Anticancer activity of the title compounds (69a69c)

Compound code

Concentration (μmol)

Percentage inhibition of cell growth

HC 29-colorectal adenoma cell line (%)

MDA 231-adenocarcinoma breast cancer cell line (%)

69a

0.03

32.39

31.18

0.07

31.43

29.35

0.17

27.96

24.47

69b

0.03

30.73

24.94

0.07

27.94

25.79

0.17

25.27

26.41

69c

0.03

34.52

33.68

0.07

32.83

30.72

0.17

28.45

25.35

Mohareb et al. [30] developed a convenient synthetic approach for novel thiophene and benzothiophene derivatives (Scheme 14). The in vitro cytotoxicity was screened against three tumor cell lines–MCF-7 (breast adenocarcinoma), NCI-H460 (non-small cell lung cancer) and SF-268 (CNS cancer) and a normal fibroblast human cell line (WI-38) compared to the anti-proliferative effects of the reference control doxorubicin. Among the series, ethyl-5-amino-3-(4-chlorostyryl)-4-cyanothiophene-2-carboxylate (74), ethyl 5-amino-4-[(4-methoxyphenyl)carbamoyl]-3-methylthiophene-2-carboxylate (76b) and ethyl 5-(3-ethoxy-3-oxopropanamido)-3-methyl-4-(phenylcarbamoyl)thiophene-2-carboxylate (77) were found to be the most active compounds against the three tumor cell lines such as MCF-7, NCI-H460 and SF-268 where as they showed low potency against the normal fibroblasts human cell line (WI-38). It was revealed that higher cytotoxicity activity of compound 74 was due to the presence of the chloro group, OCH3 group in compound 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 hydrophobic groups in the thiophene derivatives might play a very important role in enhancing the cytotoxic effect. The results of synthesized compounds presented in Table 15.
Scheme 14
Scheme 14

a Synthesis of various derivatives of thiophene, b Synthesis of various benzothiophene derivatives

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

aDrug 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

Sharkawy et al. [31] synthesized a series of thiophene incorporating pyrazolone moieties via diazo coupling of diazonium salt of 3-substituted-2-amino-4,5,6,7-tetrahydrobenzo[b]thiophenes with 3-methyl-1H-pyrazol-5(4H)-one, 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one or 3-amino-1H-pyrazol-5(4H)-one, respectively as represented in Scheme 15. Newly synthesized derivatives were tested for cytotoxicity against the well known established model ehrlich ascites carcinoma cells (EAC) in vitro. The results showed clearly that compounds 80ac exhibited high cytotoxic activity than 5-fluorouracil which may be due to the presence of amino group in position 3 of the pyrazol-5-one moiety. Further, the order of antitumor activity of this series of synthesized compounds follows 80c < 80b < 80a which may be due to replacement of CONH2 by CN or COOC2H5 groups of benzothiophene ring in position 3. The results of synthesized compounds showed in Table 16.
Scheme 15
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

Compound no

% Dead

100 µg/ml (%)

500 µg/ml (%)

25 µg/ml (%)

5-Fluorouracil

97.3

68

38.6

80a

100

98.6

94

80b

98.4

81

65

80c

98.1

79

60

The % dead refers to the % of the dead tumor cells

Seley et al. [32] synthesized tricyclic thieno-separated purine analogues using Scheme 16. These synthesized derivatives were screened for their cytotoxic activity against HCT116 colorectal cancer cell lines. In this series, compound 83 showed potent cytotoxic activity against cancer cell lines. It was due to the coupling of compound 83 to a ribo-sugar to create the thieno-separated nucleosides may increase the growth inhibitory properties of these analogues. The results of synthesized compounds presented in Table 17.
Scheme 16
Scheme 16

Synthesis of 6-Aminoimidazo[4′,5′:4,5]thieno[3,2-d]pyrimidine

Table 17

Tricyclic compound-induced inhibition of HCT116 growth

Time (h)

Compd

0.1 µM

1 µM

10 µM

100 µM

24

83

96.1 ± 3.8

106.6 ± 4.8

104.8 ± 3.8

82.0 ± 7.8

48

83

105.1 ± 3.3

98.3 ± 4.3

105.0 ± 2.1

71.5 ± 3.8b

72

83

101.3 ± 7.3

96.1 ± 6.6

93.8 ± 12.1

51.5 ± 10.7a

HCT116 cells were treated and growth was assessed. Data represent the average (SEM as a % of control-treated (DMSO) cells (n = 3–5)

ap < 0.05

bp < 0.005 when compared to control-treated cells

Mohareb et al. [33] synthesized novel heterocyclic compounds from 2-cyano-N-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-acetamide as presented in Scheme 17. The tumor cell growth inhibition activities of the newly synthesized thiophene systems were assessed in vitro on three human tumor cell lines, namely, MCF-7 (breast adenocarcinoma), NCI-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 reference control doxorubicin. In this series, compounds 89, 86, 88, 85, and 87 showed significant activity on the three tumor cell lines tested. The results of synthesized compounds showed in Table 18.
Scheme 17
Scheme 17

Synthesis ofsubstituted-1-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl) derivatives

Table 18

Antiproliferative activity GI50 (μM) of the synthesized compounds

Compound

GI50 (μM)a

MCF-7

NCI-H460

SF-268

85

10.8 ± 0.6

16.5 ± 0.8

16.7 ± 1.6

86

2.5 ± 0.5

10.4 ± 0.6

8.0 ± 0.4

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

Doxorubicin

0.0428 ± 0.0082

0.0940 ± 0.0087

0.0940 ± 0.0070

aDrug concentration required to inhibit tumor cell proliferation by 50% after continuous exposure of 48 h. Doxorubicin was used as positive control

Antioxidant activities

Madhavi et al. [34] developed a novel class of substituted 2-(2-cyanoacetamido)thiophenes by cyanoacetylation of substituted 2-aminothiophene by using an effective cyanoacetylating agent, 1-cyanoacetyl-3,5-dimethylpyrazole as presented in Scheme 18. All the synthesized compounds were evaluated for in vitro antioxidant activity by scavenging 1,1-diphenyl-2-picrylhydrazyl (DPPH) and nitric oxide free radicals at 100 μM concentration. Among these evaluated compounds, 2-(2-cyanoacetamido)-4,5-dimethylthiophene-3-carboxamide (Compound 92a) was found to possess highest anti-oxidant activity in both models of free radical scavenging. However in case of assay with nitric oxide free radical scavenging, the highest activity was exhibited by 2-(2-cyanoacetamido)-4,5-dimethylthiophene-3-carboxamide (Compound 92a, 56.9%) and 2-(2-cyanoacetamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (Compound 92b, 55.5%). The greater activity of these compounds were attributed due to the polar nature of carboxamide or nitrile group at 3rd position on thiophene ring. The results of synthesized compounds presented in Tables 19 and 20.
Scheme 18
Scheme 18

Synthesis of substituted 2-aminothiophene

Table 19

Reduction of DPPH by substituted 2-(2-cyanoacetamido) thiophenes

Compound

R1, R2

R3

% Inhibition at 100 μM

92a

–CH3

–CONH2

52.4

Ascorbic acid

  

64.7

Table 20

Effect of substituted 2-(2-cyanoacetamido)thiophenes on scavenging of nitric oxide

Compound

R1, R2

R3

% Inhibition at 100 μM

92a

–CH3

–CONH2

56.9

92b

–(CH2)4

–CONH2

55.5

Anti-inflammatory activity

Bahashwan et al. [35] synthesized new series of fused triazolo- and tetrazolopyrimidine derivatives (Scheme 19) and their anti-inflammatory activity was evaluated. Newly synthesized thienopyrimidine derivatives were screened for anti-inflammatory activity (percent inhibition of edema obtained by the reference drug and tested compounds, respectively) in comparison to that of indomethacin. Among the series, compounds 94, 95, 96, 97 and 98 possess strong anti-inflammatory activity. The high anti-inflammatory activity was mainly due to the presence of electron-donating moieties which increase the pharmacological activity. The order of anti-inflammatory properties with the substitution of electron–donating group in pyrimidine derivatives follows as: hydrazine > methyl > cyanomethyl > tetrazine > amide as exhibited in compounds 94 > 98 > 95 > 96 > 97, respectively. The results of synthesized compounds presented in Table 21.
Scheme 19
Scheme 19

Synthesis of thienotriazolopyrimidine derivatives

Table 21

Anti-inflammatory activity of the synthesized compounds

Compounds

Edema inhibition (means ± E.M)a,b (%)

1 h

2 h

3 h

94

42.3 ± 1.1

49.2 ± 1.2

57.1 ± 1.4

95

37.2 ± 1.3

46.3 ± 1.5

54.4 ± 1.1

96

34.5 ± 1.2

35.1 ± 1.5

48.2 ± 1.2

97

31.2 ± 1.2

35.1 ± 1.5

40.2 ± 1.6

98

39.1 ± 1.5

48.4 ± 1.2

55.6 ± 1.1

Indomethacin

44.7 ± 1.2

52.4 ± 1.2

61.2 ± 1.3

aDose 5 mg/kg b.m (p.o.)

b n = 6

Ouf et al. [36] synthesized hydrazones derivatives which shows significant anti-inflammatory activities as presented in Scheme 20. The synthesized compounds were screened against the standard drug flurbiprofen. Among the synthesized hydrazones, the substituted 4-methoxy- 100a, 4-chloro- 100b and 4-nitro-derivatives 100c have anti-inflammatory activities higher than that of hydrazone with an unsubstituted benzaldehyde group against the standard drug flurbiprofen. Thus, the lipophilicity plays an important role for the potent anti-inflammatory activity. The results of synthesized compounds presented in Table 22.
Scheme 20
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 (% reduction in edema induced by yeast)

Compound

Post treatment 3 h = %

Post treatment 6 h = %

100a

26.6

34.4

100b

17.2

30.0

100c

24.2

34.2

Hafez et al. [37] synthesized some of the novel benzothino-pyrimidine derivatives (Scheme 21) which showed considerable potent anti-inflammatory activity. The anti-inflammatory activity of the newly synthesized compounds were evaluated by applying carrageenan-induced paw edema bioassay in rats using indomethacin as a reference standard. Compounds 105, 106, 107, 108 and 109 caused significant decreases in paw edema after 2, 3, 4 h after drug administration. Thus, it can be concluded that spirobenzothienopyrimidine moiety, phenylpyrazolothinopyrimidine, morphonyl and piperazinylthinopyrimidine ring systems are important for anti-inflammatory activity. The results of synthesized compounds presented in Table 23.
Scheme 21
Scheme 21

Synthesis of phenylpyrazolothinopyrimidine, morphonyl and piperazinylthinopyrimidine derivatives

Table 23

Anti-inflammatory effect of synthesized compounds

Compd. no.

Oedema volume

1 h

2 h

3 h

4 h

105

49.4 ± 7.1

71.8 ± 6.7a

76.4 ± 4.8a

82.2 ± 5.2

106

44.2 ± 5.1

59.6 ± 4.7a

67.8 ± 3.3a

81.9 ± 3.2

107

61.0 ± 6.6

66.6 ± 5.9a

68.6 ± 7.0a

72.4 ± 7.4

108

66.4 ± 7.5

78.2 ± 3.5a

81.3 ± 3.3

87.1 ± 2.1

109

56.2 ± 9.9

65.1 ± 7.5a

55.9 ± 10.6a

54.7 ± 7.2a

Indomethacin

49.8 ± 5.3

42.9 ± 5.1a

45.9 ± 4.6a

46.9 ± 5.8a

ap < 0.05: Statistically significant from the control using one way ANOVA (Two-sided Dunnett as Post Hoc test)

Antiurease activity

Rasool et al. [38] synthesized variety of novel 5-aryl thiophenes derivatives containing sulphonylacetamide (sulfacetamide) using Scheme 22. The synthesized compounds were screened for their anti-urease activities by taking thiourea as standard drug. Among all the synthesized derivatives, compound 112, N-((5′-methyl-[2,2′-bithiophen]-5-yl)sulfonyl)acetamide, showed excellent urease inhibition activity at 40 µg/ml and 80 µg/ml concentrations where the percentage inhibition values were found to be 92.12 ± 0.21 and 94.66 ± 0.11, respectively with an IC50 value ~ 17.1 ± 0.15 µg/ml. It is further concluded that the urease inhibitory activity of compound might be due to the presence of the electronic and steric effects of functional groups. The results of synthesized compounds are presented in Table 24.
Scheme 22
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

Anticonvulsant activity

Dashyan et al. [39] synthesized 2,4-disubstituted pyr ano[4′′,3′′:4′,5′]pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidines derivatives by using Scheme 23. The synthesized compounds were screened for the anticonvulsant activity of by taking the comparator drug, diazepam which was performed using male albino mice weighing 18–24 g (200 animals) and rats (Wistar) weighing 120–140 g (40 animals of both sexes).
Scheme 23
Scheme 23

Synthesis of 2,4-Disubstituted pyrano[4′,3′:4,5]pyrido[2,3-b]thieno[3,2-d]pyrimidine derivatives

The anticonvulsant activity of the compounds was assessed by the prevention of clonic twitches and the clonic component of convulsions caused by subcutaneous administration of 90 mg/kg metrazol in mice. When studying anticonvulsant activity, it was found that the compounds (114a, b, c) and (115a, b, c, d, e) caused a marked protective anticonvulsive effect, which developed in mice starting with a dose of 25 mg/kg, while statistically calculated dose (ED50) ranged from 23 to 56 mg/kg (Table 25).
Table 25

Activity against metrazol convulsions for the compounds (114a, b, c), (115a, b, c, d, e), and diazepam

Compound

Activity against metrazol convulsions* (ED50, mg/kg)

114a

56.0 (36.0–100.8)

114b

40.0 (23.5–68.0)

114c

23.0 (15.9–33.1)

115a

40.0 (23.5–68.0)

115b

56.0 (36.0–100.8)

115c

34.0 (25.3–45.7)

115d

40.0 (23.5–68.0)

115e

56.0 (36.0–100.8)

Diazepam

0.51 (0.39–0.69)

* Probability levels at p = 0.05 are indicated in brackets

Antithrombotic activity

Jubair et al. [40] synthesized novel series of 2-(bromomethyl)-5-aryl-thiophenes derivatives via Suzuki cross-coupling reactions of various aryl boronic acids with 2-bromo-5 (bromomethyl)thiophene as given in Scheme 24. The synthesized compounds were screened for their antithrombolytic activity. All the Compounds (100 μL) having concentration of 1 mg/ml were added to the micro-centrifuge tubes containing venous blood, and incubated at 37 °C for 45 min. Streptokinase was used as standard clot lysis agent and water as negative control for this assay. Among all the synthesized compounds, 118 showed potent clot lysis (31.5%). However, the results were significant p < 0.05, when compared with streptokinase. Clot lysis activity results are presented in Table 26.
Scheme 24
Scheme 24

Synthesis of 2-(Bromomethyl)-5-(3,5-dimethylphenyl)thiophene

Table 26

Percentage efficiency of Clot lysis of synthetic compounds

Compounds

Clot lysis %

118

31.5 ± 0.45

Water

0.43 ± 0.005

Streptokinase

87.2 ± 0.95

The results are average ± S.D of triplicate experiments p < 0.05

Conclusion

The analytical and other informational data, available in literature so far, have reveals that thiophene and its derivatives represent an important class of compounds in the medicinal field with various therapeutic potentials, i.e., antimalarial, antimicrobial, antimycobacterial, antidepressant, anticonvulsant, antiviral, anticancer, antihypertensive, anti-inflammatory and antioxidant. Appraisal of literature reports reveals that thiophene moiety have hiked a great deal of interests of medicinal chemist and biochemist to plan, organize and implement new approaches towards discovery of novel drugs.

This particular review article, established the fact that thiophene derivatives could be a rich source of potential entities in search of new generation of biologically active compounds and be worthwhile to explore the possibility in this area by fusing differently substituted moieties which may result in better pharmacological activities. Thus the quest to explore many more modifications on thiophene moiety needs to be continued.

Declarations

Authors’ contributions

PKV designed and finalized the scheme; RS performed review work and wrote the paper. Both authors read and approved the final manuscript.

Acknowledgements

Thanks to Head, Department of Pharmaceutical Sciences, MD. University, Rohtak for kind support for providing internet facilities etc.

Competing interests

The authors declare that they have no competing interests.

Ethics approval and consent to participate

Not applicable.

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Authors’ Affiliations

(1)
Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak, Haryana, 124001, India

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