Chemistry Central Journal

, 12:38 | Cite as

Therapeutic potential of heterocyclic pyrimidine scaffolds

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Review
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  1. Organic and Medicinal Chemistry

Abstract

Heterocyclic compounds offer a high degree of structural diversity and have proven to be broadly and economically useful as therapeutic agents. Comprehensive research on diverse therapeutic potentials of heterocycles compounds has confirmed their immense significance in the pathophysiology of diseases. Heterocyclic pyrimidine nucleus, which is an essential base component of the genetic material of deoxyribonucleic acid, demonstrated various biological activities. The present review article aims to review the work reported on therapeutic potentials of pyrimidine scaffolds which are valuable for medical applications during new generation.

Keywords

Pyrimidine derivatives Antimicrobial Antioxidant Antimalarial Anticancer Anti-inflammatory 

Introduction

Pyrimidine is the six membered heterocyclic organic colorless compound containing two nitrogen atoms at 1st and 3rd positions (Fig. 1). The name of the pyrimidine was first applied by Pinner from the combination of two words pyridine and amidine). Pyrimidines(1,3-diazines) and their fused analogues form a large group of heterocyclic compounds. Pyrimidine which is an integral part of DNA and RNA imparts diverse pharmacological properties. The pyrimidine have been isolated from the nucleic acid hydrolyses and much weaker base than pyridine and soluble in water [1]. Pyrimidine and its derivatives have been described with a wide range of biological potential i.e. anticancer [2], antiviral [3], antimicrobial [4], anti-inflammatory [5], analgesic [6], antioxidant [7] and antimalarial [8] etc.
Fig. 1

Pyrimidine ring

Biological significance of pyrimidine scaffolds

Antimicrobial activity

The growing health problems demands for a search and synthesis of a new class of antimicrobial molecules which are effective against pathogenic microorganisms. Despite advances in antibacterial and antifungal therapies, many problems remain to be solved for most antimicrobial drugs available. The extensive use of antibiotics has led to the appearance of multidrug resistant microbial pathogens which necessitated the search for new chemical entities for treatment of microbial infections [9].

Anupama et al. synthesized a series of 2,4,6-trisubstituted pyrimidines by reacting chalcone with guanidine hydrochloride. All the synthesized derivatives were confirmed by physicochemical properties and spectral data (IR, NMR and elemental analyses) and screened their in vitro antimicrobial activity against bacterial and fungal strains by cup plate method using Mueller–Hinton agar medium. Among the derivatives tested, compounds, a1, a2 and a3 exhibited promising activity against microbial strains (B. pumilis, B. subtilis, E. coli, P. vulgaris. A. niger and P. crysogenium) and showed activity comparable with standard drugs. Structure activity relationship (SAR) studies indicated that compounds, a1, a2 and a3 having dimethylamino, dichlorophenyl and fluorine substituent on the phenyl ring at 4th position respectively exhibited better antimicrobial activity (Table 1, Fig. 2) [4].
Table 1

Antimicrobial activity of compounds (a1a3)

Compounds

Zone of inhibition (in mm)

Microbial species

B. subtilis

B. pumilis

E. coli

P. vulgaris

A. niger

P. crysogenium

a1

 A

15

12

11

12

11

12

 B

20

14

20

18

13

14

a2

 A

16

13

12

15

16

15

 B

20

15

21

21

18

18

a3

 A

17

14

13

14

15

14

 B

20

15

21

20

17

17

C

S

 A

25

29

26

28

23

24

 B

30

31

29

31

28

27

A: 0.05 ml (50 μg); B: 0.1 ml (100 μg); C: control (DMSO); S: standard (benzyl penicillin for bacterial strains) and fluconazole for fungal strains

Fig. 2

Chemical structure of the most active antimicrobial pyrimidine derivatives (a1a12)

Chen et al. synthesized a novel series of 4-substituted-2-{[(1H-benzo[d]imidazol-2-yl) methyl]thio}-6-methylpyrimidines from pyrimidine–benzimidazole combination. All the synthesized derivatives were fully characterized by 1H-NMR, 13C-NMR and HRMS study and screened its in vitro antimicrobial activity against Gram-positive bacteria (Staphylococcus aureus, Bacillus subtilis), Gram-negative bacteria (Escherichia coli, Stenotrophomonas maltophilia) and fungi (Candida albicans). The minimum inhibitory concentration (MIC) of the target compounds was determined by broth microdilution method and compared to two commercial antibiotics (levofloxacin and fluconazole). Among the entire synthesized derivatives, compounds, a4 and a5 were found to be the most active antimicrobial agents (Table 2, Fig. 2). Structure activity relationship showed that aromatic amines at pyrimidine ring are beneficial for the antimicrobial activity. Besides, the aniline containing para-substituted groups (especially Cl and Br) is more beneficial for the activity [10].
Table 2

Antimicrobial activity (MIC = µg/ml) of compounds a4 and a5

Compounds

Bacterial strains

Fungal strain

Staphylococcus aureus

Bacillus subtilis

Escherichia coli

Stenotrophomonas maltophilia

Candida albicans

a4

8

128

128

2

64

a5

16

128

128

4

8

Levofloxacin

0.5

0.25

0.125

0.25

Fluconazole

2

El-Gaby et al. developed a new class of pyrrolo[2,3-d]pyrimidines containing sulfonamide moieties and screened its in vitro antifungal activity against four species of fungi viz: Aspergillus ochraceus (Wilhelm), Penicillium chrysogenum (Thom), Aspergillus fleavus (Link) and Candida albicans (Robin) Berkho by disc diffusion technique. Most of the synthesized molecules in this series were found to possess antifungal activity (Table 3, Fig. 2) towards all the microorganisms’ used especially, compound a6 exhibited a remarkable antifungal activity which is comparable to the standard fungicide drug mycostatin [11].
Table 3

Antifungal activity of synthesized compound a6

Compound

Zone of inhibition (mm)

Fungal species

A. ochraceus (AUCC-230)

P. chrysogenum (AUCC-530)

A. fleavus (AUCC-164)

C. albicans (AUCC-1720)

a6

18 (45%)

14 (37%)

16 (42%)

34 (85%)

Mycostatine

40 (100)

38 (100%)

38 (100%)

40 (100%)

Hilmy et al. developed a new series of pyrrolo[2,3-d]pyrimidine derivatives. The synthesized compounds were confirmed by IR, NMR, Mass and elemental analysis study and evaluated its antimicrobial activity against bacterial (Staphylococcus aureus, Escherichia coli) and fungal (Candida albicans) organisms was carried out by serial dilution method. All synthesized derivatives showed that good antimicrobial activity, especially, compounds, a7, a8, a9 were exhibited the better antimicrobial activity and compared with the standard drug (ampicillin and fluconazole) (Table 4, Fig. 2) [12].
Table 4

The MIC (mg/ml) value of the compounds a7, a8 and a9 tested against organisms

Compounds

Antimicrobial results (MIC = mg/ml)

Escherichia coli

Staphylococcus aureus

Candida albicans

a7

1.25

0.31

0.31

a8

1.25

0.31

0.62

a9

1.25

0.31

0.31

Ampicillin

1.25

0.62

Fluconazole

1.5

Holla et al. developed a new class of pyrazolo[3,4-d]pyrimidine derivatives. The synthesized derivatives were analyzed for N content and their structures were confirmed by IR, NMR and Mass spectral data and screened their antibacterial activity against Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa and Bacillus subtilis by disk diffusion method and antifungal activity against Aspergillus flavus, Aspergillus fumigates, Candida albicans, Penicillium marneffei and Trichophyton mentagrophytes by serial plate dilution method. All synthesized pyrazolo[3,4-d]pyrimidine derivatives in this series showed that good antimicrobial and fungal activity against bacterial and fungal strains, especially compounds, a10 displayed very good antibacterial activity (Table 5, Fig. 2) and a11 exhibited antifungal activity (Table 6, Fig. 2) [13].
Table 5

Antibacterial activity data of compound a10

Compound

Zone of inhibition (mm) of bacterial species

Escherichia coli

Staphylococcus aureus

Pseudomonas aeruginosa

Bacillus subtilis (recultured)

a10

28

25

24

26

Streptomycin

20

21

24

24

Table 6

Antifungal activity data of prepared compound a11

Compound

Zone of inhibition (mm) of fungal species

Aspergillus flavus

Aspergillus fumigatus

Trichophyton mentagrophytes (recultured)

a11

25

22

24

Fluconazole

21

18

19

Mallikarjunaswamy et al. synthesized a series of novel 2-(5-bromo-2-chloro-pyrimidin-4-ylsulfanyl)-4-methoxy-phenylamine derivatives by the reaction of 2-(5-bromo-2-chloro-pyrimidin-4-ylsulfanyl)-4-methoxy-phenylamine with various sulfonyl chlorides and its molecular structures were characterized by elemental analyses, FT-IR, 1H-NMR and LC–MS spectral studies and screened in vitro antimicrobial activity against Gram-positive bacteria (Bacillus subtilis, Staphylococcus aureus) and Gram-negative bacteria (Xanthomonas campestris and Escherichia coli) in dimethylformamide by disc diffusion method on nutrient agar medium and antifungal activity against Fusarium oxysporum in dimethylformamide by poisoned food technique. Among them, compound a12 was found to be most potent against fungal strain (Fusarium oxysporum) and bacterial strains (Bacillus subtilis, Staphylococcus aureus, Xanthomonas campestris and Escherichia coli) and compared with standard antimicrobial drugs (Table 7, Fig. 2) [9].
Table 7

In vitro antibacterial and antifungal activities of compound a12

Compound

Zone of inhibition in diameter (mm) % inhibition

Microbial species

B. subtilis

S. aureus

X. campestris

E. coli

F. oxysporum

a12

33

29

32

33

96.9

Bacteriomycin

34

Gentamycin

35

30

35

Nystatin

    

100

A new series of 1,2,4-triazolo[1,5-a]pyrimidine derivatives bearing 1,3,4-oxadiazole moieties was designed and synthesized by Chen et al. The molecular structures of all new compounds were characterized by spectral means (1H-NMR, Mass and elemental analyses) and evaluated their in vitro antifungal activity against Rhizoctonia solani. In this series, compounds, a13 and a14 displayed the highest antifungal activity against Rhizoctonia solani with EC50 = 3.34 µg/ml and EC50 = 6.57 µg/ml values respectively than the carbendazim (EC50 = 7.62 µg/ml) due to presence of the sec-butyl group (Fig. 3) [14].
Fig. 3

Chemical structure of the most active antimicrobial pyrimidine derivatives (a13a21)

A new library of 5-amino-6-(benzo[d]thiazol-2-yl)-2-(2-(substituted benzylidene) hydrazinyl)-7-(4-chlorophenyl)pyrido[2,3-d]pyrimidin-4(3H)-one derivatives was synthesized by Maddila et al. and evaluated its antibacterial activity against Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Streptococcus pyogenes and antifungal activity against Aspergillus flavus, Aspergillus fumigatus, Candida albicans, Penicillium marneffei and Mucor by the twofold serial dilution method. Compounds, a15, a16 and a17 showed excellent antibacterial and antifungal activity than the standard drugs ciprofloxacin and clotrimazole respectively (Tables 8, 9, Fig. 3) [15].
Table 8

Antibacterial activity results of compounds (a15a17)

Compounds

Minimum inhibitory concentration (MIC = µg/ml)

Bacterial species

S. aureus

E. coli

K. pneumoniae

P. aeruginosa

S. pyogenes

a15

12.5

25

25

25

12.5

a16

12.5

12.5

12.5

12.5

12.5

a17

25

12.5

12.5

25

12.5

Ciprofloxacin

25

25

50

25

12.5

Table 9

Antifungal activity results of compounds (a15a17)

Compounds

Minimum inhibitory concentration (MIC = µg/ml)

Fungal species

A. flavus

A. fumigatus

C. albicans

P. marneffei

Mucor

a15

12.5

12.5

25

25

12.5

a16

12.5

12.5

12.5

12.5

12.5

a17

25

12.5

25

12.5

25

Clotrimazole

25

25

50

25

50

Fellahil et al. synthesized a new series of 5-(1,2-diarylethyl)-2,4,6-trichloro pyrimidines and 2-amino- and 2-(1-piperazinyl)-5-(1,2-diarylethyl)-4,6-dichloro pyrimidines via organozinc reagents and demonstrated its antibacterial activity against human bacterial flora. Biological tests showed that 5-[1-(4-chlorophenyl)-2-phenylethyl]-2,4,6-trichloro pyrimidine derivatives i.e. compounds a18 and a19 were found to be most active against wide range of bacterial flora of the axilla and foot, while 2-(1-piperazinyl)-4,6-dichloro pyrimidine derivatives a20 and a21 displayed a great selectivity against Corynebacterium xerosis and Arcanobacterium haemolyticum of the human axilla (Table 10, Fig. 3) [16].
Table 10

Pharmacological evaluation (MIC = µg/ml) of the 2-substituted 5-(1,2-diarylethyl)-4,6-dichloropyrimidines

 

a18

a19

a20

a21

Axillary bacterial flora

 Staphylococcus xylosus

20

100

100

100

 Staphylococcus epidermidis

100

100

100

75

 Staphylococcus haemolyticus

100

100

100

50

 Corynebacterium xerosis

20

30

30

30

 Micrococcus luteus

20

100

100

100

 Arcanobacterium haemolyticum

10

10

10

10

Foot bacterial flora

 Staphylococcus epidermidis

> 100

100

100

75

 Staphylococcus hominis

100

100

100

75

 Staphylococcus cohnii

100

100

100

75

 Corynebacterium sp. g C

100

100

100

75

 Corynebacterium sp. g B

30

100

100

50

 Corynebacterium sp. g D2

30

100

50

50

 Micrococcus luteus

20

100

100

75

 Micrococcus sedentarius

30

100

100

75

 Acinetobacter sp.

> 1000

> 500

50

30

 Moraxella sp.

300

30

100

50

 Alcaligenes sp.

1000

> 500

> 500

> 500

Nagender et al. developed a new series of novel pyrazolo[3,4-b]pyridine and pyrimidine functionalized 1,2,3-triazole derivatives using 6-trifluoro methylpyridine-2(1H) one and screened its antimicrobial activity against i.e. Micrococcus luteus MTCC 2470, Staphylococcus aureus MTCC 96, Staphylococcus aureus MLS-16 MTCC 2940, Bacillus subtilis MTCC 121, Escherichia coli MTCC 739, Pseudomonas aeruginosa MTCC 2453, Klebsiella planticola MTCC 530 and Candida albicans MTCC 3017. In this series, compounds, a22, a23 and a24 were displayed better antimicrobial activity but less than the standard drugs (ciprofloxacin) (Table 11, Fig. 4) [17].
Table 11

MIC values of the compounds a22, a23 and a24

Compounds

Minimum inhibitory concentration (µg/ml)

M. luteus

S. aureus

S. aureus

B. subtilis

E. coli

P. aeruginosa

K. planticola

a22

7.8

15.6

15.6

15.6

7.8

7.8

15.6

a23

> 250

15.6

7.8

15.6

15.6

15.6

7.8

a24

15.6

7.8

7.8

15.6

7.8

7.8

7.8

Ciprofloxacin

0.9

0.9

0.9

0.9

0.9

0.9

0.9

Fig. 4

Chemical structure of the most active antimicrobial pyrimidine derivatives (a22a30)

Patel et al. synthesized a new series of pyrimidine derivatives and demonstrated its antimicrobial activity (Minimum inhibitory concentration) against four different strains, viz two Gram positive bacteria (S. aureus and S. pyogenes) and two Gram negative bacteria and (E. coli and P. aeruginosa) compared it with standard drugs ampicillin, chloramphenicol, ciprofloxacin and norfloxacin and antifungal activities against C. albicans and A. niger using nystatin as standard drug by broth dilution method, compounds, a25 and a26 were showed promising antimicrobial activity (Table 12, Fig. 4) [18].
Table 12

Antimicrobial activity of compounds a25 and a26

Compounds

Microbial strains (µg/ml)

E. coli

P. aeruginosa

S. aureus

S. pyogenus

C. albicans

A. niger

a25

62.5

200

100

100

200

250

a26

25

50

100

50

500

250

Chloramphenicol

50

50

50

50

Ciprofloxacin

25

25

50

50

Norfloxacin

10

10

10

10

Nystatin

    

100

100

A new library of pyrazolo[3,4-d]pyrimidine derivatives was synthesized by Rostamizadeh et al. and screened for its antibacterial activity against two Gram-negative strains of bacteria: Pseudomonas aeruginosa and Klebsiella pneumonia and two Gram-positive bacteria: Staphylococcus aureus and Enterococcus raffinosus L. Amongst the tested compounds, compounds a27 and a28 exhibited higher antibacterial activity than the standard drugs (Table 13, Fig. 4) [19].
Table 13

Antibacterial activity of some novel pyrazolopyrimidine derivatives

Compounds

MIC (µmol/l)

Enterococcus raffinosus

Staphylococcus aureus

a27

12.3

3.8

a28

14.2

4.2

Penicillin G

93.5

24.4

Sriharsha et al. developed a new series of novel 1,3-thiazolidine pyrimidine derivatives and carried out its antibacterial activity against 14 bacterial strains i.e. Citrobacter sp., Escherichia coli, Klebsiella sp., Proteus mirabilis, Pseudomonas aeruginosa, S. parathyphi A, S. parathyphi B, Salmonella typhi, S. typhimurium, Shigella boydii, Shigella flexneri, Shigella sonnei, Staphylococcus aureus and Streptococcus faecalis. All compounds with free NH group in the pyrimidine moiety showed significant biological activity against all the standard strains used and in that compounds a29 and a30 showed promising activity against 14 human pathogens tested and compared with the ciprofloxacin and bacitracin used as standard drugs (Table 14, Fig. 4) [20].
Table 14

Antibacterial activity (zone of inhibition = mm) of most active compounds

S. no

Pathogens

a29

a30

Bacitracin

Ciprofloxacin

1

Citrobacter sp.

37.16 ± 0.15

28.66 ± 0.15

0.00 ± 0.00

19.62 ± 0.18

2

Escherichia coli

36.66 ± 0.15

27.83 ± 0.20

0.00 ± 0.00

0.00 ± 0.00

3

Klebsiella sp.

32.50 ± 0.13

25.50 ± 0.27

0.00 ± 0.00

20.25 ± 0.16

4

Proteus mirabilis

28.66 ± 0.25

23.33 ± 0.17

0.00 ± 0.00

18.25 ± 0.16

5

Pseudomonas aeruginosa

30.66 ± 0.12

27.83 ± 0.27

0.00 ± 0.00

34.25 ± 0.16

6

S. parathyphi A

34.66 ± 0.12

24.50 ± 0.12

0.00 ± 0.00

27.75 ± 0.16

7

S. parathyphi B

32.50 ± 0.13

27.83 ± 0.20

0.00 ± 0.00

27.63 ± 0.18

8

Salmonella typhi

29.50 ± 0.25

19.66 ± 0.11

0.00 ± 0.00

20.25 ± 0.16

9

S. typhimurium

34.66 ± 0.12

23.33 ± 0.17

0.00 ± 0.00

18.75 ± 0.31

10

Shigella boydii

37.50 ± 0.07

28.66 ± 0.25

0.00 ± 0.00

17.75 ± 0.16

11

Shigella flexneri

35.66 ± 0.08

25.50 ± 0.27

0.00 ± 0.00

27.63 ± 0.18

12

Shigella sonnei

32.50 ± 0.13

37.50 ± 0.07

0.00 ± 0.00

21.75 ± 0.16

13

Staphylococcus aureus

37.50 ± 0.07

32.50 ± 0.13

26.75 ± 0.84

18.13 ± 0.48

14

Streptococcus faecalis

38.50 ± 0.12

35.66 ± 0.08

0.00 ± 0.00

0.00 ± 0.00

Anticancer activity

Cancer is a multifaceted disease that represents one of the leading causes of mortality in developed countries. Worldwide, one in eight deaths are due to cancer and it is the second most common cause of death in the US, exceeded only by heart disease. Chemotherapy is the mainstay for cancer treatment, the use of available chemotherapeutics is often limited due to undesirable side effects. It is important to identify new molecules and new targets for the treatment of cancer [17].

Shao et al. synthesized a new derivatives of 2,4,5-trisubstituted pyrimidine CDK inhibitors as potential antitumour agents. The synthesized 2,4,5-trisubstituted pyrimidine derivatives were evaluated for their antitumour activity against a panel of cancer cell lines including colorectal, breast, lung, ovarian, cervical and pancreatic cancer cells. Among the synthesized derivatives, compound b1, possessing appreciable selectivity for CDK9 over other CDKs, is capable of activating caspase 3, reducing the level of Mcl-1 anti-apoptotic protein and inducing cancer cell apoptosis (Table 15, Fig. 5) [21].
Table 15

Anti-proliferative activity of b1 in human cancer cell lines

Compound

Human cancer cell lines

Origin

Designation

48 h-MTT GI50 (µM) ± SD

b1

Colon carcinoma

HCT-116

0.79 ± 0.08

Breast carcinoma

MCF-7

0.64 ± 0.08

 

MDA-MB468

1.51 ± 0.34

Lung carcinoma

A549

2.01 ± 0.55

Ovarian carcinoma

A2780

1.00 ± 0.11

Cervical carcinoma

HeLa

0.90 ± 0.07

Pancreatic carcinoma

Miacapa-2

1.25 ± 0.26

Fig. 5

Chemical structures of the most active anticancer pyrimidine derivatives (b1b12)

Cocco et al. synthesized a new class of 6-thioxopyrimidine derivatives and its molecular structures were confirmed by IR, NMR and elemental analyses study. The synthesized derivatives were evaluated their in vitro anticancer potential against multiple panels of 60 human cancer cell lines by Sulforhodamine B assay. All synthesized 6-thioxopyrimidine derivatives exhibited good anticancer potential, especially, compound b2 showed the best cytotoxicity (Table 16, Fig. 5) [2].
Table 16

Anticancer activity results of most active compound b2

Compound

CNS cancer cell lines

10−5 M concentration

Ovarian cancer cell lines

10−5 M concentration

b2

SF-268

2.95

IGROV1

7.71

SF-295

9.79

OVCAR-3

6.34

SF-539

3.99

OVCAR-4

3.42

SNB-19

5.42

OVCAR-8

4.92

SNB-57

2.49

U-251

3.58

A new library of sulfonamide derivatives was synthesized and investigated for its in vitro and in vivo antitumor potential by El-Sayed et al. Preliminary biological study revealed that compounds, b3, b4 and b5 showed the highest affinity to DNA and highest percentage increase in lifespan of mice inoculated with Ehrlich ascites cells over 5-flurouracil was taken as standard drug (Table 17, Fig. 5) [22].
Table 17

In vitro anticancer activity results of active compounds

Group

Normal

Control (Ehrlich only)

b3

b4

b5

5-Fluorouracil

% Increase in lifespan over control

71.43

0

71.43

57.14

42.86

42.86

Two new class of pyrido[2,3-d]pyrimidine and pyrido[2,3-d][1,2,4]triazolo[4,3-a] pyrimidines were synthesized by Fares et al. The molecular structures of synthesized derivatives were confirmed by physicochemical properties and spectral data (IR, NMR, Mass and elemental analyses) and screened for their anticancer activity against human cancer cell lines i.e. PC-3 prostate and A-549 lung. Some of the tested compounds exhibited high growth inhibitory potential against PC-3 cell, among them, compounds, b6 and b7 showed relatively potent antitumor potential (Table 18, Fig. 5) [23].
Table 18

Anticancer activity results of compounds b6 and b7

Compounds

Cancer cell lines (IC50 = µM)

A-549

PC-3

b6

3.36 ± 0.39

1.54 ± 0.19

b7

0.41 ± 0.03

0.36 ± 0.02

5-Fluorouracil

4.21 ± 0.39

12.00 ± 1.15

Hu et al. developed a new library of 2,4-diamino-furo[2,3-d]pyrimidine and carried out its in vitro anticancer activity against A459 and SPC-A-1 cancer cell lines. Their structures were confirmed by 1H-NMR, EI-Ms, IR and elemental analysis. Among them, compound b8: ethyl-6-methyl-4-(4-methylpiperazin-1-yl)-2-(phenylamino)furo[2,3-d] pyrimidine-5-carboxylate was found to be most anticancer one against lung cancer cell line (A459 with IC50 0.8 µM) (Fig. 5) [24].

Huang et al. developed a new series of pyrazolo[3,4-d]pyrimidines using 5-aminopyrazoles with formamide in presence of PBr3 as the coupling agent and its chemical structures were characterized by IR, 1H/13C-NMR, Mass, elemental analyses data. The synthesized compounds were screened their in vitro antiproliferative potential by MTT assay against human cancer cell line viz. NCI-H226 (lung carcinoma) and NPC-TW01 (nasopharyngeal carcinoma). From this series, compounds, b9, b10, b11 and b12 possessed better potency against NCI-H226 and NPC-TW01 cancer cells (Table 19, Fig. 5) [25].
Table 19

Antiproliferative results of active compounds (b9b12)

Compounds

Cancer cell lines (GI50 = µM)

NCI-H226

NPC-TW01

b9

18

23

b10

29

30

b11

39

35

b12

37

36

Song et al. synthesized a new library of fluorinated pyrazolo[3,4-d]pyrimidine derivatives by microwave (MW) irradiation method and evaluated its in vitro antitumor potential against human leukaemia (HL-60) cancer cell line by MTT assay. The preliminary results demonstrated that some of compounds exhibited potent antitumor inhibitory potential than doxorubicin (standard drug), especially compounds, b13 and b14 exhibited higher antitumor activity due to presence of CF group in its molecule structure (Table 20, Fig. 6) [26].
Table 20

Antitumor potential results of compounds b13 and b14

Compounds

Human leukaemia (HL-60) cancer cell

IC50 = µmol/l

b13

0.08

b14

0.21

Doxorubicin

0.55

Fig. 6

Chemical structures of the most active anticancer pyrimidine derivatives (b13b23)

Tangeda and Garlapati, developed new molecules of pyrrolo[2,3-d]pyrimidine and screened its in vitro anticancer activity against HCT116 colon cancer cell line. Especially, compounds, b15 and b16 were found to be most potent ones against HCT116 cell line with IC50 value of 17.61 and 17.60 µM respectively which is comparable with 5-fluorouracil (IC50 = 3.03 µM) (Fig. 6) [27].

Kurumurthy et al. prepared a novel class of alkyltriazole tagged pyrido[2,3-d] pyrimidine derivatives and its molecular structure were confirmed by IR, NMR, Mass and elemental analyses. The synthesized derivatives were evaluated their in vitro anticancer activity against three cancer cell lines i.e. U937 (human leukemic monocytic lymphoma), THP-1 (human acute monocytic leukemia) and Colo205 (human colorectal cancer) using MTT assay. Among the synthesized molecules, compounds b17 and b18 exhibited better anticancer activity than the standard etoposide (Table 21, Fig. 6) [28].
Table 21

In vitro cytotoxicity of pyrido[2,3-d]pyrimidine derivatives against U937, THP-1 and Colo205 cancer cell lines

Compounds

IC50 (µg/ml)

U937

THP-1

Colo205

b17

8.16 ± 0.68

16.91 ± 1.42

19.25 ± 1.46

b18

6.20 ± 0.68

11.27 ± 1.67

15.01 ± 1.54

Etoposide (positive control)

17.94 ± 1.19

2.16 ± 0.15

7.24 ± 1.26

Liu et al. synthesized two series of thieno[3,2-d]pyrimidine molecules containing diaryl urea moiety and screened their anticancer potential. The preliminary investigation showed that most compounds displayed good to excellent potency against four tested cancer cell lines compared with GDC-0941 and sorafenib as standard drugs. In particular, the most promising compound b19 showed the most potent antitumor activities with IC50 values of 0.081, 0.058, 0.18 and 0.23 µM against H460, HT-29, MKN-45 and MDA-MB-231 cell lines, respectively (Fig. 6) [29].

Zhu et al. developed a series of 2,6-disubstituted-4-morpholinothieno[3,2-d]pyrimidine molecules and demonstrated its in vitro cytotoxic activity against H460, HT-29, MDA-MB-231, U87MG and H1975 cancer cell lines. Most of the target compounds exhibited moderate to excellent activity to the tested cell lines. The most promising compound b20 is more active than the standard drug (Table 22, Fig. 6) [30].
Table 22

Cytotoxicity of compound b20

Compounds

IC50 = (µmol/l)

H460

HT29

MDA-MB-231

U87MG

H1975

b20

0.84

0.23

2.52

1.80

28.82

PAC-1

3.57

0.97

6.11

ND

ND

ND not determined

2,4,5-Substituted pyrimidine molecules were prepared and evaluated for their anticancer activity against different human cancer cell lines (A549, Calu-3, H460, SK-BR3, SGC-7901 and HT29) by Xie et al. Among the synthesized molecules, compounds b21 showed good inhibition of several different human cancer cell lines with IC50 values from 0.024 to 0.55 µM (Table 23, Fig. 6) [31].
Table 23

In vitro anticancer activity of compound b21

Compound

Human cancer cell lines (IC50 = µM)

A549

Calu-3

H460

SK-BR3

SGC-7901

HT29

b21

0.55

0.50

0.12

0.30

0.30

0.090

Adriamycin

0.025

0.018

Docetaxel

0.10

0.0097

0.0084

GW572016

0.017

Al-Issa, developed a new series of fused pyrimidines and related heterocycles and evaluated its in vitro antitumor activity against human liver cancer cell line (HEPG2). Structures of all synthesized compounds were supported by spectral and elemental analyses. Among the synthesized compounds, compounds b22 and b23 showed significant in vitro antitumor activity (IC50, 17.4, 23.6 µg/ml) (Fig. 6) [32].

Mohareb et al. developed a new class of fused pyran, pyrimidine and thiazole molecules and evaluated its in vitro anticancer potential against cancer cell lines i.e. NUGC- gastric; DLDI-colon; HA22T-liver; HEPG2-liver; HONEI-nasopharyngeal carcinoma; HR-gastric; MCF-breast and WI38-normal fibroblast cells. In this study, compounds, b24 and b25 exhibited more anticancer potential (Table 24, Fig. 7) [33].
Table 24

Anticancer activity results of b24 and b25

Compounds

Cytotoxicity (IC50 in nM)

NUGC

DLDI

HA22T

HEPG2

HONEI

MCF

WI38

b24

180

740

234

837

644

269

Na

b25

40

64

82

328

260

173

Na

CHS 828

25

2315

2067

1245

15

18

Na

Fig. 7

Chemical structures of the most active anticancer pyrimidine derivatives (b24b32)

A new series of novel pyrazolo[3,4-b]pyridine and pyrimidine functionalized 1,2,3-triazole derivatives were prepared from 6-trifluoro methyl pyridine-2(1H)one by Nagender et al. and screened for its cytotoxicity against four human cancer cell lines such as A549-Lung (CCL-185), MCF7-Breast (HTB-22), DU145-Prostate (HTB-81) and HeLa-Cervical (CCL-2). Among them, compounds, b26, b27 and b28 showed promising cytotoxicity (Table 25, Fig. 7) [17].
Table 25

In vitro cytotoxicity of most active compounds

Compounds

IC50 values (in µM)

A549

MCF7

DU145

HeLa

b26

4.1 ± 0.12

4.7 ± 0.18

b27

5.7 ± 0.22

24.7 ± 0.16

6.3 ± 0.21

22.7 ± 0.11

b28

4.2 ± 0.31

37.2 ± 0.31

5.8 ± 0.14

34.3 ± 0.32

5-Fluorouracil

1.3 ± 0.11

1.4 ± 0.09

1.5 ± 0.12

1.3 ± 0.14

Kumar et al. developed a new library of triazole/isoxazole functionalized 7-(trifluoromethyl)pyrido[2,3-d]pyrimidine derivatives and screened their anticancer activity against four human cancer cell lines using nocodazole as standard. Compounds b29 and b30 showed highest activity against PANC-1 (pancreatic cancer) and A549 (lung cancer) cell lines respectively (Table 26, Fig. 7) [34].
Table 26

Anticancer activity of triazole/isoxazole functionalized pyridopyrimidine derivatives

Compounds

GI50 values in µM

MDA MB-231

PANC1

A549

HeLa

b29

2.21 ± 0.08

0.02 ± 0.01

0.86 ± 0.03

0.81 ± 0.02

b30

2.83 ± 0.05

0.73 ± 0.01

0.03 ± 0.01

0.93 ± 0.03

Nocodazole

0.042 ± 0.001

0.029 ± 0.003

0.08 ± 0.001

0.063 ± 0.002

A new class of novel thieno[3,2-d]pyrimidine derivatives was synthesized by Liu et al. and studied for its anticancer potential against selected cancer cell lines viz: H460, HT-29, MKN-45 and MDA-MB-231. Most of compounds displayed good to excellent potency against four tested cancer cell lines as compared with GDC-0941 and sorafenib.

In this study, compound b31 was found to be most active anticancer one (Table 27, Fig. 7) [35].
Table 27

Cytotoxicity of compound b31

Compound

IC50 (µmol/l) ± SD

H460

HT-29

MKN-45

MDA-MB-231

b31

0.057 ± 0.011

0.039 ± 0.008

0.25 ± 0.019

0.23 ± 0.020

GDC-0941

0.87 ± 0.20

0.86 ± 0.081

0.60 ± 0.12

0.28 ± 0.06

Sorafenib

2.19 ± 0.11

3.61 ± 0.36

2.32 ± 0.35

0.94 ± 0.13

Lv et al. synthesized a new series of 2-phenylpyrimidine coumarin derivatives and evaluated its in vitro antiproliferative activity against CNE2, KB and Cal27 cancer cell lines. The results showed that most of the derivatives had a favorable effect on resisting tumor cell proliferation, among them, compound b32 exhibited the best antiproliferative activity and comparable to the standard drug (Table 28, Fig. 7) [36].
Table 28

In vitro anticancer activity of the synthesized compound

Compound

IC50 (µM)

CNE2

KB

Cal27

b32

1.92 ± 0.13

3.72 ± 0.54

1.97 ± 0.51

Doxorubicin

2.12 ± 0.56

3.04 ± 0.87

1.56 ± 0.64

Antiviral activity

Antiviral nucleoside compounds inhibit viral genome replication by acting as mimetics of the natural nucleosides. Nucleoside analogues (NAs) can either act as chain terminators after being incorporated into growing DNA/RNA strands and/or inhibit the viral polymerase function by competition with the natural nucleoside 50-triphosphate substrate [3].

A new library of 4H,6H-[1,2,5]oxadiazolo[3,4-d]pyrimidine-5,7-dione 1-oxide nucleoside was synthesized by Xu et al. and screened for its in vitro anti-vesicular stomatitis virus (VSV) activity in Wish cell. All the synthesized derivatives showed obvious anti-VSV potential whereas, compound c1 with ribofuranoside enhanced the anti-VSV potential by approximately 10–18 times compared to didanosine and acyclovir (standard drugs), respectively (Table 29, Fig. 8) [37].
Table 29

Experimental antiviral results of compound c1

Compound

Toxicity for wish cells and antivirus effect (TC0 µmol/l)

ED50

Model 1

Model 2

c1

2095

78

148

100

Acyclovir

3414

1411

Didanosine

2646

792

Fig. 8

Chemical structures of the most active antiviral pyrimidine derivatives (c1c10)

Hockova et al. synthesized a new series of 2,4-diamino-5-cyano-6[2-(phosphono methoxy)ethoxy]pyrimidine derivatives and evaluated its antiviral activity. The 5-cyano and 5-formyl derivatives (c2c4) showed pronounced antiretroviral activity, comparable to that of the reference drugs adefovir and tenofovir (Table 30, Fig. 8) [38].
Table 30

Antiviral activity results of test compounds (c2c4) in cell culture

Compounds

EC 50 a (µmol/ml)

CC 50 b

HIV (IIIB)

HIV-2 (ROD)

MSV

(µmol/ml) (CEM)

c2

0.011

0.0045

0.0095

≥ 0.3

c3

0.0045

0.0027

0.021

≥ 0.3

c4

0.080

0.050

≥ 0.2

Adefovir

0.0033

0.0066

0.0022

0.056

Tenofovir

0.0012

0.0014

0.0046

0.14

a50% effective concentration; b 50% cytostatic concentration

Tian et al. developed a novel library of 5,7-disubstituted pyrazolo[1,5-a]pyrimidine molecules and carried out its anti-HIV potential. From the series, compound c5: 4-(7-(mesityloxy)-4,5-dihydropyrazolo[1,5-a]pyrimidin-5-ylamino)benzonitrile was found to be the most active one (Fig. 8) with an EC50 = 0.07 µM against wild-type HIV-1 and very high selectivity index (SI, 3999) than the reference drugs (nevirapine and delavirdine) [39].

A new class of novel acyclic nucleosides in the 5-alkynyl and 6-alkylfuro[2,3-d] pyrimidines was synthesized by Amblard et al. and screened for its antiviral activity against human immunodeficiency virus (HIV), herpes simplex virus (HSV-1). Compounds, c6 and c7 exhibited moderate antiviral activity (Table 31, Fig. 8) [40].
Table 31

Antiviral activity results (µM) of compounds c6 and c7

Compounds

Anti-HIV-1 activity in PBMCs

HSV-1 plaque reduction assay

EC50

EC90

EC50

EC90

c6

2.7

19.8

6.3

16.4

c7

4.9

13.07

4.8

46.2

AZTa

0.016

0.20

> 10

> 10

Acyclovira

> 100

> 100

0.11

0.69

A series of pyrazole and fused pyrazolo pyrimidines was synthesized by Rashad et al. and studied for their antiviral activity against hepatitis-A virus (HAV) and herpes simplex virus type-1 (HSV-1). The substituted pyrazole and fused pyrazolopyrimidine derivatives, c8 and c9 revealed higher anti-HSV-1 activity at concentration of 10 µg/105 cells and antiviral results are compared with amantadine and acyclovir (Fig. 8) [41].

Sari et al. developed a new library of dihydropyrimidine α,γ-diketobutanoic acid molecules and screened its antiviral potential. Among the series, compound c10 ((Z)-ethyl-4-benzyl-1-(4-(3-hydroxy-4-isopropoxy-4-oxobut-2-enoyl)benzyl)-6-methyl-2-oxo-1,2-dihydro pyrimidine-5-carboxylate) was found to be most active anti-HIV agent (Table 32, Fig. 8) [42].
Table 32

Antiviral activity results of compound c10

Compound

EC50 (µM)

c10

17.2

AZT

0.0074

Antimalarial activity

Malaria is the most serious and widespread parasitic disease because of its prevalence, virulence and drug resistance, having an overwhelming impact on public health in developing regions of the world. Plasmodium falciparum is the main cause of severe clinical malaria and death. Endemic mapping indicates that P. falciparum and P. vivax account for 95% of the malarial infections [43]. According to a WHO report, malaria accounted for 207 million cases and an estimated 627,000 deaths worldwide in 2013 [8].

Kumar et al. synthesized a new series of 4-aminoquinoline-pyrimidine hybrids and evaluated its antimalarial potential. Several compounds showed promising in vitro antimalarial activity against both CQ sensitive and CQ-resistant strains with high selectivity index. The in vitro evaluation of these hybrids against D6 and W2 strains of P. falciparum depicted the antimalarial activity in the nanomolar range. Also, these hybrids exhibited high selectivity indices and low toxicity against the tested cell lines. Compounds (d1, d2 and d3) (Fig. 9) exhibited very potent antimalarial activity with IC50 = 0.033, 0.019 and 0.028 µM respectively which were comparable to the standard drug chloroquine (IC50 = 0.035 µM) against CQ-sensitive strain [8].
Fig. 9

Chemical structures of the most active antimalarial pyrimidine derivatives (d1d12)

Maurya et al. developed a new series of novel N-substituted 4-aminoquinoline-pyrimidine hybrids via simple and economic route and evaluated its antimalarial activity. Most compounds showed potent antimalarial activity against both CQ-sensitive and CQ-resistant strains with high selectivity index. All the compounds were found to be non-toxic to the mammalian cell lines. The most active compound d4 was analyzed for heme binding activity using UV spectrophotometer. Compound d4 was found to interact with heme and a complex formation between compound d4 and heme in a 1:1 stoichiometry ratio was determined using job plots. The interaction of these hybrids was also investigated by the molecular docking studies in the binding site of wild type Pf-DHFR-TS and quadruple mutant Pf-DHFR-TS (Table 33, Fig. 9) [44].
Table 33

In vitro antimalarial activity of AQ-furfural-2-carbaldehyde-pyrimidine hybrids

Compound

P. falciparum D6

P. falciparum W2

VERO cells

Resistance index

IC50 (µM)

(SI)

IC50 (µM)

(SI)

d4

0.038 ± 0.000

> 263.15

0.040 ± 0.001

> 250.0

NC

1.05

Chloroquine

0.011 ± 0.004

> 909.09

0.317 ± 0.051

> 31.54

NC

28.81

Pyrimethamine

0.009 ± 0.003

> 1111.1

NA

NC

Artemisinin

0.045 ± 0.001

> 222.22

0.023 ± 0.001

434.78

NC

0.511

Agarwal et al. developed a new series of 2,4,6-trisubstituted-pyrimidines and evaluated its in vitro antimalarial activity against Plasmodium falciparum. All the synthesized compounds showed good antimalarial activity against Plasmodium falciparum whereas, compound d5 exhibited higher antimalarial activity than pyrimethamine used as standard drug (Table 34, Fig. 9) [43].
Table 34

Antimalarial in vitro activity against P. falciparum

Compound

MIC (µg/ml)

d5

0.25

Pyrimethamine

10

Pretorius et al. synthesized a new library of quinoline–pyrimidine hybrids and evaluated its in vitro antimalarial activity against the D10 and Dd2 strains of Plasmodium falciparum. The compounds were all active against both strains. However, hybrid (d6, Fig. 9) featuring piperazine linker stood as the most active of all. It was found as potent as CQ and PM against the D10 strain and possessed a moderately superior potency over CQ against the Dd2 strain (IC50: 0.157 vs 0.417 µM) and also displayed activity comparable to that of the equimolar fixed combination of CQ and PM against both strains [45].

Azeredo et al. synthesized a new series of 7-aryl aminopyrazolo[1,5-a]pyrimidine derivatives with different combinations of substituent’s at positions 2-,5- and 7- of the pyrazolo[1,5-a]pyrimidine ring. The compounds were tested against Plasmodium falciparum, as antimalarials in mice with P. berghei and as inhibitors of PfDHODH. From this series, compounds, d7, d8, d9 and d10 were found to be the most active ones (Table 35, Fig. 9) [46].
Table 35

In vitro antimalarial activity results of active compounds

Compounds

(%) Activity PfDHODH

IC50 against PfDHODH (µM)

d7

67.474 ± 0.002

6 ± 1

d8

41 ± 3

4 ± 1

d9

77 ± 1

d10

60 ± 3

0.16 ± 0.01

A series of N-aryl and heteroaryl sulfonamide derivatives of meridianins were prepared by Yadav et al. and screened for its antimalarial activity against D6 and W2 strains of Plasmodium falciparum. Especially, compounds, d11 and d12 displayed promising antiplasmodial activity and comparable to the standard drugs (Table 36, Fig. 9) [47].
Table 36

In vitro antimalarial activity of N-aryl and heteroaryl sulfonamide derivatives

Compounds

P. falciparum (IC50 in µM (µg/ml))

P. falciparum (D6)

P. falciparum (W2)

IC50

SI

IC50

SI

d11

4.86 (2.3)

> 10.8

6.39 (3.02)

> 8.2

d12

2.56 (1.38)

> 18

3.41 (1.84)

> 13.5

Artemisinin

< 0.09 (< 0.03)

< 0.09 (< 0.03)

Chloroquine

< 0.08 (< 0.03)

0.72 (0.23)

Anti-inflammatory activity

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used therapeutics, primarily for the treatment of pain, rheumatic arthritis and various types of inflammatory conditions. However, their use is mainly restricted by their well known and serious adverse gastrointestinal side effects such as gastroduodenal erosions, ulcerations and nephrotoxicity [6].

Tozkoparan et al. synthesized a new class of 2-benzylidene-7-methyl-3-oxo-5-(substituted phenyl)-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-6-carboxylic acid methyl esters and evaluated its anti-inflammatory activity by carrageenan induced edema test using indomethacin as reference drug. Test results revealed that compounds, e1, e2, e3, e4 exerted moderate anti-inflammatory activity at the 100 mg/kg dose level compared with indomethacin (Table 37, Fig. 10) [5].
Table 37

Anti-inflammatory activity in percentage (%) of synthesized compounds (e1e4)

Compounds

Anti-inflammatory activity (%)a

e1

41

e2

38

e3

16

e4

28

Indomethacin

32

a 100 mg/kg p.o. (n = 6)

Fig. 10

Chemical structures of the most active anti-inflammatory pyrimidine derivatives (e1e15)

Two new series of thieno[2′,3′:4,5]pyrimido[1,2-b][1,2,4]triazines and thieno[2,3-d][1,2,4]triazolo[1,5-a]pyrimidines were synthesized by Ashour et al. and evaluated for their anti-inflammatory and analgesic activity using diclofenac as reference drug. In general, the thieno[2,3-d][1,2,4]triazolo[1,5-a]pyrimidine derivatives exhibited better anti-inflammatory activity than the thieno[2′,3′5′:4,5]pyrimido[1,2-b][1,2,4]triazines. The thienotriazolo pyrimidine derivatives, e5, e6 and e7 (Fig. 10) were proved to display distinctive anti-inflammatory activity at the acute and sub acute models as well as good analgesic profile with a delayed onset of action. The anti-inflammatory screening results are presented in Tables 38 and 39 [6].
Table 38

Anti-inflammatory activity of compounds (e5e7) in formal in induced rat paw edema bioassay (sub-acute inflammatory model)

Compounds

Volume of edema (ml)a

0

1st day

8th day

e5

0.31 ± 0.01

0.51 ± 0.03b (44)c

0.68 ± 0.02b (31)

e6

0.35 ± 0.02

0.54 ± 0.01b (47)

0.67 ± 0.02b (40)

e7

0.33 ± 0.02

0.15 ± 0.01b (50)

0.67 ± 0.02b (37)

Control

0.32 ± 0.01

0.68 ± 0.01

0.86 ± 0.03

Diclofenac

0.32 ± 0.02

0.52 ± 0.02b (44)

0.64 ± 0.02b (40)

aValues are expressed as mean ± S.E. (Number of animals N = 5 rats)

bSignificantly different compared to corresponding control P ≤ 0.05

cBetween parentheses (percentage anti-inflammatory activity %)

Table 39

Anti-inflammatory activity of the fused thienopyrimidines in formalin-induced rat paw edema bioassay (acute inflammatory model)

Compounds

Volume of edema (ml)a

ED50 (mg/kg)

0

1 h

2 h

4 h

e5

0.31 ± 0.01

0.44 ± 0.02b (38)c

0.49 ± 0.01b (43)

0.52 ± 0.02b (52)

23.45d

e6

0.35 ± 0.02

0.46 ± 0.01b (47)

0.50 ± 0.01b (53)

0.54 ± 0.02b (56)

28.15

e7

0.33 ± 0.02

0.46 ± 0.01b (42)

0.53 ± 0.01b (37)

0.59 ± 0.02b (40)

26.12

Control

0.32 ± 0.01

0.55 ± 0.01

0.64 ± 0.02

0.76 ± 0.01

Diclofenac

0.32 ± 0.02

0.45 ± 0.01b (38)

0.50 ± 0.02b (43)

0.53 ± 0.02b (52)

25.13

aValues are expressed as mean ± SE (number of animals N = 5 rats)

bSignificantly different compared to corresponding control P ≤ 0.05

cBetween parentheses (percentage anti-inflammatory activity %)

dED50 is the effective dose calculated after 2 h

Yejella and Atla, synthesized a new series of 2,4,6-trisubstituted pyrimidines and screened its in vivo anti-inflammatory activity by carrageenan induced rat paw edema model. Compounds, e8: 2-amino-4-(4-aminophenyl)-6-(2,4-dichlorophenyl)pyrimidine and e9: 2-amino-4-(4-aminophenyl)-6-(3-bromophenyl)pyrimidine were found to be the most potent anti-inflammatory agents compared with ibuprofen (Table 40, Fig. 10) [48].
Table 40

Anti-inflammatory activity of pyrimidine derivatives

Comp.

Percent inhibition ± SEM at various time intervals

0.5 h

1.0 h

2.0 h

3.0 h

4.0 h

6.0 h

e8

15.22 ± 0.68*

50.45 ± 1.23*

87.23 ± 2.61*

62.51 ± 2.33*

56.94 ± 1.79

48.39 ± 2.65

e9

18.26 ± 0.68*

49.35 ± 1.41*

86.99 ± 2.62*

62.13 ± 2.25*

53.32 ± 2.01

42.11 ± 2.75

Ibuprofen

20.26 ± 0.90*

53.95 ± 0.97*

97.09 ± 2.86*

79.97 ± 2.38*

67.93 ± 2.22*

58.02 ± 1.87*

All values are represented as mean ± SEM (n = 6). *P < 0.01 compared to saline control group. One-way ANOVA, Dunnett’s t test. Dosage: Ibuprofen-10 mg/kg and test compounds-10 mg/kg body weight by orally

Zhou et al. synthesized a new series of imidazo[1,2-a]pyrimidine derivatives and screened its anti-inflammatory potential with selective cyclooxygenase-2 (COX-2) inhibitors. In this series, compound e10 exhibited potent activity (63.8%) than ibuprofen (44.3%). The human whole blood assay still revealed that e10 (Fig. 10) has selective COX-2 inhibition (IC50 = 13 µmol/l) which is 13 times more potent than its inhibitory activity to COX-1 (IC50 = 170 µmol/l) and swollen inhibition 63.8%. The results indicated that imidazo[1,2-a] pyrimidine compounds keep moderate anti-inflammatory activity as compared to ibuprofen (standard drug) [49].

Gondkar et al. prepared a new class of substituted 1,2,3,4-tetrahydropyrimidine and screened its in vitro anti-inflammatory activity by inhibition of protein denaturation method using diclofenac (standard drug). The results revealed that almost all the tested compounds showed potent anti-inflammatory potential. All synthesized derivatives were tested their in vitro anti-inflammatory activity using inhibition of albumin denaturation technique compared to standard diclofenac. Derivatives, e11, e12, e13, e14 and e15 (Fig. 10) showed significant in vitro anti-inflammatory activity with % inhibition of albumin denaturation 98, 97, 90, 94, and 96% respectively [50].

Keche et al. developed a new series of novel 4-(3-(trifluoromethyl)phenylamino-6-(4-(3-arylureiodo/arylthioureido/arylsulfonamido)-pyrimidine derivatives by the sequential Suzuki cross coupling and screened for their anti-inflammatory activity. Among all the synthesized derivatives, compounds, e16, e17, e18, e19, e20 and e21 were found to have moderate to potent anti-inflammatory activity and compared to dexamethasone used as reference drug (Table 41, Fig. 11) [51].
Table 41

Anti-inflammatory activity of novel pyrimidine derivatives

Compounds

% Inhibition at 10 µM NF-α

IL-6

e16

78

96

e17

71

90

e18

61

80

e19

68

82

e20

50

62

Dexamethasone

72

86

Fig. 11

Chemical structures of the most active anti-inflammatory pyrimidine derivatives (e16e24)

Mohamed et al. synthesized a new library of thio containing pyrrolo[2,3-d]pyrimidine derivatives and carried out its in vitro anti-inflammatory potential using the carrageenan-induced rat paw oedema assay. The potency and duration of action was compared to ibuprofen was taken as standard drug. From tested compounds, compounds e21, e22 and e23 showed best anti-inflammatory activity (Table 42, Fig. 11) [52].
Table 42

In vivo anti-inflammatory activity

Compounds

Oedema induced by carrageenan (% oedema % inhibition relative to control)

1 h

2 h

3 h

4 h

Swel

% inh

Swel

% inh

Swel

% inh

Swel

% inh

e21

0.206

10.43

0.101

61.15

0.142c

73.9

0.132b

79.04

e22

0.196

14.78

0.182

30

0.022c

95.58

0.282

67.43

e23

0.216

6.08

0.012b

95.38

0.024c

95.95

0.202a

76.82

Ibuprofen

0.216

6.08

0.14

45

0.214b

60.66

0.192a

69.52

As indicated: a P < 0.05; b P < 0.01; c P < 0.001

Sondhi et al. synthesized new derivatives of pyrimidine and screened their anti inflammatory activity carried out using carrageenin-induced paw oedema assay. All compounds exhibited good activity whereas, compound e24 was found to be most active one comparable to the standard drug ibuprofen (Table 43, Fig. 11) [53].
Table 43

Anti-inflammatory of compound e24

Compound

Dose mg/kg po

Anti-inflammatory activity %

e24

100

65

Ibuprofen

100

66.8

Antioxidant activity

Oxidative stress seems to play a significant role in various human diseases, including cancers. Antioxidant compounds are the agents that neutralize free radicals, which scavenge reactive oxygen species, may have potent value in preventing the onset and propagation of oxidative diseases such as neurovascular, cardiovascular diseases. Pyrimidine and its derivatives have recently attracted the attention of medicinal chemists in exploring their potential as antioxidant agents [1].

Bhalgat et al. developed a new class of novel pyrimidines and its triazole fused derivatives and investigated its in vitro antioxidant by various methods as scavenging of hydrogen peroxide, scavenging of nitric oxide radical and lipid per oxidation inhibitory activity. Compounds, f1 showed good antioxidant activity as compared to standard by scavenging of nitric oxide radical and hydrogen peroxide, while f2 showed most potent antioxidant activity by scavenging of nitric oxide (Table 44, Fig. 12) [7].
Table 44

Antioxidant activity (IC-50 values) of compounds f1 and f2

Compound

IC-50 (mean ± SD)a (µg/ml)

Scavenging of nitric oxide radical

Scavenging of hydrogen peroxide

Lipid peroxidation inhibitory activity

f1

51 ± 0.058

41 ± 0.087

40 ± 0.121

f2

47 ± 0.052

52 ± 0.279

43 ± 0.333

Standard

56 ± 0.087

38 ± 0.121

26 ± 0.333

aAverage of three determination

Fig. 12

Chemical structures of the most active antioxidant pyrimidine derivatives (f1f10)

Kotaiah et al. synthesized new molecules of novel 1,2,4-triazolo[3,4-b][1,3,4]thiadiazol-6-yl)selenopheno[2,3-d]pyrimidines with substituted anilines and benzoic acid. The antioxidant activity of the synthesized compounds was evaluated by DPPH, NO and H2O2 radical scavenging methods. In this series, compounds, f3, f4 and f5 showed promising antioxidant activity compared to standard drug (Table 45, Fig. 12) [54].
Table 45

Antioxidant activity of most compounds

Compounds

Scavenging activity (IC50 µg/ml)

DPPH

NO

H2O2

f3

11.02 ± 0.27

13.72 ± 1.26

15.38 ± 0.96

f4

10.41 ± 0.23

12.74 ± 0.18

17.08 ± 0.12

f5

9.46 ± 0.91

8.20 ± 1.60

12.54 ± 1.17

AA

12.27 ± 0.86

14.62 ± 0.97

15.24 ± 0.44

BHT

16.53 ± 1.74

19.06 ± 1.04

17.82 ± 0.28

Lower IC50 values indicate higher radical scavenging activity

AA ascorbic acid, BHT butylated hydroxy toluene

Mohana et al. reported a new series of pyrimidine derivatives and evaluated its antioxidant activity by DPPH method. The structures of all the new compounds are established on the basis of FT-IR, 1H-NMR and Mass spectral data. All the compounds showed DPPH radical scavenging activity, whereas, compounds, f6, f7 and f8 exhibited best radical scavengers due to presence of electron donating methoxy group at different position (ortho, meta and para) (Table 46, Fig. 12) [55].
Table 46

DPPH radical scavenging activity of the tested compounds

Compounds

Scavenging effect (%)

Concentration of the tested compounds (µg/ml)

100

150

200

f6

51.1

60.8

68.1

f7

35.2

46.3

52.1

f8

32.2

43.4

54.8

Ascorbic acid

73.0

85.3

98.2

Quiroga et al. developed a new library of 5-aryl-4-oxo-3,4,5,8-tetrahydropyrido[2,3-d] pyrimidine-7-carboxylic acids and carried out their antioxidant activity by DPPH (1,1-diphenyl-2-picryl-hydrazyl) radical scavenging assay. Compounds f9 and f10 showed antioxidant properties and compared to standard drugs (Table 47, Fig. 12) [56].
Table 47

Free radical scavenging (FRS50) for the tested pyrido[2,3-d]pyrimidines (f9 and f10)

Compounds

FRS50 (µg/ml)

Mean

%RSD

f9

367

10

f10

472

10

Asc. acid

1.1

12

Quercetin

3.4

7

Antileishmanial activity

Leishmaniasis, a vector-borne parasitic disease, is a major cause of concern in developing countries. The disease is caused by more than 20 species of protozoan Leishmania and transmitted by the bite of female phlebotomine sand flies. Leishmaniasis has traditionally been classified into three major clinical forms: visceral leishmaniasis (VL), cutaneous leishmaniasis (CL) and mucocutaneous leishmaniasis (MCL) which differs in immunopathologies and degree of morbidity and mortality. VL caused by Leishmania donovani is the most severe form of leishmaniasis and is usually fatal in the absence of treatment. Most of the first line drugs available for the treatment of leishmaniasis such as sodium stibogluconate, meglumine antimoniate, pentamidine etc. cause serious side effects and toxicity [57].

A new series of substituted aryl pyrimidine derivatives was synthesized by Suryawanshi et al. and evaluated for its in vitro antileishmanial potential against intracellular amastigotes of Leishmania donovani using reporter gene luciferase assay. All synthesized compounds showed promising IC50 values ranging from 0.5 to 12.9 µM. Selectivity indices (S.I.) of all these compounds are far better than sodium stibogluconate (SSG) and miltefosine used as standard drugs. On the basis of good selectivity indices compounds were further screened their in vivo antileishmanial activity against L. donovani/hamster model. Compounds, g1, g2 and g3 showed good inhibition (Table 48, Fig. 13) of parasitic multiplication that is 88.4, 78.1 and 78.2%, respectively at a daily dose of 50 mg/kg × 5 days, when administered intraperitoneally [57].
Table 48

In vitro and in vivo antileishmanial activity and cytotoxicity results of synthetic pyrimidine derivatives

Compounds

In vitro assessment

Selectivity index

CC50/IC50

In vivo activity (dose—50 mg/kg × 5 days, ipb)

% Inhibition ± SD

IC50 (µM)

CC50 (µM)

g1

2.0 ± 0.1

375.9 ± 5.1

188

88.4 ± 10.6

g2

0.5 ± 0.1

57.8 ± 5.9

116

78.1 ± 17.7

g3

2.7 ± 0.5

345.4 ± 19.6

128

78.2 ± 4.4

SSGa

59.8 ± 7.5

> 400 ± 0

> 7

88.5 ± 4.4

Miltefosinec

12.5 ± 0.9

54.7 ± 6.9

4

98.1 ± 1.0

IC50 and CC50 values are the mean ± SD of two independent experiments

The selectivity index is defined as the ratio of CC50 on vero cells to IC50 on L. donovani intramacrophagic amastigotes

aSSG = sodium stibogluconate (40 mg/kg × 5 days, ip)

bip = intraperitonial; c Miltefosine (30 mg/kg × 5 days, po) used as a reference drugs

Fig. 13

Chemical structures of the most active antileishmanial pyrimidine derivatives (g1g7)

Pandey et al. synthesized some novel terpenyl pyrimidine from α/β-ionone keteneacetals and screened their in vivo leishmanicidal activity against amastigote stage of Leishmania donovani was determined in Golden hamsters (Mesocricotus aurctus) infected with HOM/IN/80/DD8 strain of L. donovani. The compounds, g4, g5, g6 and g7 showed promising in vivo antileishmanial activity (Table 49, Fig. 13) [58].
Table 49

Antileishmanial activity of compounds against amastigotes of Leishmania donovani in hamsters

Compounds

Dose (mg/kg)

In vivo inhibition (%)

Day-7

Day-28

g4

50

66

g5

50

22

63

g6

50

64

g7

50

64

Miscellaneous activities

A new series of strobilurin-pyrimidine derivatives was synthesized by Chai et al. The synthesized compounds were evaluated for their acaricidal activity. Preliminary bioassays demonstrated that compounds, h1 and h2 exhibited significant control against Tetranychus cinnabarinus (Boisd.) at 0.625 mg/l, and their acaricidal potencies were higher than pyriminostrobin in a green house. Compounds, h1 and h2 (Fig. 14) were chosen as candidates for extensive greenhouse bioassays on larvae and eggs of T. cinnabarinus. Both of them showed potency consistent with pyriminostrobin against larvae and weaker potency than pyriminostrobin against eggs, as shown in Table 50 [59].
Fig. 14

Chemical structures of the most active pyrimidine derivatives (h1h15)

Table 50

Acaricidal activity of h1 and h2 against T. cinnabarinus

Compounds

T. cinnabarinus

(% mortality at given concentration mg/l)

10

25

0.625

h1

Larvae

100

98

77

Eggs

100

70

25

h2

Larvae

100

100

100

Eggs

75

20

10

Pyriminostrobin

Larvae

100

100

96

Eggs

100

100

20

Amin et al. synthesized a new series of novel coumarin–pyrimidine hybrids and evaluated its vasorelaxant activity against nor-adrenaline-induced spasm on thoracic rat aorta rings and compared to prazocin (reference drug). From the series, compounds, h3: (6-(4,6-dimethylpyrimidin-2-ylamino)-2H-chromen-2-one) and h4: (6-(diethylamino)-5-isocyano-2-(2-oxo-2H-chromen-6-ylamino)pyrimidin-4(3H)-one) were found to be most prospective vasorelaxant agent with IC50 = 0.411 and IC50 = 0.421 mM respectively when compared with reference drug prazocin (IC50 = 0.487 mM). The chemical structure depicted in Fig. 14 [60].

Duan et al. designd and synthesized a new series of S(−)-2-(4-chlorophenyl)-N-(5,7-di- substituted-2H-[1,2,4]-thiadiazolo[2,3-a]pyrimidin-2-ylidene)-3-methylbutanamide derivatives. The synthesized compounds were evaluated for their herbicidal activity against three monocotyledon weeds and two dicotyledon weeds i.e. Echinochloa crusgallis L., Sorghum bicolort, Digitaria sanguinalis (L.) scop Chenopodium serotinum (L.) and Amaranthus retroflexus L., respectively. Compounds h5 and h6 showed the highest inhibitory activity against root and stalk of Amaranthus retroflexus L. in higher concentration (1.0 × 10−4 µg/ml), while compounds h7 and h8 showed good activity against root of Echinochloa crusgallis L. and stalk of Chenopodium serotinum L., respectively (Table 51, Fig. 14). The chiral target compounds showed improved herbicidal activity to some extent over their racemic counterparts against a variety of tested weeds, which might be contributed by the introduction of chiral active unit [61].
Table 51

The inhibition percentage of the target compounds against various weeds

Compounds

Concentration (ppm)

Echinochloa crusgallis L.

Chenopodium serotinum L.

Amaranthus retroflexus L.

Stalk

Root

Stalk

Root

Stalk

Root

h5

50

50

30

50

50

50

50

100

80

30

80

85

95

100

h6

50

10

70

80

80

90

85

100

30

90

85

90

100

100

h7

50

60

80

10

10

0

0

100

70

100

20

10

20

30

h8

50

30

70

70

50

60

50

100

40

80

100

80

95

90

Katiyar et al. developed a new series of trisubstituted pyrimidine derivatives and evaluated its in vitro topoisomerase II inhibitory activity against filarial parasite Setaria cervi. Compounds (h9h15) have shown 60–80% inhibition at 40 and 20 µg/ml concentrations. Structure activity relationship of most active compounds have given clear indication that amino group and 4-aminophenyl group at position-2 are very crucial in exerting topoisomerase II inhibitory activity against filarial parasite Setaria cervi than standard antifilarial drug (DEC) and enzyme topoisomerase II inhibitors (novobiocin, nalidixic acid) (Table 52, Fig. 14) [62].
Table 52

Topoisomerase II inhibitory activity against filarial parasite Setaria cervi

Compounds

% Inhibition at different concentrations

40 µg/ml

20 µg/ml

10 µg/ml

5 µg/ml

h9

60

60

h10

60

60

h11

80

80

80

h12

80

80

80

60

h13

80

80

80

60

h14

80

80

80

25

h15

70

70

70

40

DEC (antifilarial)

45

10

Novobiocin (topo II inhibitor)

80

20

10

Nalidixic acid (topo II inhibitor)

80

40

20

A new class of 2,4,6-trisubstituted bis-pyrimidines was synthesized by Parveen et al. and screened for its in vitro antiamoebic activity against HM1:IMSS strain of Entamoeba histolytica and toxicological studies on PC12-rat pheochoromocytoma cell line.

Bis-pyrimidine having methyl-substituent exhibited higher antiamoebic activity than the reference drug metronidazole (IC50 = 1.9 µM). Compound h16: 1,3-bis(2-(piperidin-1-yl)-6-(p-tolyl)pyrimidin-4-yl)benzene was found most active (IC50 = 0.10 µM) and least toxic among all the synthesized compounds (Table 53, Fig. 15) [63].
Table 53

Antiamoebic activity and toxicity profile of compound h16

Compound

Antiamoebic activity

Toxicity profile

(IC50 = µM)

SD (±)

(IC50 = µM)

Safety index

h16

0.10

0.014

> 100

> 1000

Metronidazole

9

0.020

> 100

> 52.63

SD standard deviation

Fig. 15

Chemical structures of the most active pyrimidine derivatives (h16h18)

A new class of pyrido[2,3-d]pyrimidine derivatives was designed and synthesized by Ibrahim and Ismail. The pyrido[2,3-d]pyrimidine derivatives were evaluated for their in vitro anti-proliferative activity against A431a, SNU638b, HCT116 and inhibition of CDK2-Cyclin A, CDK4/Cyclin D and EGFR enzyme. In this class, the anti-proliferative and CDK2-Cyclin A inhibitory activity of compounds, h17 and h18 (Fig. 15) was significantly more active than roscovotine (as standard drug) with IC50 values of 0.3 and 0.09 µM respectively [64].

Conclusion

In conclusion, the biological potentials i.e. antimicrobial, anticancer, antiviral, anti-inflammatory, analgesic, antioxidant and antimalarial of pyrimidine derivatives are summarized. Pyrimidine is the important heterocyclic compound as they are being an essential constituent of cells and large number of marketed drugs. The biological activities of the pyrimidine derivatives indicated the maneuverability and versatility, which offer the medicinal chemist a continued interest in the pyrimidine skeleton in medicinal field.

Notes

Authors’ contributions

Authors BN and SK have designed and prepared the manuscript. Both authors read and approved the final manuscript.

Competing interests

The authors declare that they have no competing interests.

Availability of data and materials

Present in manuscript.

Ethics approval and consent to participate

Not applicable.

Funding

Not applicable.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Authors and Affiliations

  1. 1.Faculty of Pharmaceutical SciencesMaharshi Dayanand UniversityRohtakIndia

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