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Development of Antimicrobial, Antimalarial and Antitubercular Compounds Based on a Quinoline-Pyrazole Clubbed Scaffold Derived via Doebner Reaction

  • Keyur M. PandyaEmail author
  • Arpan H. Patel
  • P. S. Desai
Original Article
  • 149 Downloads

Abstract

In an effort for the development of novel antimicrobial, antimalarial and antitubercular agents, series of quinoline carboxylic acid derivatives bearing substituted pyrazole moiety were synthesized from derivatives of substituted pyrazole aldehydes, substituted aniline and pyruvic acid, through a one-pot Doebner reaction. Then the Carboxylic group was converted to an acyl chloride, N-(3-(dimethylamino) propyl) carboxamide, and alcohol functional groups. All the compounds were characterized by elemental analysis, MS, 1H NMR and 13C NMR spectroscopy and were screened against bacterial strains. Majority of these compounds showed potent antibacterial and antifungal activities against the tested strains of bacteria and fungi. Compounds were also screened for antitubercular and antimalarial activities. Quinoline-Pyrazole clubbed derivative showed better results when compared with the reference drugs based on their MIC values. Thus, these studies suggest that quinoline derivatives bearing pyrazole moiety are interesting scaffolds for the development of novel antimicrobial, antimalarial, and antimycobacterial agents.

Graphic Abstract

Keywords

Quinoline-pyrazole Antimicrobial Antimalarial Antitubercular 

1 Introduction

Antimicrobial [1, 2] and anti-tubercular [3] drug discovery for the past half- century has evolved exponentially with the advancements in the field of medicinal chemistry coupled with a computational screening of potential drug targets [4]. However, continuously evolving multi-drug resistant strains of bacteria and fungi such as Methicillin-resistant Staphylococcus aureus (MRSA) [5] along with the systemic side effects of the potent drugs have proven to be the key setbacks in discovering a novel treatment. In order to overcome these setbacks mounting emphasis has been given on methods for synthesizing scaffold of compounds with proven efficacy [6], thereby retaining the systemic tolerability with enhanced antimicrobial activity. The pharmacological properties of the quinoline ring are well explained by the huge number of commercially available drugs containing this heterocyclic ring system [7, 8] (Fig. 1). These molecules have been examined for decades and SAR (structure–activity relationship) analyses have been performed to determine their biological effects [9]. Derivatives containing quinoline ring has been reported as great antimicrobial [10, 11], antimalarial [12, 13] and anti-tubercular activities and also exist as structural sub-units of natural substances. Pyrazoles are popular illustrations of aromatic heterocycles incorporating two nitrogen atoms in their five-membered rings [14, 15]. They create an imperative heterocyclic class covering a wide range of synthetic as well as natural products that demonstrate numerous chemical, biological, agrochemical and pharmacological properties [16, 17]. Pyrazole derivatives serve as one of the most effective families of compounds and possess a broad spectrum of biological activities [18, 19, 20, 21, 22, 23, 24, 25]. In recent years, various drugs have been developed from pyrazole derivatives [26] (Fig. 2).
Fig. 1

Drug molecules containing quinoline scaffolds

Fig. 2

Drug molecules containing pyrazole scaffolds

The current focus of the field suggests that drugs of azole [27, 28] class, pyrazole in particular if coupled with derivatives containing quinoline as core moiety could overcome the problem of drug resistance. On the other hand, drugs containing azole like pyrazoles, derivatives possess a wide range of pharmacological activities like anti-inflammatory [29, 30], analgesic, anticancer [31, 32], antiulcer, antimicrobial [33, 34, 35], antiviral [36, 37], antimalarial [38], and anti-arrhythmic [39]. Additionally, quinoline moiety is found to be at the base of a wide variety of naturally existing substances and a key synthon possessing various bioactivities. A library of compounds corresponding to this template with different substituents on both the pharmacophores has been synthesized to explore the possibility of developing new potent antibacterial, antifungal, antitubercular and antimalarial agents. Thus, in the present scheme of reactions (design strategy Fig. 3) quinoline skeleton was taken to design new compounds by fusing pyrazole moiety using modified Doebner reaction creating a number of bioactive molecules containing quinoline-pyrazole scaffold.
Fig. 3

The design strategy of quinoline-pyrazole clubbed conjugates (7a–n), (8a–g), (9a–g), and (10a–g)

2 Results and Discussion

A series of substituted quinoline-pyrazole pharmacophore clubbed compounds were designed and synthesized by employing Doebner reaction Scheme 1. The preparation of substituted pyrazole aldehydes [40] compounds were depicted in Scheme 2. Condensation of substituted acetophenones 1 with substituted phenylhydrazine hydrochlorides 2 in the presence of acetic acid at room temperature provided the corresponding phenylhydrazones 3. Vilsmeier-Haack reaction of 3 in presence of DMF with POCl3 afforded substituted pyrazole carboxaldehydes 4.
Scheme 1

Synthesis of substituted pyrazole aldehydes

Scheme 2

Synthetic route for the title compounds (7a–n), (8a–g), (9a–g) and (10a–g)

All the titled compounds yielded in the range of 39-78%. Different derivatives of the title compounds are presented in Table 1. Newly synthesized compounds (7a–n), (8a–g), (9a–g) and (10a–g) were characterized by 1H NMR, 13C NMR and Mass spectroscopic methods.
Table 1

Preliminary characterization of the synthesized compounds (7a–n), (8a–g), (9a–g) and (10a–g)

Compound

R1

R2

R3

Yielda (%)

7a

-H

-H

-H

54

7b

-H

p-Br-

-H

63

7c

-H

p-CH3-

-H

61

7d

-H

-H

p-F-

68

7e

-H

-H

p-NO2-

52

7f

-H

-H

p-Cl-

60

7g

-H

-H

2,4-diCl-

58

7h

-CH3

-H

-H

66

7i

-CH3

p-Br-

-H

49

7j

-CH3

p-CH3-

-H

61

7k

-CH3

-H

p-F-

65

7l

-CH3

-H

p-NO2-

54

7m

-CH3

-H

p-Cl-

39

7n

-CH3

-H

2,4-diCl-

48

8a

-H

-H

-H

71

8b

-H

p-Br-

-H

69

8c

-H

p-CH3-

-H

74

8d

-H

-H

p-F-

78

8e

-H

-H

p-NO2-

68

8f

-H

-H

p-Cl-

72

8g

-H

-H

2,4-diCl-

77

9a

-H

-H

-H

60

9b

-H

p-Br-

-H

62

9c

-H

p-CH3-

-H

59

9d

-H

-H

p-F-

64

9e

-H

-H

p-NO2-

69

9f

-H

-H

p-Cl-

70

9 g

-H

-H

2,4-diCl-

73

10a

-CH3

-H

-H

58

10b

-CH3

p-Br-

-H

55

10c

-CH3

p-CH3-

-H

67

10d

-CH3

-H

p-F-

71

10e

-CH3

-H

p-NO2-

71

10f

-CH3

-H

p-Cl-

69

10g

-CH3

-H

2,4-diCl-

61

aIsolated yields

2.1 Pharmacology

2.1.1 In Vitro Antimicrobial Activity

The antibacterial activity of all synthesized compounds (7a–n), (8a–g), (9a–g) and (10a–g) were screened against three Gram-positive bacteria (Bacillus subtilis, Clostridium tetani, Streptococcus pneumonia) and three Gram-negative bacteria (Escherichia coli, Salmonella typhi, Vibrio cholerae) by using ampicillin, norfloxacin and ciprofloxacin as the standard antibacterial drugs. Antifungal activity was screened against two fungal species (Candida albicans and Aspergillus fumigatus) where nystatin and griseofulvin were used as the standard antifungal drugs. The minimal inhibitory concentration (MIC) of all compounds (7a–n), (8a–g), (9a–g) and (10a–g) was determined by the broth microdilution method according to National Committee for Clinical Laboratory Standards (NCCLS) [41]. The inoculum concentration of the test strain was adjusted to 108 CFU (colony-forming units) per cm3 by comparing the sample turbidity. Mueller–Hinton broth was used as a nutrient medium to grow and dilute the drug suspension for the test. DMSO was used as the diluent to get the desired concentration of compounds to test upon the standard bacterial strains. The obtained results are presented in Table 2.
Table 2

In vitro antimicrobial activity (MIC, µg/mL) of compounds (7a–n), (8a–g), (9a–g) and (10a–g)

Entry

Gram positive bacteria

Gram negative bacteria

Fungi

S.P.

MTCC 1936

C.T.

MTCC 449

B.S.

MTCC 441

S.T.

MTCC 98

V.C.

MTCC 3906

E.C.

MTCC 443

C.A.

MTCC 227

A.F.

MTCC 3008

7a

100

200

250

125

200

250

500

250

7b

200

250

200

200

200

200

> 1000

250

7c

200

250

250

200

250

200

1000

500

7d

125

250

250

200

100

62.5

250

500

7e

200

200

200

250

200

250

1000

200

7f

250

200

250

200

125

250

> 1000

> 1000

7g

200

250

250

200

200

200

> 1000

> 1000

7h

125

250

200

200

250

200

> 1000

1000

7i

200

250

200

250

200

250

1000

> 1000

7j

200

200

200

200

200

200

200

500

7k

250

250

250

250

200

250

> 1000

500

7l

100

200

100

250

250

250

> 1000

200

7m

200

200

250

250

250

200

1000

250

7n

200

200

200

100

62.5

125

500

250

8a

250

250

250

250

200

200

> 1000

200

8b

125

250

200

200

200

250

> 1000

250

8c

100

150

250

200

125

200

1000

1000

8d

200

200

100

125

250

250

> 1000

> 1000

8e

250

250

250

200

250

250

1000

1000

8f

125

250

125

200

250

250

> 1000

500

8g

200

250

200

200

200

200

1000

500

9a

250

250

200

250

200

200

1000

250

9b

100

500

250

250

200

250

1000

500

9c

200

500

200

250

200

200

> 1000

500

9d

250

500

125

250

250

200

500

200

9e

200

500

500

250

62.5

200

1000

250

9f

100

250

125

200

250

250

1000

> 1000

9g

250

250

500

200

62.5

200

> 1000

> 1000

10a

250

200

500

200

200

200

> 1000

1000

10b

250

250

250

200

200

250

1000

500

10c

200

250

200

200

250

200

1000

500

10d

200

250

250

200

200

250

1000

500

10e

250

250

200

200

200

250

> 1000

> 1000

10f

200

200

200

200

250

250

> 1000

1000

10g

250

250

200

200

200

200

1000

500

A

100

250

250

100

100

100

_

_

B

10

50

100

10

10

10

_

_

C

25

100

50

25

25

25

_

_

D

_

_

_

_

_

_

100

100

E

_

_

_

_

_

_

500

100

S.P. Streptococcus pneumoniae, C.T. Clostridium tetani, B.S. Bacillus subtilis, S.T. Salmonella typhi, V.C. Vibrio cholerae, E.C. Escherichia coli, C.A. Candida albicans, A.F. Aspergillus fumigatus, MTCC Microbial Type Culture Collection. A Ampicillin, B Norfloxacin, C Ciprofloxacin, D Nystatin, E Griseofulvin, “_” not tested

2.1.2 In Vitro Antituberculosis Activity

All the synthesized compounds (7a–n), (8a–g), (9a–g) and (10a–g) were evaluated for their in vitro antituberculosis activity against the Mycobacterium tuberculosis H37Rv strain. Screening of all the newly synthesized compounds was conducted at 250 µg/cm3 by using Lowenstein–Jensen medium as described by Rattan [42]. Rifampicin and Isoniazid were used as standard drugs. The results of antituberculosis screening data are shown in Table 3.
Table 3

In vitro antituberculosis activity (% inhibition) of compounds (7a–n), (8a–g), (9a–g) and (10a–g) against M. tuberculosis H37Rv (at concentrations 250 µg/mL)

% Inhibition

% Inhibition

Entry

250 μg/mL

Entry

250 μg/mL

7a

24

8f

30

7b

11

8g

34

7c

20

9a

61

7d

40

9b

55

7e

48

9c

49

7f

37

9d

67

7g

51

9e

92

7h

32

9f

60

7i

37

9g

95

7j

24

10a

38

7k

16

10b

22

7l

77

10c

28

7m

71

10d

43

7n

74

10e

82

8a

15

10f

87

8b

17

10g

73

8c

23

Rifampicin

98

8d

7

Isoniazid

99

8e

10

  

Table 3 in vitro antituberculosis activity (% inhibition) of compounds (7a–n), (8a–g), (9a–g) and (10a–g) against M. tuberculosis H37Rv (at concentrations 250 µg/cm3).

2.1.3 In Vitro Antimalarial Activity

All newly clubbed quinoline-pyrazole derivatives (7a–n), (8a–g), (9a–g) and (10a–g) were evaluated for their antimalarial activity against P. falciparum strain. Chloroquine and quinine were used as reference drugs. The results of the pharmacological screening are expressed as the drug concentration resulting in 50% inhibition (IC50) of parasite growth. The obtained results are presented in Table 4.
Table 4

In vitro antimalarial activity of compounds (7a–n), (8a–g), (9a–g) and (10a–g)

Entry

IC50 (µg/mL)

Entry

IC50 (µg/mL)

7a

1.88

8f

0.55

7b

0.78

8g

0.83

7c

0.82

9a

0.97

7d

1.55

9b

0.32

7e

0.86

9c

0.77

7f

0.40

9d

1.23

7g

0.31

9e

0.91

7h

1.47

9f

0.092

7i

0.63

9g

0.036

7j

0.86

10a

1.54

7k

1.27

10b

0.57

7l

0.78

10c

0.42

7m

1.040

10d

1.11

7n

0.22

10e

0.73

8a

1.36

10f

0.087

8b

0.52

10g

0.98

8c

0.91

Chloroquine

0.020

8d

1.54

Quinine

0.268

8e

0.88

  

2.2 Biological Results

2.2.1 In Vitro Antibacterial and Antifungal Activity

Upon investigation of antimicrobial screening data, it has been observed that the majority of the compounds showed good activity against Gram-positive bacteria. Compounds 7a, 7 l, 8d, 8c, 9b, 9f showed equal potency to ampicillin (MIC = 100 µg/cm3) against B. subtilis and S. pneumoniae. Whereas in inhibiting Gram-negative bacteria, the compounds 7n, 9e, 9 g and 7d showed excellent activity (MIC = 62.5 µg/cm3) against V. cholera and E. coli as compared to ampicillin (MIC = 100 µg/cm3). Compounds 3c against V. cholera showed equal activity as compared to ampicillin (MIC = 100 µg/mL). Aginst C. Albicans, compounds 7d and 7j showed better activity (MIC = 250 and 200 µg/cm3, respectively) and aginst A. Fumigatus compounds 7d and 7j showed equivalent activity (MIC = 500 and 500 µg/cm3, respectively) compared to standard drug Griseofulvin (MIC = 500 µg/cm3). Whereas compound 9d showed similar activity (MIC = 500 µg/cm3) compared to standard drug Griseofulvin (MIC = 500 µg/cm3) against C. Albicans.

2.2.2 Antituberculosis Activity

The cheering results from the antibacterial activity encouraged us to go for preliminary screening of all synthesized compounds for their in vitro antituberculosis activity. Antituberculosis screening of all quinolone-pyrazole derivatives (7a–n), (8a–g), (9a–g) and (10a–g) was conducted at a concentration 250 mg/cm3 against M. tuberculosis H37Rv strain (Table 2). At the commencement of this study in the preliminary screening, compound 9e displayed better activity and showed 92% inhibition. Compound 5g was found to possess excellent activity at both the concentrations i.e. 95%. While compounds 10e and 10f are moderately active against M. tuberculosis H37Rv. All other compounds showed poor inhibition of M. tuberculosis growth. From the above results, it can be concluded that compounds 9e and 9g may become a new class of antitubercular agents in future.

2.2.3 In Vitro Antimalarial Activity

All the compounds (7a–n), (8a–g), (9a–g) and (10a–g) were evaluated for their antimalarial activity against the P. falciparum strain. All experiments were performed in duplicate and the mean value of IC50 is given in Table 3. Compounds 9f and 9g were found to have IC50 in the range of 0.036–0.092 for the P. falciparum strain. These compounds showed principal activity against P. falciparum strain as compared to quinine IC50 0.268. Whereas compound 9f was found to possess moderate activity i.e. IC50 0.036 aligned with chloroquine. All other compounds were found to be not as much active as chloroquine and quinine against P. falciparum strain.

2.2.4 Structure–Activity Relationship (SAR)

The substitution on quinoline nucleus (R1) and the FGI (functional group interconversion) increases the biological activity as well as pyrazole substitution (R2 and R3) also responsible for enhancing the biological potency. The structure–activity relationship study is shown in Fig. 4.
Fig. 4

Structure-activity relationships for the antimicrobial, antimalarial and antituberculosis activities of the synthesized compounds (7a–n), (8a–g), (9a–g) and (10a–g)

3 Conclusion

A library of quinoline-pyrazole clubbed derivatives (7a–n), (8a–g), (9a–g) and (10a–g) were developed from substituted aniline, substituted-1H-pyrazole-4-carbaldehydes and pyruvic acid. All the synthesized compounds were characterized by analytical and spectral data (1H NMR, 13C NMR and Mass Spectroscopy) and are in full compliance with the suggested structure. Pyrazole-quinoline core structure derivatives enhanced their antibacterial, antimalarial and anti-mycobacterial activity, as is conspicuous from the biological evaluation results. Most of the compounds were found to be potent against tested microorganisms with moderate to good activity. For the specific bacterial strains, a majority of the compounds acquired the adjacent antibacterial potential to ampicillin, Norfloxacin, Ciprofloxacin, Nystatin and Griseofulvin.

4 Experimental

4.1 Materials

All the reactants were reagent grade, and purchased from Sigma Aldrich, and used without further purification unless otherwise stated. DCM (dichloromethane) and THF (tetrahydrofuran) were distilled from Calcium hydride (desiccant) and sodium benzophenone ketyl, respectively. All solvents were used without further drying or purification and were of ACS grade purchased from local suppliers. TLC plates (Silica Gel) were purchased from Sigma-Aldrich.

4.2 Instrumentation

Melting points were determined in open capillary tubes on a Stuart SMP 10 melting point apparatus and are uncorrected. Elemental analysis data were obtained with Perkin Elmer C, H, N analyser model 2400. Nuclear Magnetic Spectroscopy (NMR) spectra were produced using the Varian 400 MHz spectrometer. The instrument was maintained at 25 °C operating at 400 MHz for 1H NMR, and 100 MHz for 13C NMR. The deuterated solvent (DMSO-d6) used for each respective spectrum is referenced to the appropriate literature peak shift. Mass spectra were recorded on a Shimadzu LC/MS 2010 spectrometer. The Microwave-assisted reactions were performed in a QLABPro closed vessel microwave digestion system.

4.3 General Procedure for the Synthesis of (7a–n)

Into a 2 dm3 three-neck round-bottom flask equipped with a stirring bar magnet, a reflux condenser, and a dropping funnel and set above a heating mantle, (0.0535 mol) substituted pyrazole aldehydes, (0.0535 mol) Substituted aniline, and 520 cm3 absolute ethanol was introduced. The mixture was stirred and heated gently until pyrazole aldehydes and aniline had dissolved to form a brown solution. The mixture was then allowed to reflux for ~ 60 min. In the meantime, a mixture of (0.0535 mol) pyruvic acid and 208.3 cm3 absolute ethanol were prepared and placed in an addition funnel. After the reaction mixture had refluxed for ~ 60 min, the pyruvic acid solution was allowed to drop at a rate of two drops per second into the mixture. Within ~ 30 min, the addition of the pyruvic acid solution was complete, and the reaction mixture was allowed to reflux for approximately 5 days. Good yield of a white, powdery compound was collected (suction filtered) and recrystallized from ethanol.

4.4 General Procedure for the Synthesis of 8a–g

5.0 g pyrazole-quinolinecarboxylic acid, 62.63 cm3 dried and redistilled thionyl chloride was added to a 250 cm3 round-bottom flask equipped with a condenser tube, a drying tube and a magnetic stir bar, then heated with stirring for 6 h. The mixture was cooled to room temperature, and distilled under reduced pressure to remove excess thionyl chloride, then dried in vacuum. The residues were washed with petroleum ether and then dissolved in 10 cm3 toluene and concentrated under reduced pressure to afford the title compound.

4.5 General Procedure for the Synthesis of 9a–g

To the 250 cm3, three neck flask equipped with the thermometer, the addition funnel and the stirrer, 70 cm3 of tetrahydrofuran or ether, 5.3 g of N, N-dimethylaminoethylamine and 35 cm3 of triethylamine or DIPEA (diisopropylethylamine) was taken up. The solution was cooled to 0 °C and the solution of 9.4 g of compounds (8a–g) in 65 cm3 tetrahydrofuran or ether was added dropwise for 40 min under cooling and stirring so as the temperature did not exceed 0–15 °C. The mixture was then stirred for 24 h at room temperature. 150 cm3 of petroleum ether or hexane was added to the mixture. The semi-solid product was filtered off and macerated with 20 cm3 of ice-cooled saturated aqueous sodium chloride solution. The solid product was separated, washed once with 15 cm3 saturated aqueous sodium chloride solution, two times with ice water and purified with crystallization from the water: ethanol (2:1). The crude product was purified by column chromatography using ethyl acetate/NMM/methanol (98/1/1). Afforded white solid.

4.6 General Procedure for the Synthesis of 10a–g

BH3·THF 1 M solution in THF (65 cm3) was slowly added to a stirred suspension of quinoline-pyrazole carboxylic acid derivatives 7h–n (2.6 g, 66 mmol) in THF (90 cm3) at 0 °C under argon atmosphere. The reaction mixture was stirred 2–5 days at RT after complete addition. The reaction mixture was then quenched by the dropwise addition of H2O (15 cm3) and concentrated until ~ 50% of the volume. A solution of NaOH (6 M, 60 cm3) was added and the reaction mixture was refluxed for 1.5 h. The THF was evaporated and the reaction mixture was diluted with H2O (200 cm3) and extracted with EtOAc (3 × 70 cm3). The organic fraction was dried over Na2SO4, filtered by suction and concentrated in vacuum. The resulting crude material was purified by flash silica gel column chromatography (EtOAc/pet-ether 1:3 → 1:0), The product was further purified via preparative reversed phase HPLC using a 10 μm Gemini C18 column (Phenomenex) under isocratic conditions with acetonitrile/water (26:74; v/v) mobile phase. After evaporation of the solvent pure product was obtained.

2-(1,3-diphenyl-1H-pyrazol-4-yl)quinoline-4-carboxylic acid (7a C25H17N3O2). White solid; m.p. 230–232 °C; 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 8.35–8.31 (m, 2H), 8.15 (s, 1H), 8.08 (d, J = 7.4 Hz, 2H), 8.01 (dd, J = 7.6, 1.5 Hz, 2H), 7.93–7.86 (m, 2H), 7.71 (ddd, J = 7.4, 1.5, 0.8 Hz, 1H), 7.60–7.50 (m, 2H), 7.45 (dd, J = 4.8, 1.7 Hz, 3H), 7.43–7.37 (m, 1H).13C NMR (100 MHz, CDCl3) δ 169.55, 153.12, 149.52, 148.07, 139.22, 135.92, 135.55, 133.01, 131.66, 130.08, 129.81, 129.37, 129.33, 128.53, 127.87, 127.27, 126.14, 123.65, 122.25, 120.20, 119.70. MS (m/z) Calculated for C25H17N3O2 [M]+ = 392.13, found 392.10. Anal. Calcd. for C25H17N3O2. C, 76.71; H, 4.38; N, 10.74; found: C, 76.70; H, 4.36; N, 10.71.

2-(1,3-diphenyl-1H-pyrazol-4-yl) quinoline-4-carbonyl chloride (8a C25H16ClN3O). White solid; m.p. 218–220 °C; 1H NMR (400 MHz, CDCl3) δ 8.65 (d, J = 0.5 Hz, 1H), 8.26–8.23 (m, 1H), 8.21–8.17 (m, 3H), 8.04–8.00 (m, 2H), 7.93–7.88 (m, 2H), 7.85 (ddd, J = 7.2, 4.6, 1.9 Hz, 1H), 7.55 (t, J = 7.4 Hz, 2H), 7.51–7.45 (m, 4H), 7.44–7.38 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 166.83, 153.12, 150.42, 148.43, 139.22, 138.73, 133.01, 131.38, 130.11, 130.08, 129.81, 129.33, 128.53, 127.87, 127.82, 127.27, 125.28, 124.89, 122.88, 120.20, 120.01. MS (m/z) Calculated for C25H16ClN3O [M]+ = 409.10, found 409.1. Anal. Calcd for C25H16ClN3O. C, 73.26; H, 3.93; N, 10.25. found: C, 73.23; H, 3.90; N, 10.24.

N-(3-(dimethylamino)propyl)-2-(1,3-diphenyl-1H-pyrazol-4-yl)quinoline-4-carboxamide (9a C30H29N5O). White solid; m.p. 222–224 °C; 1H NMR (400 MHz, CDCl3) δ 8.55–8.50 (m, 1H), 8.33 (s, 1H), 8.27–8.21 (m, 1H), 8.17 (s, 1H), 8.07–7.98 (m, 3H), 7.95–7.79 (m, 4H), 7.58–7.50 (m, 2H), 7.50–7.45 (m, 3H), 7.45–7.37 (m, 1H), 3.13 (t, J = 7.1 Hz, 2H), 2.86 (t, J = 7.1 Hz, 2H), 2.48 (s, 6H), 1.76 (p, J = 7.1 Hz, 2H).13C NMR (100 MHz, CDCl3) δ 167.65, 153.12, 149.54, 149.52, 139.87, 139.22, 133.01, 131.12, 130.08, 129.81, 129.33, 128.89, 128.53, 127.87, 127.76, 127.27, 126.25, 124.00, 120.72, 120.20, 119.51, 56.91, 44.56, 37.95, 26.39. MS (ESI) m/z Calculated for C30H29N5O [M]+ = 476.24, found 476.24 Anal. Calcd for C30H29N5O. C, 75.76; H, 6.15; N, 14.73; found: C, 75.75; H, 6.12; N, 14.70.

(2-(1,3-diphenyl-1H-pyrazol-4-yl)-6-methylquinolin-4-yl) methanol (10a C26H21N3O). White solid; m.p. 243–245 °C; 1H NMR (400 MHz, CDCl3) δ 8.14 (s, 1H), 8.04–7.98 (m, 5H), 7.94–7.87 (m, 2H), 7.73 (ddd, J = 7.4, 1.5, 0.8 Hz, 1H), 7.59–7.51 (m, 2H), 7.50–7.45 (m, 5H), 7.44–7.37 (m, 1H), 5.54 (s, 2H), 2.45 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 152.79, 150.81, 148.31, 147.18, 139.22, 136.04, 133.01, 131.21, 130.08, 129.81, 129.33, 128.53, 128.14, 127.47, 127.27, 125.30, 122.53, 120.65, 120.20, 117.21, 61.63, 21.29. MS (m/z) Calculated for C26H21N3O [M]+ = 392.17, found 392.20. Anal. Calcd for C26H21N3O. C, 79.77; H, 5.41; N, 10.73. found: C, 79.74; H, 5.38; N, 10.71.

Notes

Acknowledgements

The authors KMP and PSD gratefully thanks the Head of the Department of Chemistry, Arts, Science and Commerce College (Affiliated to Veer Narmad South Gujarat University, Surat) for providing the necessary research facilities. The author KMP also gratefully appreciates Dr. Filip Petronijevic, Scientist, Department of Small Molecules Process Chemistry, Genentech Inc., SSF, California, USA for help in editing this manuscript.

Supplementary material

42250_2019_96_MOESM1_ESM.pdf (3.5 mb)
Supplementary material 1 (PDF 3544 kb)

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Copyright information

© The Tunisian Chemical Society and Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Chemistry, Arts, Science, and Commerce CollegeVeer Narmad South Gujarat UniversitySuratIndia
  2. 2.Department of Clinical DevelopmentImmunocore LLCConshohockenUSA

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