Molecular hybrid design, synthesis and biological evaluation of N-phenyl sulfonamide linked N-acyl hydrazone derivatives functioning as COX-2 inhibitors: New anti-inflammatory, anti-oxidant and anti-bacterial agents

Page 1 of 141

New Journal of Chemistry

View Article Online

DOI: 10.1039/C7NJ03332J

Molecular Hybrid Design, Synthesis and Biological Evaluation of Nꢀ

Phenyl Sulfonamide Linked NꢀAcyl Hydrazone Derivatives Functioning

as COXꢀ2 Inhibitors: New AntiꢀInflammatory, AntiꢀOxidant and Antiꢀ

Bacterial Agents

5

a,b

c

b

Vasubabu Gorantla , Rambabu Gundla * Surender Singh Jadav , Sreenivasa Reddy Anugu ,

d

b

a

Jithendra Chimakurthy , Kameswara Rao NS , Raghubabu Korupolu *

Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX

1

0

DOI: 10.1039/b000000x

We report the design, synthesis and the biological evaluation of antiꢀinflammatory activities of Nꢀphenyl

sulfonamide linked Nꢀacylhydrazones (NPSꢀNAH) using molecular hybridization approach. Hybrid

compounds were further validated with theoretical studies. Among these, compound 1f from seriesꢀ1 and

compound 2a from seriesꢀ2 exhibited strong selective COXꢀ2 enzyme inhibition at IC₅₀= 8.9 ꢁM, 8.4 ꢁM

respectively. An effective invivo antiꢀinflammatory profiling of potent and selective COXꢀ2 inhibitors

including compound 1f and 2a was carried out and compared with known COXꢀ2 inhibitors. Subsequently,

these compounds were tested for antioxidant activity and 1h (IC₅₀= 28.62 ꢁM) from seriesꢀ1 and compound

1

5

2

d (IC₅₀= 25.34 ꢁM) from seriesꢀ2 were found to be potent antiꢀoxidants. Additionally, these compounds

were screened for antibacterial activity wherein compound 1l and 2b exhibited better gram +ve and –ve antiꢀ

bacterial activity than reference standards: Ciprofloxacin and Norfloxacin. These results validated the idea of

exploiting the hybridization strategy for identification of new NꢀPhenyl sulfonamideꢀNAH derivatives for

optimizing antiꢀinflammatory, antioxidant and antiꢀbacterial activities.

2

0

2

5

Introduction

5

6

0

5

0

Additionally, inflammation affects the world economy by

reducing the workꢀhours and the quality of life of its work force .

The expenses that incur to health agencies and individuals to

4

1,2

manage pain and inflammation has been ever increasing

.

Despite the concerted and multifarious efforts by various global

pharmaceutical companies over the past few decades, a potent,

safe and selective drug to treat inflammation remains largely

unrealized. The challenge in achieving the selectivity to treat

inflammation can be attributed to the structural similarity of

enzymes: COXꢀ1 and COXꢀ2 that are involved in the process of

According to the Institute of Medicine’s (IOM) historic 2011

report, it was estimated that an annual budget of $261ꢀ$300

billion was spent in the United States alone on the treatment of

3

0

3

patients with various inflammatory conditions in 2010 . The cost

of pain was nearly 30% more than the combined cost of cancer

and diabetes. These expenses, when combined with the value of

lost productivity (an estimated $109 billion) cast a huge burden

on the national economy.

5,6

inflammation . Despite their similarity in structure they perform

7

different functions . The constitutive COXꢀ1 is responsible for

3

5

the maintenance of mucosal integrity whereas the induced COXꢀ2

_

_________________________________________________________

8

plays more important role in inflammation and pain . Aspirin is

a

9,10

Department of Engineering Chemistry, Andhra University College of

the most sold drug in the world . The next generation synthetic

Engineering (A), Vishakhapatnam, India, 530003

GVK Biosciences Private Limited, Medicinal Chemistry Laboratory,

pain killers, COXꢀ2 inhibitors (coxibs), in spite of being selective

for COXꢀ2 inhibition, showed to cause cardio toxicity and some

b

4

0

Hyderabad, India, 500076

c

65 drugs like Rofecoxib and Valdecoxib had to be banned or

Department of Chemistry, School of Technology, GITAM University,

11ꢀ14

Hyderabad (T.S), India, 502 102

voluntarily withdrawn from the market

. This impelled the

d

Department of Pharmacology, Bapatla College of Pharmacy, Bapatla

global pharmaceutical companies to explore new structural

scaffolds with diverse functionalities that would mitigate these

adverse side effects while retaining the desired COXꢀ2

selectivity.

Guntur (Dist.)

,

Andhra Pradesh, Bapatla, India, 522 101

1

13

4

5

†Electronic Supplementary Information (ESI) available: H NMR and C

NMR spectra of compounds are provided. See DOI: 10.1039/b000000x/

70

This journal is © The Royal Society of Chemistry [year]

[journal], [year], [vol], 00–00 |1

New Journal of Chemistry

Page 2 of 141

View Article Online

DOI: 10.1039/C7NJ03332J

The sulfonamide moiety prevails among the most ubiquitous

pharmacophoric functional groups in medicinal chemistry. The

diverse pharmacological activity that sulfonamide group brings

about in organic molecules makes it a first choice of functional

acyl NH, C=O and sulfonamide portions of ligands (1f and 2a,

Figure 2) at COXꢀ2 site. Whereas, methoxy substituted

derivatives were involved with Ser530. Similarly, Arg120 of

COXꢀ1 enzyme showed πꢀcation interactions with ringꢀA of a

5

0

5

0

5

group to be incorporated in the optimizations by hybrid approach. 60 few ligands (1h and 2d), side chain hydrogen bond of Arg83 with

It is present in most of the essential medicines that are available

amide C=O was observed in most circumstances. Arg469 of

COXꢀ1 contributed backbone hydrogen bond interactions with

aldehyde / acetophenone substitutions. Parallel to next case of

COXꢀ2 studies, here we found that Arg120 of COXꢀ1 enzyme

was responsible for hydrogen bonding with amide portion of

ligands and this might be a key point for their strong binding

energies. The other residues like Tyr355 were also made

important ligand contacts at acyl portion and sometimes Glu524

interacted with sulfonamide NH atom (2a). To confirm the exact

binding orientation of compounds, we tried to align them with

marketed drugs like Isoxicam, Meloxicam and Diclofenac at both

COX sites. The sulfonyl portion of oxicams and our ligands were

successfully aligned, the NAH aldehyde/ acetophenones part was

found to be matching with Diclofenac binding motif (Figure 3).

However, withrespect to crystal ligands, the designed library

found tobe more selective towards mefanamic acid binding site.

1

5

in the market today: antiꢀbacterials , carbonic anhydrase

16

17

18

inhibitors , hypoglycemics , antiꢀthyroids , proton pump

1

9

inhibitors and antiꢀinflammatory agents . Nimesulide is the

example of small molecule NSAIDS sold in the market today that

1

2

6

7

5

0

5

2

0, 21

has the sulfonamide functionality

. Among the recently

published independent pursuits of selective COXꢀ2 inhibitors, Nꢀ

acyl hydrazones (NAHs), a new class of antiꢀinflammatory

compounds, showed great promise in terms of selectivity in

2

2, 23

COXꢀ2 binding and their antiꢀinflammatory activity

. These

results have inspired us to validate the idea of amalgamating acyl

hydrazone with sulphonamide moieties to design a library of

compounds, study their in silico binding potential, and test their

in vitro and in vivo activities. In the present study, 38 new hybrid

compounds were designed, synthesized and their in silico binding

affinities were studied, along with their in vitro and in vivo COX

inhibitions. These compounds also exhibited good antioxidant

properties. Additionally, a literature survey revealed that many Nꢀ

Acyl Hydrazone (NAH) analogues have been identified as

antibacterial agents. These observations prompted us to screen

Chemistry

Scheme 1 outlines the synthesis of the 38 compounds used in

the current series of NAH analogues as antibacterial agents using 80 the present study. Benzoic acid was sulfonylated using standard

2

4

31

both gram positive and negative strains

.

conditions to give 3ꢀ(chloroꢀsulfonyl)benzoic acid B which was

32

coupled with 2ꢀchloro aniline to furnish sulfonamide derivative

C. The sulfonamide derivative C was coupled with methyl

glycinate using HATU/ triethylamine to give ester D, which in

85 turn was derivatized into acid hydrazide E, by treating with

hydrazine hydrate. Intermediate E was used as the common

intermediate to prepare both the scaffolds. Compounds 1a to 1w

were prepared by condensing Ewith various substituted

benzaldehydes by refluxing in ethanol using catalytic amount of

Results &Discussion

Rational design and study of binding ability at COX active

site

3

0

Previous reports on NꢀAcyl Hydrazones (NAHs) shown as

good antiꢀinflammatory agents by targeting COX enzymes

(

Figure 1). Despite showing promising antiꢀinflammatory

9

0

acetic acid. Compounds 2a to 2o were prepared in similar fashion

by derivatizing various substituted acetophenones with E.

The characterization of all the final compounds was done by

properties by virtue of their COX inhibition, suffered selectivity

issues due to their undesired COXꢀ1 inhibition

2

5ꢀ28

35

40

45

50

55

. Due to the

potential pharmacophoric properties of sulfonamide group

present in the small molecule NSAIDs, we envisaged that

introduction of Nꢀphenyl sulfonamide group into the NAH

containing compounds might result in synergistically improved

selective inhibition of COXꢀ2 enzyme, the idea that was not

exhaustively explored. In the process, two scaffolds were

designed that vary in their NAH component. The first scaffold

contained Nꢀacyl hydrazone derivatives of substituted

benzaldehydes whereas the second scaffold was derivatized from

substituted acetophenones. We calculated the drug like properties

of these 38 compounds and docking scores for COX inhibition

were tabulated in Table 1.

The imperative alignment of designed NPSꢀNAH derivatives was

investigated using Flurbiprofen (PDB: 1CQE) and Mefenamic

acid (PDB: 5IKR) therapeutic functional sites

types of ligand contacts with actives residues were noticed with

respect to both target proteins. In first case, active site residues

Arg120, Tyr355, Ser530, Ser119, Lys83 and His122 displayed

vital interactions with 1h and 2dat COXꢀ2 site. In the next case,

Arg120, Tyr115 and Tyr355 exhibited precise interactions with

1

13

recording H NMR, C NMR, IR, ESIꢀMS, and HRMS spectra.

The formation of possible rotamers around acyl hydrazone

HC=NꢀNH was evidenced from NMR integration of CH proton

that split into two peaks in a ratio of 1:3, Eꢀisomer being the

95

33, 34

major

. Similarly CH₂signal from glycine also showed

splitting in a ratio of 3:1 which can be attributed to the restricted

1

rotation around the amide bond. H NMR spectra recorded at

o

1

00 elevated temperature (100 C) resulted in convalescence of these

signals indicating the presence of rotamers.

In vitro COXꢀ1 and COXꢀ2 inhibiting activity

05

The NPSꢀNAH hybrid derivatives 1aꢀw and 2aꢀo were

screened for their ability to inhibit COX enzymes (COXꢀ1 and

COXꢀ2) as described by Copeland et al., (1994). All the

compounds were evaluated at 50 ꢁM concentration and the

obtained results were provided in Table 2 and Figure 4. To

2

9, 30

. Two variant

10 confirm COXꢀ1/COXꢀ2 enzyme inhibition, we further

investigated the concentrationꢀactivity responses at various

2

|

Journal Name, [year], [vol], 00–00

This journal is © The Royal Society of Chemistry [year]

Page 3 of 141

New Journal of Chemistry

View Article Online

DOI: 10.1039/C7NJ03332J

concentrations to determine IC₅₀values. Celecoxib (selective

COXꢀ2 inhibitor) and Indomethacin (selective COXꢀ1 inhibitor)

were used as reference standards for the current studies. The

of Inhibition of COXꢀ2)/ (% of Inhibition of COXꢀ1)) of all

compounds against COXꢀ1 and COXꢀ2 enzymes were generated.

The selective COXꢀ2 inhibitor Celecoxib was found to inhibit

enzyme assay was performed at five different concentrations (5ꢀ 10 COX1 and COXꢀ2 enzymes at 32 ꢁM and 0.35 ꢁM respectively.

50 ꢁM) and IC₅₀(ꢁM) value for each compound was calculated.

5

Based on this information, the selectivity ratios (SR values) ((%

Cl

Diclofenac

Salicylic acid

OH

H

N

NH

N

NH

OH

H

O

Cl

NSIADs

N

O

OH

N

Naproxen

O

Ketoprofen

H

N

OH

N

O

NH

OH

O

H

NO₂

N

Nimesulide

O

R

N

H

N

O

N

O

C

O

A

H

O

HN

Diflumidone

Pyridazine NAH

S

OO

O S O

HN

R = H (Series 1)

CH (Series 2)

O

=

3

B

O

HN S

O

F

H

Cl

N

F

N

O

H

O

Isoxazole NAH

N

H

O

Ph

OH

O

N

OH

Quinoxaline NAH

HN CH₃

N

S

N

O

H

N

S

O

N

H

O O

Cinnamoyl NAH

O

N

Meloxicam

OH

O

N

OH

H

Pyrazine NAH

N

O

H

N

R

S

O

N

H

O O

R

Isoxicam

Benzahydrazide NAH

PyridylNAH

Figure 1: Rational design approach of hybrid of NꢀPhenyl sulfonamide linkedNAH derivatives as antiꢀinflammatory agents.

1

2

3

5

0

5

0

3

5

Figure 2: Binding motif’s of COXꢀ2 inhibitors a) Compound 1f and 2a with COXꢀ2 active site, b) overview with COXꢀ2

This journal is © The Royal Society of Chemistry [year]

Journal Name, [year], [vol], 00–00 |3

New Journal of Chemistry

Page 4 of 141

View Article Online

DOI: 10.1039/C7NJ03332J

5

0

5

0

5

1

2

Figure 3: 3a) Overlap of Compoundꢀ1f with Pyridazine NAH, 3b) Overlap of Compoundꢀ1f with Isoxazole NAH, 3c) Overlap of

Compoundꢀ1f with Oxicams (blue), Diclofenac (red) and Coxibs (Ball and Stick); 3d) Over view all 3a, b & c at COXꢀ2 active site.

30

Scheme 1.Schematic procedure

4|

Journal Name, [year], [vol], 00–00

This journal is © The Royal Society of Chemistry [year]

Page 5 of 141

New Journal of Chemistry

View Article Online

DOI: 10.1039/C7NJ03332J

Table 1.ADME and Docking properties

Rule

Of

Five

Docking

Score COXꢀ Score COXꢀ

Docking

%

Human Oral

S.No Molecule

MW

HBD HBA logP

Absorption

1

2

1

2

3

4

5

6

7

8

9

1a

1b

1c

1d

1e

1f

488.92 2.25

8.75 3.832

8.75 3.87

89.84

90.116

79.924

80.634

80.845

82.39

0

1

0

1

2

1

0

1

0

1

2

1

2

1

2

1

ꢀ6.75

ꢀ6.08

ꢀ5.37

ꢀ5.17

ꢀ8.72

ꢀ6.79

ꢀ7.77

ꢀ6.5

ꢀ7.89

ꢀ7.58

ꢀ6.02

ꢀ6.49

ꢀ6.86

ꢀ10.09

ꢀ7.5

489.90 2.25 10.25 3.075

538.92 2.25

486.92 3.25

536.93 2.25

8.75 4.545

8.75 4.576

8.75 4.702

1g

1h

1i

9.5

3.036

2.818

4.47

76.433

74.018

80.444

54.006

81.176

77.673

76.522

82.206

79.703

73.963

66.092

79.619

93.903

76.47

ꢀ6.98

ꢀ7.57

ꢀ6.84

ꢀ6.97

ꢀ8.69

ꢀ9.15

ꢀ8.21

ꢀ8.05

ꢀ7.25

ꢀ6.43

ꢀ6.89

ꢀ8.12

ꢀ5.69

ꢀ6.66

ꢀ6.49

ꢀ7.56

ꢀ9.26

ꢀ6.5

8.75

ꢀ7.79

ꢀ4.72

ꢀ4.63

ꢀ6.59

ꢀ6.83

ꢀ9.8

1

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

1j

549.01 2.25 12.75 2.379

513.0 2.25 8.75 4.546

1

2

3

1k

1l

514.98 2.25

518.94 2.25

556.91 2.25

523.36 2.25

606.92 2.25

565.82 3.25

584.95 2.25

498.98 2.25

524.90 2.25

476.95 2.25

9.5

4.171

3.915

4.76

1m

1n

1o

1p

1q

1r

1s

8.75

8.75 4.325

8.75 5.479

ꢀ6.36

ꢀ5.55

ꢀ8.03

ꢀ6.19

ꢀ4.48

ꢀ4.56

ꢀ3.74

ꢀ5.19

ꢀ6.24

ꢀ4.02

ꢀ3.9

9.5

3.416

4.742

8.75 4.226

8.75 4.071

8.75 3.517

1t

1u

1v

1w

2a

2b

2c

2d

2e

2f

88.466

58.282

86.691

81.795

79.629

79.869

64.906

65.237

73.078

83.113

58.537

71.967

84.604

61.429

78.358

77.033

81.424

80.984

478.95 3.25 10.75 1.766

476.97 2.25

502.94 2.25

514.98 2.25

500.95 3.25

568.95 2.25

528.02 2.25

8.75 3.586

8.25 4.429

9

4.418

4.364

3.359

3.335

5.38

ꢀ3.31

ꢀ7.02

ꢀ6.69

ꢀ6.14

ꢀ6

ꢀ6.96

ꢀ7.22

ꢀ8.35

ꢀ5.24

ꢀ7.22

ꢀ7.46

ꢀ7.11

ꢀ6.91

ꢀ7.6

9

8.25

2g

2h

2i

9.25 4.684

563.04 2.25 12.25 2.86

ꢀ5.49

ꢀ4.45

ꢀ4.69

ꢀ5.09

ꢀ4.2

527.03 2.25

554.06 2.25

8.25 5.103

9.25 4.999

2j

2k

2l

569.07 3.25 10.75 3.74

570.06 2.25 10.95 4.301

ꢀ7.48

ꢀ8.53

ꢀ6.45

ꢀ8.62

2m

2n

2o

595.04 2.25

520.93 2.25

545.00 2.25

8.75 5.878

8.25 4.499

9.75 4.464

ꢀ6.52

ꢀ4.48

ꢀ7.23

5

This journal is © The Royal Society of Chemistry [year]

Journal Name, [year], [vol], 00–00 |5

New Journal of Chemistry

Page 6 of 141

View Article Online

DOI: 10.1039/C7NJ03332J

Figure 4: In vitro IC₅₀value for COXꢀ1 and COXꢀ2 enzyme inhibition.

5

Table 2. In vitro COXꢀ1 and COXꢀ2 activities

Percentage of COX Inhibition at

0µM

COX Inhibition (IC₅₀

µM)

Selectivity COXꢀ

5

Compounds

R'

1

/COXꢀ2

COXꢀ1

34.2

COXꢀ2

41.92

53.8

COXꢀ1

NT

COXꢀ2

NT

1

2

3

1a

1b

1c

2ꢀF

4ꢀF

0.82

0.4

21.4

NT

12.5

3ꢀFꢀ(4ꢀpyridyl)

2ꢀCF₃

36.53

33.23

1.1

NT

12.5

4

5

1d

1e

36.89

63.23

41.12

28.17

0.9

NT

3ꢀCF₃

2.24

6

7

8

9

1f

1g

1h

1i

4ꢀCF₃

43.76

59.02

51.12

51.44

69.96

52.66

55.63

66.28

0.63

1.12

0.92

0.78

NT

8.9

2ꢀOH

14.1

17.5

18.6

19.6

14.1

4ꢀOH

4ꢀOCHF₂

1

0

1

2

1j

1k

1l

4ꢀSO CH

43.86

35.54

37.21

63.86

47.67

65.01

0.69

0.75

0.57

NT

10.3

NT

2

3

1

2ꢀIsopropyl

3ꢀOC H

NT

2

5

1

3

1m

2ꢀF & 4ꢀOCH₃

48.54

55.01

0.88

NT

8.4

1

4

5

6

7

8

1n

1o

1p

1q

1r

2ꢀF & 4ꢀCF₃

2ꢀCl & 4ꢀF

2 & 4ꢀ CF₃

3ꢀBr & 4ꢀOH

65.51

38.85

43.47

50.62

44.46

71.07

51.59

57.24

51.67

40.51

0.92

0.75

0.76

0.98

1.1

10.3

NT

9.3

NT

12.5

15.5

NT

16.8

NT

2

ꢀOCH & 5ꢀ

3

OCF₃

1

9

1s

2 & 6ꢀCH₃

48.63

52.51

0.93

NT

10.2

2

0

1

1t

2,3 & 6ꢀF

2ꢀThionyl

27.92

35.72

46.81

44.2

0.6

NT

1u

0.81

6

|

Journal Name, [year], [vol], 00–00

This journal is © The Royal Society of Chemistry [year]

Page 7 of 141

New Journal of Chemistry

View Article Online

DOI: 10.1039/C7NJ03332J

2

3

4

1v

1w

2a

Piperizinyl

Cyclohexyl

4ꢀF

46.91

28.37

34.54

45.36

39.77

77.87

1.03

0.71

0.44

NT

8.4

NT

2

5

6

2b

2c

2ꢀOCH₃

4ꢀOCH₃

37.99

21.07

45.63

77.6

0.83

0.27

NT

13.4

17.3

11.6

15.6

2

7

8

2d

2e

3ꢀOH

4ꢀOH

57.67

53.47

51.59

54.22

1.12

0.99

14.3

19.4

2

3

9

0

1

2f

2g

2h

4ꢀOCF₃

30.62

44.46

48.63

58.54

65.51

58.85

0.52

0.68

0.83

NT

4ꢀN(CH₃)₂

4ꢀSO CH

11.5

2

3

10.7

3

2

3

4

5

2i

2j

2k

2l

4ꢀIsopropyl

4ꢀPyrrolindine

4ꢀpiperazinyl

4ꢀmorphine

27.92

35.72

46.91

28.37

57.24

69.67

50.51

62.51

0.49

0.51

0.93

0.45

NT

12.3

11.5

10.6

10.1

4

Ph

ꢀ(4ꢀFꢀPhenoxy)ꢀ

3

6

7

8

2m

2n

2o

34.54

37.99

57.99

56.81

44.2

0.61

0.86

0.89

NT

9.5

NT

9.2

2 & 5ꢀF

2 & 4ꢀOCH₃

65.36

12.4

4

0

1

Indomethacin

Celecoxib

65.4

15.1

23.2

93.4

2.8

0.1

0.19

32

14

0.35

(IC₅₀= 9.3 ꢁM). Compound 1p (IC₅₀= 12.5ꢁM) is a ditrifluoro

Most of the compounds from both series (1b, 1f, 1j, 1p and

s from seriesꢀ1 and 2a, 2c, 2i, 2j, 2k, 2l and 2m from seriesꢀ2)

were found to be most active (IC₅₀= <10ꢁM) and selective COXꢀ

methylated derivative that exerted a potent COXꢀ2 enzyme

inhibition. Introduction of additional bromine on 1h gave a

moderately dual inhibiting compound 1q (COXꢀ2: IC₅₀= 15.5

1

5

0

5

0

5

0

2

inhibitors. A few compounds (1g, 1h, 1i, and 1q from seriesꢀ1 35 ꢁM / COXꢀ1: IC₅₀= 16.8 ꢁM). The combination of various esters

and 2d, 2h, 2i and 2o from seriesꢀ2) exhibited dual COX enzyme

inhibition (IC₅₀= <15ꢁM for COXꢀ2 and IC₅₀= <18ꢁM). The

selective COXꢀ1 enzyme inhibition was not found in the case of

any compound.

Compound 1f (IC₅₀= 8.9 ꢁM) was found to be stronger and

more selective COXꢀ2 inhibitor among the fluorinated

derivatives. The presence of trifluoromethyl group at para

position in compound 1f resulted in selective COXꢀ2 inhibition

and others failed to exhibit activity. The hydroxyl substituted

compounds 1g and 1h displayed moderate dual COX enzyme 45 derivatives. Polar hydrophilic group like hydroxyl and its

inhibition (COXꢀ2 activity for 1g and 1h: IC₅₀= 19.6 ꢁM, IC₅₀

1

=

resulted in loss of activity in 1r. Dimethyl substituted compound

1s (IC₅₀= 10.2 ꢁM) was shown to a selective COXꢀ2 inhibitor.

The presence of trifluoro (1t), thionyl (1u), piperizinyl (1v) and

cyclohexyl (1w) groups rendered them inactive.

1

2

3

40

The NPSꢀNAH derivative with substituted monofluorinated

acetophenone (seriesꢀ2), compound 2a exhibited potent and

selective COXꢀ2 enzyme inhibition at IC₅₀= 8.4 ꢁM. The para

methoxy substituted compound 2c showed the best selectivity

(IC₅₀= 13.4 ꢁM) for COXꢀ2 selectivity among methoxy

=

derivatives 2d and 2e imparted dual COX enzyme inhibition

(COXꢀ2 activity for 2d and 2e: IC₅₀= 17.3 ꢁM, IC₅₀= 11.6 ꢁM;

COXꢀ1 for 2d and 2e: IC₅₀= 14.3 ꢁM and IC₅₀= 19.4 ꢁM).

Among these 2e displayed better COXꢀ2 inhibition than COXꢀ1.

4.1 ꢁM; COXꢀ1 activity for 1g and 1h: IC₅₀= 14.1 ꢁM and IC₅₀

17.5 ꢁM). Similarly, the difluoro methoxy compound 1i

showed moderate dual COX enzyme inhibition. Introduction of

monomethyl sulfonyl group at para position in compound 1j 50 The presence of electronegative groups like tifluoromethoxy in

(IC₅₀= 10.3ꢁM) improved COXꢀ2 selectivity, whereas the mono

compound 2f proved to increase COXꢀ2 selectivity (IC₅₀= 15.6

ꢁM). Compounds 2g, 2h and 2i exhibited potent COXꢀ2 enzyme

inhibition at lower micromolar concentrations (IC₅₀= <13ꢁM).

The para pyrrolidine (2j), piperizinyl (2k) and morpholine (2l)

alkyl and ester group (1k and 1l) were not found to be favorable

for inhibition of any of the enzymes. Presence of additional

methoxy group on 1a rendered compound 1m (IC₅₀= 8.4ꢁM) the

most selective COXꢀ2 inhibitor among seriesꢀ1 compounds. On 55 substituted acetophenones displayed potent COXꢀ2 enzyme

the other hand, trifluoromethyl substitution on 1a furnished

compound 1n, which turned out to be a potent dual COX enzyme

inhibitor (COXꢀ2: IC₅₀= 9.3 ꢁM / COXꢀ1: IC₅₀= 10.3 ꢁM).

Introduction of chlorine (1b) enhanced COXꢀ2 enzyme inhibition

inhibition, among which 2l was the most active compound (IC₅₀

10.1ꢁM). The fluorophenoxy derivative 2m showed

=

pronounced COXꢀ2 inhibition ((IC₅₀= 9.5ꢁM). While the

difluoro substituted derivative 2n was inactive, the dimethoxy

This journal is © The Royal Society of Chemistry [year]

Journal Name, [year], [vol], 00–00 |7

New Journal of Chemistry

Page 8 of 141

View Article Online

DOI: 10.1039/C7NJ03332J

compound 2o was found to have dual COX enzyme inhibition

with slightly higher COXꢀ2 activity (COXꢀ2: IC₅₀= 9.2 ꢁM/IC₅₀

=

12.4 ꢁM).

From the above COX enzyme assay findings, it was observed

5

that the para substitution was favourable for COX activity. It

was also noted, in most of the compounds, the presence of

halogens, hydroxyl, alkyl, ester and heteroaryl were positively

influenced the potency. Compounds from both series imparted a

recognizable COX inhibitory activity.

10

In vivo antiꢀinflammatory activity

The COX selectivity and inhibitory potentials of new hybrid

NPSꢀNAH analogs were clearly demonstrated by in vitro COX

enzyme assay. The NPSꢀNAH hybrids that were shown to be

potent COX inhibitors (1f, 1j, 1m, 1n, 1o, 1s, 2a, 2h, 2k, 2l, 2m

and 2o) as determined by in vitro studies were further taken to

confirm their antiꢀinflammatory behavior by subjecting them to

3

0

Figure 5: In vivo IC₅₀value for COXꢀ1 and COXꢀ2 enzyme

inhibition

15

20

25

The effects of various functional groups attached to NPSꢀNAH

analogs on COX inhibitory activity were analyzed with respect to

their invivo biological studies to interpret antiꢀinflammatory

invivo studies using carrageenan induced rat paw edema analysis 35 behavior. The selective COXꢀ2 inhibitors with mono electroꢀ

(Winter et al 1962). An accurate amount (10 mg/kg body weight)

negative substitutions (1f and 2a) at para position inhibited

inflammation at 3 h interval and exhibited much more antiꢀ

inflammatory response at second interval than standard. The

disubstituted compounds (1mꢀo) with halogen (ortho) and

of each test compound was administered orally before 30 minutes

of carrageenan injection induced inflammation. Ibuprofen

reference standard was employed as positive control for current

invivo research. The antiꢀinflammatory response was monitored 40 methoxy (para) or halogen (para) group displayed an increasing

at 3 h and 5 h time period following the injection. All the selected

test compounds exhibited potent to good antiꢀinflammatory

responses at both intervals when compared with Ibuprofen as

shown in Table 3 and Figure 5.

antiꢀinflammatory profile, whereas in case of compound 2o it was

decreased. The substitution of methyl sulfonyl group in 1j and 2h

resulted in opposite antiꢀinflammatory profile. Among all hetero

aryl substituted acetophenones, piperizinyl (2k) and

fluorophenoxy (2m) groups delivered the desired profile. The

selective COXꢀ2 compounds were having good agreement with

in vivo antiꢀinflammatory test results. The selective fluorinated

COXꢀ2 inhibitors 1f, 2a and 2m were displayed prolonged antiꢀ

inflammatory profile. The compound 1j, 1s, 2h, 2l and 2o having

the good in vitro COXꢀ2 inhibition (IC₅₀= 9.2ꢀ10.7ꢁM) with

the extended in vivo activity.

45

Table 3. In vivo antiꢀinflammatory activity

Antiꢀ

Change in Paw edema

inflammatory

S.No

Compds

volume (ml) after drug

treatment

activity % of

inhibition

50

3

h

5h

3h

ꢀꢀ

5h

ꢀꢀ

1

2

Control

1f

0.86±0.173 0.87±0.140

An effective antiꢀinflammatory profile of selective COXꢀ2

inhibitors include compound 1f from seriesꢀ1 (60.62% inhibition

at 3 hꢀcarrageenan and 84.94% inhibition at 5 hꢀcarrageenan) and

compound 2a from seriesꢀ2 (75.04% inhibition at 3 hꢀcarrageenan

and 85.56% inhibition at 5 hꢀcarrageenan) were observed.

Compound 2m exhibited significant, antiꢀinflammatory profile at

both intervals (80.62% inhibition at 3 hꢀcarrageenan and 81.25%

inhibition at 5 hꢀcarrageenan) than standard. A slightly lower and

0

.11 ±

.051

0.10 ±

0.051

60.62 84.94

3

4

5

6

7

8

9

1j

1m

1n

1o

1s

0.31±0.038 0.22±0.157 62.71 62.56

0.27±0.045 0.24±0.122 61.24 65.93

0.28±0.069 0.18±0.040 67.44 68.31

0.28±0.078 0.26±0.086 60.62 61.23

55

0.22±0.55

0.26±0.205 70.97 69.76 60 varied antiꢀinflammatory profiles of compounds 1m, 1n, 1o and

k at 3 hꢀcarrageenan (between 60.62ꢀ70.97% inhibitions) and 5

2

2a

2h

2k

2l

0.35±0.035 0.39±0.050 75.04 85.56

0.27±0.069 0.38±0.040 66.44 56.38

0.17±0.078 0.16±0.086 60.62 61.24

0.28±0.069 0.38±0.040 57.44 55.31

0.17±0.078 0.15±0.086 80.62 81.25

hꢀcarrageenan (61.24ꢀ69.76% inhibitions) intervals were

observed. In case of compounds 1j, 1s, 2h, 2l and 2o (between

57.44ꢀ7.97% inhibition at 3 hꢀcarrageenan and 55.31ꢀ69.76%

inhibition at 5 hꢀcarrageenan) displayed an opposite antiꢀ

inflammatory profile.

1

0

1

2

3

4

65

2m

2o

DPPH antioxidant activity

0.21±0.55

0.20±0.205 75.97 69.75

61.3

Ibuprofen 0.24±0.135 0.34±0.145 72.48

An accurate antiꢀoxidant property of newer NPSꢀNAH

derivatives were still under investigation, in this regard a few of

these were reported to have an efficient DPPH radical scavenging

70

35ꢀ37

antiꢀoxidant capability

. Antiꢀoxidant activity of the

8|Journal Name, [year], [vol], 00–00

This journal is © The Royal Society of Chemistry [year]

Page 9 of 141

New Journal of Chemistry

View Article Online

DOI: 10.1039/C7NJ03332J

compounds from the current study has been measured and

majority of the active compounds were hydroxy derivatives from

both the series Table 4. Ascorbic acid was used as reference

2

5

6

2b

2c

2d

2e

2f

33.05

NT

24.33

69.97

67.25

13.53

18.56

15.76

24.88

57.15

73.5

standard, it displayed 89.01% antioxidant activity with IC₅₀

20.7 ꢁM. Para and meta hydroxy substituted compounds 1h and

exhibited 98.11% and 88.36% inhibition at initial

=

27

25.34

48.5

NT

5

0

5

0

2

8

9

1

g

concentrations. Similarly, compounds 2d and 2e with hydroxy

substitution from the next series also displayed 69.97% and

30

2g

2h

2i

NT

3

7

6

7.25% antiꢀoxidant activity . Whereas, para hydroxy and meta

3

1

2

3

4

5

6

NT

1

2

bromo combination (1q) resulted in decreased antiꢀoxidant

activity. The piperizinyl group positively influenced the activity

in compounds 1v and 2k (61.34% and 73.5% inhibition).

The compounds that showed activity were further studied to

determine their experimental IC₅₀values. Among all, compound

NT

2j

68.5

46.73

NT

2k

2l

8.56

2d (IC₅₀= 25.34 ꢁM) from seriesꢀ2 and compound 1h (IC₅₀

=

2m

15.76

NT

2

8.62 ꢁM) from seriesꢀ1 were found to be potent antiꢀoxidants.

Piperizinyl derivatives 2k and 1vexhibited antiꢀoxidant activity at

lIC50 = 46.73 ꢁM and 74.53 ꢁM concentrations and displayed

better activity than other heteroaryl analogs. The presence of

hydroxy substituents on NPSꢀNAH scaffold has shown to be

3

4

7

8

0

2n

2o

14.84

43.05

89.01

NT

Ascorbic acid

20.7

3

4, 37

essential for the DPPH antiꢀoxidant activity

Table 4. Binding DPPH antioxidant activity

.

Antimicrobial screening

2

3

4

5

0

5

0

%

of inhibition

at 100µM

The halogen and hetero aryl derived acyl hydrazones were

S.No

Compounds

IC50(µM)

NT

3

9

reported to show promising antiꢀmicrobial activities . The acyl

hydrazones were recognized as potent antiꢀbacterial agents

against Methicillin resistant gram positive strains. Further, in

1

1a

22.9

2

3

4

1b

1c

1d

20.45

22.45

18.46

NT

depth validations proved them as selective bacterial pyruvate

40,41

kinase inhibitors

. As the exact acyl hydrazone antibiotics are

not available, based on the ease of availability, the marketed

drugs i.e, Ciprofloxacin and Norfloxacin choosed as reference

standards for current antimicrobial investigation. The concurrent

antiꢀbacterial screening of our newly designed NPSꢀNAH

compounds delivered a wide range of selective, potent to

moderate and promising drugꢀlike antiꢀmicrobial agents. The

marketed known drugs Ciprofloxacin and Norfloxacin were used

as positive controls for the present antiꢀbacterial investigation.

The sulfonamide derived compound 2h was found to be an

effective drug like candidate, delivering the desired antiꢀbacterial

activity against both gram positive and negative (Escherichia

coli, Klebsiellapneumoniae, Pseudomonas species and

staphylococcus aureus). The detailed antibacterial data was

5

6

7

8

9

1e

1f

55.69

65.65

88.36

98.11

26.54

26.87

20.43

21.34

61.63

38.87

19.88

48.55

68.36

50.13

26.55

23.87

22.43

61.34

28.36

17.99

69.04

58.14

33.45

28.62

NT

1g

1h

1i

1

2

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

1j

NT

1k

1l

NT

1m

1n

1o

1p

1q

1r

1s

34.76

NT

45 shown in Table 5. A careful examination of antiꢀbacterial

screening results demonstrated NPSꢀNAH compounds from both

the series as selective to potent gram positive bacterial inhibitors

NT

(

1h, 1i, 1j, 1l, 1n, 1w, 2e and 2f). A few other compounds (1k, 1r,

55.62

98.6

NT

1v, 2b and 2n) also displayed potent to moderate and effective

antiꢀbacterial activity than reference standards against either of

the strains. Some of these exhibited selective and coherent gram

negative bacterial inhibitions (1q, 1t, 2c, 2k, 2m and 2o). At last,

remaining compounds (1a, 1, 1u, 1f, 2d and 2g) exhibited

equivalent antiꢀbacterial activities as seen with reference

standards. The previous reports explained the presence of

hydroxyl, methoxy, halogens and piperizinyl, cyclohexyl on

hetero aryl ring systems was found to be crucial for their efficacy

5

0

1t

NT

1u

1v

1w

2a

NT

5

74.53

NT

4

2, 43

and the current results are also in line with this prediction.

NT

This journal is © The Royal Society of Chemistry [year]

Journal Name, [year], [vol], 00–00 |9

New Journal of Chemistry

Page 10 of 141

View Article Online

DOI: 10.1039/C7NJ03332J

5

10

Table 5. Antiꢀmicrobial activities

Test

Diameter of Zone of Inhibition (mm) at Concentration of 1.0mg/50ꢁl

S.No

Escherichia coli (ꢀ

ve)

Klebsiellapneumoniae (ꢀ

ve)

Pseudomonas species

(+ve)

staphylococcus aureus

(+ve)

Compounds

1

2

3

4

5

6

7

8

9

1a

1b

1c

1d

1e

1f

32

0

40

10

0

41

29

0

56

27

26

21

29

0

28

23

0

25

19

22

31

15

18

22

11

0

28

22

0

27

0

1g

1h

1i

16

14

28

16

10

24

18

0

1

2

3

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

1j

0

1k

1l

12

0

1m

1n

1o

1p

1q

1r

1s

21

0

22

0

11

0

19

21

18

12

19

22

12

0

18

24

22

0

29

0

28

0

11

15

0

16

0

1t

15

28

0

1u

1v

1w

2a

2b

2c

2d

2e

2f

22

11

28

34

0

28

16

10

0

14

30

21

0

11

33

24

0

10

0

29

16

34

28

10

0

28

17

36

0

2g

2h

2i

25

10

14

0

26

10

11

0

12

10

36

0

2j

34

0

2k

14

11

1

0|

Journal Name, [year], [vol], 00–00

This journal is © The Royal Society of Chemistry [year]

Page 11 of 141

New Journal of Chemistry

View Article Online

DOI: 10.1039/C7NJ03332J

3

5

6

7

8

2l

2m

2n

2o

0

34

0

36

0

21

19

32

24

18

31

16

0

17

0

3

4

9

0

Ciprofloxacin

Norfloxacin

30

28

33

29

31

29

35

31

Conclusions

using a diode array detector. IR spectra were recorded on a FTꢀIR

spectrometer and only major peaks were reported in cmꢀ1.

In summary, we designed and synthesized 38 new Nꢀphenyl

sulfonamide linked Nꢀacyl hydrazones (NPSꢀNAH) based on

molecular hybridization as well as in silico studies as potential

new antiꢀinflammatory agents. Subsequently, all these derivatives

were tested to evaluate their in vitro antiꢀinflammatory activities

using COXꢀ1 and COXꢀ2 enzyme assays. Majority of the

compounds from both series (1b, 1f, 1j, 1p and 1s from seriesꢀ1

and 2a, 2c, 2i, 2j, 2k, 2l and 2m from seriesꢀ2) were found to be

active and selective COXꢀ2 inhibitors. A few compounds (1g, 1h,

5

0

3

-(Chlorosulfonyl)benzoic acid (B)

5

0

5

0

5

0

Chlorosulfonic acid (A) (250 mL) was added to benzoic acid (50

g, 409 mmol) and the mixture was heated at 120ꢀ125°C for 2

hours. The mixture was cooled, quenched in ice cold water,

extracted with ethyl acetate, dried over sodium sulphate and the

solvent was removed under reduced pressure. The crude product

was washed with hexane to give 70.3 g (78%) of 3ꢀ(chloro

5

6

7

5

0

5

0

5

1

2

3

1

i, and 1q from seriesꢀ1 and 2d, 2h, 2i and 2o from seriesꢀ2)

o

1

sulfonyl)benzoic acid (B)as a white solid. mp: 127ꢀ131 C; Hꢀ

NMR (400 MHz, DMSOꢀd6): δ = 13.95 (br, 1H, COOH), 8.28 (s,

1H, ArꢀH), 7.98 (d, 1H, J = 7.6 Hz, ArꢀH), 7.92 (d, 1H, J = 7.6

exhibited dual COX enzyme inhibition. None of the compound

exhibited selective COXꢀ1 enzyme inhibition. An effective invivo

antiꢀinflammatory profile of selective COXꢀ2 inhibitors include

compound 1f from seriesꢀ1 (60.62% inhibition at 3 hꢀcarrageenan

and 84.94% inhibition at 5 hꢀcarrageenan) and compound 2a

from seriesꢀ2 (75.04% inhibition at 3 hꢀcarrageenan and 85.56%

inhibition at 5 hꢀcarrageenan) which were shown to be more

active than standards. These compounds were also subjected to

testing for antioxidant activity and 1h (IC₅₀= 28.62 ꢁM) from

seriesꢀ1 and compound 2d (IC₅₀= 25.34 ꢁM) from seriesꢀ2 were

found to be potent antiꢀoxidants. These compounds were also

screened for their antibacterial activities and compounds 1l and

13

Hz, ArꢀH), 7.55 (t, 1H, J = 7.6 Hz, ArꢀH); CNMR (125 MHz,

DMSOꢀd6) δ = 167.47, 148.24, 131.16, 130.51, 130.41, 129.12,

1

27.05; ESIꢀMS: m/z = 219.01 [MꢀH]

3

-(N-(2-chlorophenyl)sulfamoyl)benzoic acid (C)

A solution of 3ꢀ(chloroꢀsulfonyl)ꢀbenzoic acid B (70 g, 318

mmol) in ethyl acetate (50 mL) was added to ice cold solution of

4

ꢀchloroaniline (40 mL, 381 mmol) and pyridine (154 mL, 1.9

o

mol) in ethyl acetate (300 mL) at 0 C and stirred 16h at room

temperature. The mixture was diluted with 5% methanol in

dichloromethane (300 mL) and then washed with 2N

hydrochloric acid (100 mL) and water (80 mL). The organic

phase was dried (magnesium sulfate) and the solvent removed in

2

b exhibited dominant gram +ve and –ve antiꢀbacterial activity

when compared with reference standards Ciprofloxacin and

Norfloxacin. We consider this study as a valuable starting point

for further lead optimization efforts aiming at finding more potent

antiꢀinflammatory agents with an improved physicochemical

profile.

vacuum to give

a pink solid. Purification by column

chromatography on silica eluting with 50% ethyl acetate in

hexane and then ethyl acetate gave 63 g (63.6%) of 3ꢀ(2ꢀ

chlorophenylsulfamoyl)benzoic acid C as offꢀwhite solid. mp:

o

1

83ꢀ187 C; HꢀNMR (400 MHz, DMSOꢀd6): δ = 13.45 (br, 1H,

Experimental Section

COOH), 10.19 (s, 1H, SO NHAr), 8.25 (s, 1H, ArꢀH), 8.17 (d,

2

1

H, J = 8 Hz, , ArꢀH), 7.89 (d, 1H, J = 6.4 Hz, , ArꢀH), 7.69 (t,

Chemistry

80 1H, J = 7. 8 Hz, , ArꢀH), 7.40 (d, 1H, J = 8 Hz, ArꢀH), 7.32ꢀ7.28

13

(m, 1H, ArꢀH), 7.24ꢀ7.20 (m, 2H, ArꢀH); CNMR (125 MHz,

3

4

5

0

5

Thinꢀlayer chromatography was performed on 250 mm silica

plates and column chromatographic purifications were performed

on 100–200 mesh silica gel. All aldehydes, acetophenones and

DMSOꢀd6) δ = 166.00, 140.97, 133.44, 133.21, 131.80, 130.66,

130.00, 129.86, 129.51, 128.08, 128.08, 127.87, 127.47; HRMS

+

(ESI): m/z calcd for C H ClNO S [M + H] 312.0097, found

1

3

11

4

all other reagents were obtained from commercial suppliers and 85 312.0093.

1

were used without further purification. H NMR spectra were

Methyl 2-(3-(N-(2-chlorophenyl)sulfamoyl)benzamido)acetate

(D)

HATU (76 g, 0.2mol) was added to a stirred suspension of the 3ꢀ

(Nꢀ(2ꢀchlorophenyl)sulfamoyl)benzoic acid (C) (62 g, 0.20 mol)

1

3

collected either at 500 MHz or at 400 MHz and C NMR spectra

collected either at 125MHz or at 100 MHz, are referenced to the

carbon resonance of the deuterated solvent. Spectra were obtained

either in DMSOꢀd6 (see specific compound descriptions below). 90 and methylglycinate hydrochloride (25.1 g, 0.20 mol) in

High resolution mass spectrometry was performed at the Mass

Spectrometry Laboratory at GVK Biosciences Pvt. Ltd. LCꢀMS

analyses were performed with electro spray ionization (ESI), and

operated in the positive ion mode. LC analysis was performed

dichloromethane at room temperature, the mixture was stirred for

15 min, trimethylamine (83.6 mL, 0.60 mol) was added to the

reaction mixture and stirred for 18 h at room temperature. The

reaction mixture was diluted with dichloromethane, washed with

This journal is © The Royal Society of Chemistry [year]

Journal Name, [year], [vol], 00–00 |11

New Journal of Chemistry

Page 12 of 141

View Article Online

DOI: 10.1039/C7NJ03332J

water, bicarbonate and finally dried over sodium sulfate. The

organic layer was concentrated under reduced pressure to give

crude compound. The crude compound was purified by flash

3255, 1697; HRMS (ESI): m/z calcd for C H ClFN O S [M +

22 19 4 4

H] 489.0800, found 489.0807.

3-(N-(2-chlorophenyl)sulfamoyl)-N-(2-(2-(4-fluorobenzylidene)

+

chromatography to give pure product 26 g (34.14%) of methyl 2ꢀ 60 hydrazinyl)-2-oxoethyl) benzamide (1b)

o

1

5

0

5

0

5

0

5

0

5

0

5

(3ꢀ(Nꢀ(2ꢀchlorophenyl)sulfamoyl)benzamido)acetate (D) as white

Yield: 76%; mp:205ꢀ209 C; H NMR (500 MHz, DMSOꢀd6) δ

o

1

color solid. mp: 183ꢀ187 C; HNMR (400MHz, DMSOꢀd6) δ =

0.15 (brs, 1H, SO NHAr), 9.19 (t, J = 6 Hz, 1H, NHCH ), 8.24

11.54 (s, 1H, CONHNCH), 10.17 (s, 1H, SO NHAr), 9.15 and

8.98 (2t, J = 5.9 Hz, 1H, CONHCH ), 8.30 (s, 1H, ArꢀH), 8.16 (d,

J = 7.5 Hz, 1H, ArꢀH), 8.23 and 8.01 (2s, 1H), 7.86 (d, J = 6.2

2

1

2

(s, 1H, ArꢀH), 8.11 (d, J = 8 Hz, 1H, ArꢀH), 7.85 (d, J = 8.4 Hz,

1

H, ArꢀH), 7.68 (t, J = 8Hz, 1H, ArꢀH), 7.40 (d, J = 8 Hz, 1H, 65 Hz, 1H, ArꢀH), 7.81 – 7.72 (m, 2H, ArꢀH), 7.70 (t, J = 7.8 Hz,

1

2

3

4

5

ArꢀH), 7.31ꢀ7.19 (m, 3H, ArꢀH), 3.83 (d, J = 6 Hz, 2H, CH );

1H, ArꢀH), 7.41 (d, J = 7.9 Hz, 1H, ArꢀH), 7.29 – 7.23 (m, 5H,

ArꢀH), 4.43 and 3.99 (2d, J = 5.8 Hz, 2H, NHCH CO); . C NMR

(126 MHz, DMSOꢀd6) δ 170.00, 165.03, 162.94, 142.31, 140.89,

134.85, 133.29, 131.26, 130.82, 130.68, 129.95, 129.45, 129.13,

70 128.99, 128.92, 127.79, 127.70, 125.81, 125.74, 115.93, 115.75,

2

1

3

13

CNMR (125 MHz, DMSOꢀd6) δ = 170.62, 165.63, 141.41,

2

1

34.87, 133.72, 131.78, 130.45, 130.05, 129.95, 129.85, 128.40,

28.29, 126.24, 52.28, 41.75; HRMS (ESI): m/z calcd for

+

C H ClN O S [M + H] 383.0468, found 383.0477.

1

6

16

2

5

ꢀ

1

3-(N-(2-chlorophenyl)sulfamoyl)-N-(2-hydrazinyl-2-oxoethyl)be

nzamide (E)

Hydrazine hydrate (13.0 g, 261.78 mmol) was added to a stirred

solution ofmethyl 2ꢀ(3ꢀ(Nꢀ(2ꢀchlorophenyl)sulfamoyl)benzamido

40.85; IR (KBr pellet, cm ): 3408, 3278, 1676; HRMS (ESI):

+

m/z calcd for C22

489.0818.

H19ClFN O S [M + H] 489.0800, found

4 4

3-(N-(2-chlorophenyl)sulfamoyl)-N-(2-(2-((3-fluoropyridin-4-

)

acetate (D) (25 g, 65.44 mmol) in ethanol (150.0 mL) and heated 75 yl)-methylene)-hydrazinyl)-2-oxoethyl)-benzamide (1c)

o

1

to 50 C for 5 h. After completion of the reaction, ethanol was

concentrated under reduced pressure to obtain crude compound.

The crude compound was dissolved in ethanol (50 mL) at 45°C to

get clear solution and cooled to 10°C, filtered at high vacuum

Yield: 70%; mp:213ꢀ217 C; HNMR (500 MHz, DMSOꢀd6) δ

11.93 (brs, 1H, CONHNCH), 10.17 (s, 1H, SO NHAr), 9.21 and

9.04 (2t, J = 5.8 Hz, 1H, CONHCH ), 8.67 (s, 1H, ArꢀH), 8.51

(m, 1H, ArꢀH), 8.31 (s, 1H, ArꢀH) 8.22 (s, 1H, ArꢀH), 8.44 and

2

pump and dried to obtain 18

g

(72%) of 3ꢀ(Nꢀ(2ꢀ 80 8.17 (2s, 1H), 7.92–7.84 (m, 2H, ArꢀH), 7.71 (t, J = 7.8 Hz, 1H,

chlorophenyl)sulfamoyl)ꢀNꢀ(2ꢀhydrazinylꢀ2ꢀoxoethyl)benzamide

ArꢀH), 7.41 (d, J = 7.9 Hz, 1H, ArꢀH), 7.30ꢀ7.23 (m, 3H, ArꢀH),

4.47 and 4.04 (2d, J = 5.9 Hz, 2H, NHCH CO); C NMR (126

MHz, DMSOꢀd6) δ 170.50, 165.13, 146.08, 140.91, 138.98,

138.80, 134.78, 134.07, 134.04, 133.28, 131.40, 131.30, 129.96,

o

1

13

(

E) an offꢀwhite solid,; mp: 184ꢀ188 C; HNMR (400MHz,

2

DMSOꢀd6) δ = 9.16 (brs, 1H, CONH), 8.98 (t, J = 6 Hz, 1H,

NHCH ), 8.26 (s, 1H, ArꢀH), 8.13 (d, J = 8 Hz, 1H, ArꢀH), 7.83

2

(

d, J = 8.4 Hz, 1H, ArꢀH), 7.66 (t, J = 8Hz, 1H, ArꢀH), 7.40 (d, J 85 129.49, 128.92, 128.70, 128.64, 127.87, 127.74, 125.77, 119.60,

= 8 Hz, 1H, ArꢀH), 7.28ꢀ7.18 (m, 3H, ArꢀH), 3.83 (d, J = 6 Hz,

40.88; IR (KBr pellet, cmꢀ1): 3390, 3257, 1703; HRMS (ESI):

m/z calcd for C H ClFN O S [M + H] + 490.0752, found

1

3

2

1

H, CH₂). CNMR (100MHz, DMSOꢀd6) δ = 168.00, 164.95,

21

18

5

4

40.81, 134.86, 133.34, 131.40, 129.95, 129.30, 129.24, 129.18,

27.78, 127.57, 125.85, 41.64; HRMS (ESI): m/z calcd for

490.0742

3-(N-(2-chlorophenyl)sulfamoyl)-N-(2-oxo-2-(2-(2-(trifluoromet

+

C H ClN O S [M + H] 383.0581, found 383.0567.

90 hyl)benzylidene) hydrazinyl) ethyl)benzamide (1d)

1

5

16

4

o

1

General procedure for the reaction of the carbonyl compound

with 3-(N-(2-chlorophenyl)sulfamoyl)-N-(2-hydrazinyl-2-oxoeth

yl)benzamide

Yield: 69%; mp:265ꢀ269 C; H NMR (400 MHz, DMSOꢀd6) δ

11.88 and 11.79 (2s, 1H, CONHNCH), 10.16 (s, 1H, SO NHAr),

9.18 and 9.01 (t, J = 5.9 Hz, 1H, CONHCH ), 8.60 and 8.38 (2s,

1H, ArꢀH), 8.31 (s, 1H, ArꢀH), 8.23ꢀ8.15 (m, 2H, ArꢀH), 7.87–

2

To a stirred solution of compound (300 mg, 2.60 mmol) in

ethanol (15 mL) was added corresponding carbonyl compound 95 7.61 (m, 5H, ArꢀH), 7.41 (d, J = 7.6 Hz, 1H, ArꢀH), 7.31 – 7.20

(170 mg, 1.61 mmol) and heated to 50°C for 24ꢀ48 h. On

completion of reaction, the mixture was cooled to 10°C, filtered

the precipitated compound and washed the residue with cold

ethanol and followed by hexane to obtain a pure compound.

Yields of the product varied between 66 and 90%

(m, 3H, ArꢀH), 4.45 and 4.02 (2d, J = 5.8 Hz, 2H, NHCH CO);

2

C NMR (101 MHz, DMSOꢀd6) δ 170.25, 165.08, 140.88,

13

138.71, 134.81, 133.25, 132.82, 131.90, 131.36, 131.26, 130.04,

129.88, 129.44, 129.31, 127.83, 127.77, 127.70, 126.85, 125.75,

100 125.46, 122.74, 40.88; IR (KBr pellet, cmꢀ1): 3388, 3251, 1701;

3-(N-(2-chlorophenyl) sulfamoyl)-N-(2-(2-(2-fluorobenzylidene)

hydrazinyl)-2-oxoethyl) benzamide (1a)

HRMS (ESI): m/z calcd for C23

+539.0768, found 539.0758.

H19ClF N O S [M + H]

3 4 4

o

1

Yield: 70%; mp:218ꢀ222 C; H NMR (400 MHz, DMSOꢀd6) δ

3-(N-(2-chlorophenyl)sulfamoyl)-N-(2-oxo-2-(2-(3-(trifluoromet

hyl)benzylidene) hydrazinyl)ethyl)benzamide (1e)

1

8

1.66 (s, 1H, CONHNCH), 10.16 (s, 1H, SO NHAr), 9.16 and

2

o

1

.99 (2t, J = 5.9 Hz, 1H, CONHCH ), 8.31 (d, J = 1.8 Hz, 1H, 105 Yield: 78%; mp:237ꢀ241 C; H NMR (400 MHz, DMSOꢀd6) δ

2

ArꢀH), 8.48 and 8.25 ((2s, 1H), 8.13 (s, 1H, ArꢀH), 7.99 – 7.82

m, 2H, ArꢀH), 7.70 (m, 1H, ArꢀH), 7.54 – 7.38 (m, 2H, ArꢀH),

.34 – 7.18 (m, 5H, ArꢀH), 4.44 and (2d, J = 5.8 Hz, 2H,

11.73 and 11.70 (2s, 1H, CONHNCH), 10.16 (s, 1H, SO NHAr),

9.17 and 9.00 (t, J = 5.9 Hz, 1H, CONHCH ), 8.30 (s, 1H), 8.17

(d, J = 7.8 Hz, 1H, ArꢀH), 8.32 and 8.10 (2s, 1H), 8.04ꢀ7.99 (m,

2H, ArꢀH), 7.86 (d, J = 7.7 Hz, 1H, ArꢀH), 7.77 (d, J = 7.2 Hz,

2

(

2

7

13

NHCH CO); C NMR (101 MHz, DMSOꢀd6) δ 170.09, 165.05,

2

1

60.58, 140.87, 136.33, 136.29, 134.83, 133.25, 131.76, 131.68, 110 1H, ArꢀH), 7.72– 7.66 (m, 2H, ArꢀH), 7.41 (d, J = 7.6 Hz, 1H,

131.25, 129.94, 129.32, 129.25, 127.84, 127.70, 126.29, 125.73, ArꢀH), 7.34 – 7.20 (m, 3H, ArꢀH), 4.45 and 4.02 (d, J = 5.8 Hz,

13

1

24.88, 121.63, 116.05, 40.82; IR (KBr pellet, cmꢀ1): 3385,

2H, NHCH CO); C NMR (101 MHz, DMSOꢀd6) δ 170.22,

2

1

65.07, 144.95, 141.82, 140.88, 135.23, 134.85, 134.61, 133.27,

1

2

|

Journal Name, [year], [vol], 00–00

This journal is © The Royal Society of Chemistry [year]

Page 13 of 141

New Journal of Chemistry

View Article Online

DOI: 10.1039/C7NJ03332J

1

3

31.35, 130.84, 130.53, 129.93, 129.78, 129.43, 129.25, 127.77,

26.07, 125.74, 125.33, 123.07, 40.87; IR (KBr pellet, cmꢀ1):

165.05, 151.94, 145.62, 142.35, 140.89, 134.87, 133.27, 131.37,

131.26, 131.03, 129.95, 129.45, 129.35, 128.73, 128.53, 127.79,

387, 3250, 1691; HRMS (ESI): m/z calcd for C H ClF N O S 60 125.82, 118.79, 116.13, 113.56, 40.84; IR (KBr pellet, cmꢀ1):

2

3

19

3

4

[

M + H] +539.0768, found 539.0751

3375, 3097, 1676; HRMS (ESI): m/z calcd for C H ClF N O S

23 20 2 4 5

[M + H] 537.0811, found 537.0802.

+

5

0

5

0

5

0

5

0

5

0

5

3-(N-(2-chlorophenyl)sulfamoyl)-N-(2-oxo-2-(2-(4-(trifluoromet

hyl)benzylidene) hydrazinyl)ethyl)benzamide (1f)

Yield: 78%; mp:184ꢀ188 C; H NMR (400 MHz, DMSOꢀd6) δ

1

9

3-(N-(2-chlorophenyl)sulfamoyl)-N-(2-(2-(4-(methylsulfonyl)be

nzylidene)hydrazinyl)-2-oxoethyl)benzamide (1j)

o

1

o

1

1.73 (s, 1H, CONHNCH), 10.16 (s, 1H, SO NHAr), 9.17 and 65 Yield: 82%; mp: 218ꢀ222 C; H NMR (400 MHz, DMSOꢀd6) δ

2

.01 (t, J = 5.8 Hz, 1H, CONHCH ), 8.30 (s, 1H, ArꢀH), 8.17 (d,

11.77 (s, 1H, CONHNCH), 10.14 (s, 1H, SO NHAr), 9.17 and

2

1

2

3

4

5

J = 7.8 Hz, 1H, ArꢀH), 8.31 and 8.09 (2s, 1H), 7.97ꢀ7.72 (m, 5H,

ArꢀH), 7.70 (t, J = 7.8 Hz, 1H, ArꢀH), 7.41 (d, J = 8.8 Hz, 1H,

ArꢀH), 7.31ꢀ7.18 (m, 3H, ArꢀH), 4.47 and 4.03 (2d, J = 5.7 Hz,

9.01 (2t, J = 5.9 Hz, 1H, CONHCH ), 8.30 (s, 1H, ArꢀH), 8.17 (d,

J = 7.9 Hz, 1H, ArꢀH), 8.32 and 8.10 (2s, 1H), 8.09ꢀ7.94 (m, 4H,

ArꢀH), 7.86 (d, J = 7.6 Hz, 1H, ArꢀH), 7.70 (t, J = 7.8 Hz, 1H,

2

1

3

2

1

H, NHCH CO); C NMR (101 MHz, DMSOꢀd6) δ 170.25, 70 ArꢀH), 7.41 (d, J = 7.8 Hz, 1H, ArꢀH), 7.30ꢀ7.20 (m, 3H, ArꢀH),

2

65.07, 141.79, 140.88, 138.20, 138.00, 134.82, 133.26, 131.36,

1

3

4.47 and 4.03 (d, J = 5.8 Hz, 2H, NHCH CO), 3.25 (s, 3H);

C

2

129.94, 129.63, 129.44, 129.31, 128.11, 127.77, 127.56, 127.37,

NMR (101 MHz, DMSOꢀd6) δ 170.30, 165.08, 144.76, 141.60,

141.20, 140.89, 138.83, 134.81, 134.59, 133.26, 131.36, 131.26,

129.94, 129.45, 129.31, 127.84, 127.78, 127.71, 127.60, 127.44,

1

3

25.74, 125.62, 125.41, 122.70, 40.86; IR (KBr pellet, cmꢀ1):

390, 3255, 1697; HRMS (ESI): m/z calcd for C H ClF N O S

2

3

19

3

4

[

M + H] +539.0768, found 539.0767

75 125.73, 43.41, 40.89; IR (KBr pellet, cmꢀ1): 3388, 3118, 1676;

+

3

-(N-(2-chlorophenyl)sulfamoyl)-N-(2(2(3-hydroxybenzylidene)

HRMS (ESI): m/z calcd for C23

found 549.0688.

H22ClN

4

O

6

S [M + H] 549.0669,

hydrazinyl)-2-oxoethyl) benzamide (1g)

o

1

Yield: 69%; mp: 210ꢀ214 C; H NMR (400 MHz, DMSOꢀd6) δ

1.48 (s, 1H, CONHNCH), 10.16 (s, 1H, SO NHAr), 9.60 (s, 1H,

3-(N-(2-chlorophenyl)sulfamoyl)-N-(2-(2-(2-isopropylbenzylide

ne)hydrazinyl)-2-oxoethyl)benzamide (1k)

1

2

o

1

ArꢀH), 9.14 and 8.96 (t, J = 5.9 Hz, 1H, CONHCH ), 8.31 (s, 1H, 80 Yield: 66%; mp:204ꢀ208 C; HNMR (400 MHz, DMSOꢀd6) δ =

2

ArꢀH), 8.17 (d, J = 6.4 Hz, 1H, ArꢀH), 8.14 and 7.93 (2s, 1H),

7.86 (d, J = 7.6 Hz, 1H, ArꢀH), 7.70 (t, J = 5.9 Hz, 1H, Arꢀ

H),7.41 (d, J = 7.6 Hz, 1H, ArꢀH), 7.32ꢀ7.09 (m, 6H, ArꢀH), 6.83

11.77 and 11.43 (s, 1H, CONHNCH), 10.15 (s, 1H, SO NHAr),

2

9.15 and 8.97 (2t, J = 5.6 Hz, 1H, CONHCH ), 8.65 and 8.42

2

(2s, 1H), 8.30 (s, 1H, ArꢀH), 8.17 (d, J = 7.2 Hz, 1H, ArꢀH), 8.09ꢀ

7.94 (m, 4H, ArꢀH), 7.85 (d, J = 7.2 Hz, 1H, ArꢀH), 7.80 (d, J =

(

d, J = 8.2 Hz, 1H, ArꢀH), 4.43 and 4.00 (2d, J = 5.7 Hz, 2H,

1

3

NHCH CO); C NMR (101 MHz, DMSOꢀd6) δ 169.91, 165.04, 85 7.6 Hz, 1H, ArꢀH), 7.69 (t, J = 8.0 Hz, 1H, ArꢀH), 7.42ꢀ7.34 (m,

2

1

57.61, 143.64, 140.88, 135.28, 134.85, 133.28, 131.38, 131.28,

3H, ArꢀH), 7.31ꢀ7.20 (m, 4H, ArꢀH), 4.42 and 4.00 (d, J = 6.0

129.96, 129.86, 129.45, 129.33, 129.27, 127.79, 127.67, 125.75,

Hz, 2H, NHCH CO), 3.39ꢀ3.34 (m, 1H) 1.24 (d, J = 7.6 Hz, 6H);

2

13

1

18.36, 117.20, 112.48, 40.79; IR (KBr pellet, cmꢀ1): 3381,

250, 1680; HRMS (ESI): m/z calcd for C H ClN O S [M + H]

C NMR (101 MHz, DMSOꢀd6) δ 169.82, 165.04, 146.88,

3

142.18, 140.88, 134.87, 133.27, 131.26, 130.77, 129.94, 129.89,

90 129.44, 129.24, 127.78, 126.19, 125.98, 125.83, 125.74, 125.53,

125.45, 40.85, 28.18, 23.47; IR (KBr pellet, cmꢀ1): 3373, 3265,

2

20

4

5

+

4

87.0843, found 487.0821.

-(N-(2-chlorophenyl)sulfamoyl)-N-(2-(2-(4-hydroxybenzyliden

e)hydrazinyl)-2-oxoethyl) benzamide (1h)

3

1695; HRMS (ESI): m/z calcd for C25

513.1363, found 513.1379.

H26ClN

O

5

S [M + H]

4

o

1

+

Yield: 78%; mp:262ꢀ266 C; H NMR (400 MHz, DMSOꢀd6) δ

1

9

1.35 (s, 1H, CONHNCH), 10.19 (s, 1H, SO NHAr), 9.92 and

.91 (2s, 1H, ArꢀH), 9.15 and 8.97 (2t, J = 5.9 Hz, 1H, 95 hydrazinyl)-2-oxoethyl) benzamide(1l)

3-(N-(2-chlorophenyl)sulfamoyl)-N-(2-(2-(3-ethoxybenzylidene)

2

o

1

CONHCH ), 8.31 (s, 1H, ArꢀH), 8.17 (d, J = 6.0 Hz, 1H, ArꢀH),

Yield: 77 %; mp:197ꢀ201 C; H NMR (400 MHz, DMSOꢀd6) δ

2

8.12 and 7.91 (2s, 1H), 7.86 (d, J = 6.8 Hz, 1H, ArꢀH), 7.70 (t, J

11.53 (s, 1H, CONHNCH), 10.16 (s, 1H, SO NHAr), 9.14 and

2

=

7.8 Hz, 1H, ArꢀH), 7.53 (d, J = 8.0 Hz, 2H, ArꢀH), 7.41 (d, J =

8.98 (2t, J = 5.9 Hz, 1H, CONHCH ), 8.30 (s, 1H, ArꢀH), 8.17 (d,

2

7

2

.8 Hz, 1H, ArꢀH), 7.30 ꢀ7.23 (m, 3H, ArꢀH), 6.83 (d, J = 8.0 Hz,

J = 8.0 Hz, 1H, ArꢀH), 8.20 and 7.97 (2s, 1H), 7.85 (d, J = 7.2

100 Hz, 1H, ArꢀH), 7.69 (t, J = 7.8 Hz, 1H, ArꢀH), 7.41 (d, J = 7.9

Hz, 1H, ArꢀH), 7.36 – 7.20 (m, 6H, ArꢀH), 6.98 (d, J = 6.8 Hz,

13

H, ArꢀH), 4.41 and 3.98 (2d, J = 5.7 Hz, 2H, NHCH CO);

C

2

NMR (101 MHz, DMSOꢀd6) δ 169.68, 164.96, 159.22, 143.80,

140.89, 134.92, 133.30, 131.42, 131.31, 130.00, 129.49, 129.35,

1H, ArꢀH), 4.44 and 4.00 (2d, J = 5.8 Hz, 2H, NHCH CO), 4.09ꢀ

2

13

1

28.80, 128.53, 127.84, 125.87, 125.17, 125.10, 115.69, 40.86;

4.03 (m, 2H), 1.34 (t, J = 6.9 Hz, 3H); C NMR (101 MHz,

DMSOꢀd6) δ 170.01, 165.04, 158.78, 143.33, 140.87, 135.43,

105 134.88, 133.26, 131.25, 129.94, 129.87, 129.43, 129.31, 127.84,

127.77, 127.71, 125.81, 119.41, 116.26, 111.77, 63.09, 40.85,

14.58; IR (KBr pellet, cmꢀ1): 3311, 3253, 1689; HRMS (ESI):

IR (KBr pellet, cmꢀ1): 3398, 3269, 1674; HRMS (ESI): m/z calcd

+

for C H ClN O S [M + H] 487.0843, found 487.0837.

22

20

4

5

3

-(N-(2-chlorophenyl)sulfamoyl)-N-(2-(2-(4-(difluoromethoxy)

benzylidene)hydrazinyl)-2-oxoethyl)benzamide (1i)

o

1

+

Yield: 74%; mp: 249ꢀ253 C; HNMR (400 MHz, DMSOꢀd6) δ =

m/z calcd for C H ClN O S [M + H] 515.1156, found

24

4

5

1

8

1.54 (s, 1H, CONHNCH), 10.15 (s, 1H, SO NHAr), 9.14 and

515.1144.

2

.97 (2t, J = 5.2 Hz, 1H, CONHCH ), 8.30 (s, 1H, ArꢀH), 8.16 (d, 110 3-(N-(2-chlorophenyl)sulfamoyl)-N-(2-(2-(2-fluoro-4-methoxyb

2

J = 6.0 Hz, 1H, ArꢀH), 8.23 and 8.01 (2s, 1H), 7.86 (d, J = 6.8

Hz, 1H, ArꢀH), 7.78ꢀ7.75 (m, 2H, ArꢀH), 7.69 (t, J = 7.8 Hz, 1H,

ArꢀH), 7.50ꢀ7.13 (m, 7H, ArꢀH), 4.43 and 4.00 (d, J = 5.2 Hz,

enzylidene)hydrazinyl)-2-oxoethyl)benzamide (1m)

o

1

Yield: 82%; mp:216ꢀ220 C; H NMR (400 MHz, DMSOꢀd6) δ

11.52 (s, 1H, CONHNCH), 10.17 (s, 1H, SO NHAr), 9.16 and

2

1

3

2

H, NHCH CO); C NMR (101 MHz, DMSOꢀd6) δ 170.00,

8.99 (2t, J = 5.8 Hz, 1H, CONHCH ), 8.30 (s, 1H, ArꢀH), 8.17 (d,

2

This journal is © The Royal Society of Chemistry [year]

Journal Name, [year], [vol], 00–00 |13

New Journal of Chemistry

Page 14 of 141

View Article Online

DOI: 10.1039/C7NJ03332J

o

1

J = 8.0 Hz, 1H, ArꢀH), 8.39 and 8.14 (2s, 1H), 7.85 (d, J = 8.2

Hz, 1H, ArꢀH), 7.82ꢀ7.77 (m, 1H, ArꢀH), 7.69 (t, J = 7.9 Hz, 1H,

Yield: 70%; mp: 250ꢀ254 C; H NMR (500 MHz, DMSOꢀd6) δ =

11.44 and 11.42 (2s, 1H, CONHNCH), 10.74 and 10.72 (2s, 1H),

ArꢀH), 7.41 (d, J = 7.9 Hz, 1H, ArꢀH), 7.32 – 7.20 (m, 3H, ArꢀH), 60 10.15 (s, 1H, SO NHAr), 9.92 and 9.91 (2s, 1H), 9.12 and 8.95

2

6

.94 – 6.86 (m, 2H, ArꢀH), 4.42 and 3.99 (2d, J = 5.8 Hz, 2H,

(2t, J = 5.2 Hz, 1H, CONHCH ), 8.29 (s, 1H, ArꢀH), 8.16 (d, J =

2

1

3

5

0

5

0

5

0

5

0

5

0

5

NHCH CO), 3.82 (s, 3H); C NMR (101 MHz, DMSOꢀd6) δ

1

7.6 Hz, 1H, ArꢀH), 7.87 (d, J = 8.8 Hz, 1H, ArꢀH), 8.09 and 7.84

(2s, 1H), 7.69 (t, J = 7.8 Hz, 1H, ArꢀH), 7.53 (d, J = 8.0 Hz, 2H,

ArꢀH), 7.41 (d, J = 7.8 Hz, 1H, ArꢀH), 7.31ꢀ7.20 (m, 3H, ArꢀH),

2

69.86, 165.03, 161.93, 161.59, 140.88, 136.49, 134.87, 133.28,

31.38, 131.27, 129.95, 129.45, 129.33, 127.85, 127.79, 127.08,

1

25.75, 114.02, 111.77, 101.47, 55.87, 40.83; IR (KBr pellet, 65 7.00 (d, J = 8.0 Hz, 2H, ArꢀH), 4.41 and 3.98 (d, J = 5.7 Hz, 2H,

1

3

cmꢀ1): 3425, 3089, 1670; HRMS (ESI): m/z calcd for

C H ClFN O S [M + H] 519.0905, found 519.0903.

3

methyl)benzylidene) hydrazinyl)-2-oxoethyl)benzamide (1n)

Yield: 70%; mp: 234ꢀ238 C; H NMR (400 MHz, DMSOꢀd6) δ 70 3268, 1689; HRMS (ESI): m/z calcd for C H ClF N O S [M +

1

9.21 and 9.04 (2t, J = 5.9 Hz, 1H, CONHCH ), 8.30 (s, 1H, Arꢀ

H), 8.23 (s, 2H, ArꢀH), 8.17 (d, J = 8.0 Hz, 1H, ArꢀH), 8.49 and

8

1

NHCH CO); C NMR (101 MHz, DMSOꢀd6) δ 169.79, 165.070,

2

+

1

2

3

4

5

155.72, 142.21, 140.86, 134.89, 133.26, 131.36, 131.26, 131.00,

129.94, 129.42, 129.32, 127.84, 127.70,126.91, 126.81, 125.81,

125.74, 116.47, 109.82, 40.83; IR (KBr pellet, cmꢀ1): 3371,

2

3

21

4

5

-(N-(2-chlorophenyl)sulfamoyl)-N-(2-(2-(2-fluoro-4-(trifluoro

o

1

23

20

2

4

5

+

1.85 and 11.80 (2s, 1H, CONHNCH), 10.18 (s, 1H, SO NHAr),

H] 564.9948, found 564.9930.

2

3-(N-(2-chlorophenyl)sulfamoyl)-N-(2-(2-(2-methoxy-5-(trifluor

omethoxy)benzylidene) hydrazinyl)-2-oxoethyl)benzamide (1r)

Yield: 78%; mp: 292ꢀ296 C; H NMR (400 MHz, DMSOꢀd6) δ

o

1

.14 (2s, 1H), 7.87(d, J = 8.2 Hz, 1H, ArꢀH)), 7.71 (t, J = 7.8 Hz,

H, ArꢀH), 7.56 (t, J = 9.6 Hz, 1H, ArꢀH), 7.41 (d, J = 7.8 Hz, 75 11.63 and 11.58 (2s, 1H, CONHNCH), 8.97 and 8.79 (2t, J = 5.9

H, ArꢀH), 7.32ꢀ7.24 (m, 3H, ArꢀH), 4.48 and 4.03 (d, J = 5.7

Hz, 1H, CONHCH ), 8.55–8.26 (m, 2H, ArꢀH), 7.85ꢀ7.66 (m,

2

1

3

Hz, 2H, NHCH CO); C NMR (101 MHz, DMSOꢀd6) δ 170.34,

3H, ArꢀH), 7.46ꢀ7.39 (m, 2H, ArꢀH), 7.21 (d, J = 9.2 Hz, 1H, Arꢀ

H), 7.09 (t, J = 9.7 Hz, 2H, ArꢀH), 6.79 (t, J = 8.4 Hz, 1H, ArꢀH),

6.40 (t, J = 7.5 Hz, 1H, ArꢀH), 4.40and 3.96 (2d, J = 5.8 Hz, 2H,

2

1

3

65.10, 140.87, 137.98, 134.89, 134.83, 133.26, 131.27, 129.95,

29.46, 129.32, 127.85, 127.79, 125.75, 124.95, 123.49, 122.87,

22.76, 122.25, 117.66, 117.44, 40.88; IR (KBr pellet, cmꢀ1): 80 NHCH CO), 3.88 (s, 3H); C NMR (101 MHz, DMSOꢀd6) δ

13

2

388, 3251, 1697; HRMS (ESI): m/z calcd for C H ClF N O S

170.27, 166.08, 156.17, 147.94, 147.06, 141.89, 140.68, 137.36,

133.87, 128.79, 128.65, 127.91, 127.76, 126.29, 125.25, 123.95,

123.60, 119.87, 117.62, 116.22, 113.42, 56.27, 40.76; IR (KBr

2

3

18

4

+

[M + H] 557.0673, found 557.0684.

N-(2-(2-(2-chloro-4-fluorobenzylidene)hydrazinyl)-2-oxoethyl)-

-(N-(2-chlorophenyl) sulfamoyl)benzamide (1o)

ꢀ

1

3

pellet, cm ): 3408, 3277, 1705; HRMS (ESI): m/z calcd for

o

1

+

Yield: 68%; mp: 248ꢀ252 C; H NMR (400 MHz, DMSOꢀd6) δ 85 C H ClF N O S [M + H] 585.0822, found 585.0807.

1

9.17 and 8.99 (2t, J = 5.9 Hz, 1H, CONHCH ), 8.59 and 8.35 (2s,

1

8

1

2

4

21

3

4

6

1.77 and 11.71 (2s, 1H, CONHNCH), 10.15 (s, 1H, SO NHAr),

3-(N-(2-chlorophenyl)sulfamoyl)-N-(2-(2-(2,6-dimethylbenzylid

ene)hydrazinyl)-2-oxoethyl)benzamide (1s)

Yield: 80%; mp: 223ꢀ227 C; H NMR (400 MHz, DMSOꢀd6) δ

2

o

1

H), 8.29 (s, 1H, ArꢀH), 8.17 (d, J = 7.7 Hz, 1H, ArꢀH), 8.38 and

.12 (2s, 1H), 7.86 (d, J = 7.1 Hz, 1H, ArꢀH), 7.70 (t, J = 7.9 Hz,

11.48 and 11.42 (2s, 1H, CONHNCH), 10.15 (s, 1H, SO NHAr),

2

H, ArꢀH), 7.54 (d, J = 8.8 Hz, 1H, ArꢀH), 7.41 (d, J = 7.8 Hz, 90 9.13 and 8.96 (t, J = 5.9 Hz, 1H, CONHCH ), 8.53 and 8.39 (2s,

2

H, ArꢀH), 7.34–7.20(m, 4H, ArꢀH), 4.45 and 4.01 (2d, J = 5.7

1H), 8.29 (s, 1H, ArꢀH), 8.16 (d, J = 7.4 Hz, 1H, ArꢀH), 7.85 (d, J

= 8.0 Hz, 1H, ArꢀH), 7.69 (t, J = 7.8 Hz, 1H, ArꢀH), 7.41 (d, J =

7.8 Hz, 1H, ArꢀH), 7.31ꢀ7.15 (m, 4H, ArꢀH), 7.11 (d, J = 7.6 Hz,

1

3

Hz, 2H, NHCH CO); C NMR (101 MHz, DMSOꢀd6) δ 170.13,

2

1

3

65.05, 162.47,140.88, 138.57, 134.82, 134.59, 133.73, 133.26,

31.25, 129.93, 129.44, 128.62, 128.16, 127.82, 127.77, 127.69,

25.81, 117.15, 115.45, 40.87; IR (KBr pellet, cmꢀ1): 3387, 95 (s, 3H); C NMR (101 MHz, DMSOꢀd6) δ 169.79, 165.06,

2H, ArꢀH), 4.36 and 4.01 (2d, J = 5.7 Hz, 2H, NHCH CO), 2.43

2

13

255, 1697; HRMS (ESI): m/z calcd for C H Cl FN O S [M +

146.63, 143.57, 140.87, 137.12, 134.87, 134.68, 133.25, 131.01,

130.48, 129.93, 129.43, 129.30, 129.23, 128.78, 128.66, 127.77,

127.68, 125.71, 40.87, 21.16, 20.86; IR (KBr pellet, cmꢀ1):

2

18

2

4

+

H] 523.0410, found 523.0408.

N-(2-(2-(2,4-bis(trifluoromethyl)benzylidene)hydrazinyl)-2-

oxoethyl)-3-(N-(2-chlorophenyl)sulfamoyl)benzamide (1p)

Yield: 74%; mp: 258ꢀ262 C; H NMR (500 MHz, DMSOꢀd6) δ 100 + H] 499.1229, found 499.1207.

3365, 369, 1685; HRMS (ESI): m/z calcd for C24H24ClN O S [M

4 4

o

1

+

1

1.78 (s, 1H, CONHNCH), 10.17 (s, 1H, SO NHAr), 9.19 and

3-(N-(2-chlorophenyl)sulfamoyl)-N-(2-oxo-2-(2-(2,3,6-trifluoro

benzylidene) hydrazinyl) ethyl)benzamide (1t)

Yield: 90%; mp: 241ꢀ245 C; H NMR (500 MHz, DMSOꢀd6) δ

2

8.99 (2t, J = 5.9 Hz, 1H, CONHCH ), 8.29 (s, 1H, ArꢀH), 8.17 (d,

J = 7.5 Hz, 1H, ArꢀH), 8.20ꢀ8.10 (m, 2H, ArꢀH), 7.90 – 7.83 (m,

1

ArꢀH), 4.37 and 4.02 (2d, J = 5.7 Hz, 1H, NHCH CO); C NMR

(126 MHz, DMSOꢀd6) δ 170.69, 165.59, 156.22, 141.37, 137.04,

1

2

o

1

H, ArꢀH), 7.70 (td, J = 2.4, 7.8 Hz, 1H, ArꢀH), 7.61ꢀ7.58 (m,

12.06 and 11.97 (2s, 1H, CONHNCH), 10.17 (s, 1H, SO NHAr),

2

H, ArꢀH), 7.41 (d, J = 7.9 Hz, 1H, ArꢀH), 7.31 – 7.23 (m, 4H, 105 9.23 and 9.06 (2t, J = 5.8 Hz, 1H, CONHCH ), 8.63ꢀ8.37 (m, 2H,

2

1

3

ArꢀH), 8.30 (s, 1H, ArꢀH), 8.18 – 8.08 (m, 2H, ArꢀH), 7.91 –

7.84 (m, 1H, ArꢀH), 7.71 (t, J = 7.9 Hz, 1H, ArꢀH), 7.41 (d, J =

7.9 Hz, 1H, ArꢀH), 7.31ꢀ7.20 (m, 3H, ArꢀH), 4.50 and 4.05 (d, J

2

35.27, 135.07, 133.75, 133.49, 131.77, 130.45, 129.97, 129.84,

29.79, 128.36, 128.29, 128.23, 126.23, 118.57, 113.70, 112.63,

13

= 5.7 Hz, 2H, NHCH CO); C NMR (126 MHz, DMSOꢀd6) δ

2

12.44, 41.14; IR (KBr pellet, cmꢀ1): 3390, 3257, 1705; HRMS 110 170.50, 165.15, 140.91, 137.18, 136.21, 134.78, 133.27, 131.40,

+

(ESI): m/z calcd for C H ClF N O S [M + H] 607.0641, found

129.96, 129.49, 129.32, 128.14, 127.86, 127.33, 126.54, 125.77,

124.36, 123.08, 122.19, 120.01, 40.91; IR (KBr pellet, cmꢀ1):

2

4

18

6

4

5

607.0622.

N-(2-(2-(3-bromo-4-hydroxybenzylidene)hydrazinyl)-2-

oxoethyl)-3-(N-(2-chlorophenyl) sulfamoyl)benzamide (1q)

3388, 3251, 1701; HRMS (ESI): m/z calcd for C22

[M + H] 525.0611, found 525.0610.

H17ClF

3

N

4

O

4

S

+

1

4|

Journal Name, [year], [vol], 00–00

Page 15 of 141

New Journal of Chemistry

View Article Online

DOI: 10.1039/C7NJ03332J

3

-(N-(2-chlorophenyl)sulfamoyl)-N-(2-oxo-2-(2-(thiophen-2-

3-(N-(2-chlorophenyl)sulfamoyl)-N-(2-(2-(1-(2-methoxyphenyl)

ethylidene)hydrazinyl)-2-oxoethyl)benzamide (2b)

Yield: 69%; mp: 211ꢀ215 C; H NMR (400 MHz, DMSOꢀd6) δ

ylmethylene)hydrazinyl) ethyl)benzamide (1u)

Yield: 78%; mp: 172ꢀ176 C; H NMR (400 MHz, DMSOꢀd6) δ

o

1

o

1

1.50 and 11.47 (2s, 1H, CONHNCH), 10.16 (s, 1H, SO NHAr), 60 10.67 and 10.44 (2s, 1H, CONHNCH), 10.16 (s, 1H, SO NHAr),

2

5

0

5

0

5

0

5

0

5

0

5

9.14 and 8.95 (2t, J = 5.8 Hz, 1H, CONHCH ), 8.29 (s, J = 1.8

9.09 and 8.91 (2t, J = 5.9 Hz, 1H, CONHCH ), 8.29 (s, 1H, Arꢀ

2

Hz, 1H, ArꢀH), 8.45 and 8.19 (2s, 1H), 8.16 (d, J = 8.0 Hz, 1H,

ArꢀH), 7.85 (d, J = 7.2 Hz, 1H, ArꢀH), 7.71 (t, J = 7.9 Hz, 1H,

ArꢀH), 7.64ꢀ7.63 (m, 1H, ArꢀH), 7.45–7.42 (m, 2H, ArꢀH), 7.35–

H), 8.16 (d, J = 8.0 Hz, 1H, ArꢀH), 7.85 (d, J = 7.8 Hz, 1H, Arꢀ

H), 7.69 (t, J = 7.8 Hz, 1H, ArꢀH), 7.41 – 7.34 (m, 3H, ArꢀH),

7.31– 7.19 (m, 3H, ArꢀH), 7.08 (d, J = 8.3 Hz, 1H, ArꢀH), 6.98 (t,

7

.20 (m, 3H, ArꢀH), 7.12 (t, J = 4.4 Hz, 1H, ArꢀH), 4.35 and 3.98 65 J = 7.3 Hz, 1H, ArꢀH), 4.35 and 4.10 (2d, J = 5.8 Hz, 2H,

13

1

2

3

4

5

(d, J = 5.7 Hz, 2H, NHCH CO). C NMR (101 MHz, DMSOꢀd6)

NHCH CO), 3.82 (s, 3H), 2.19 and 2.18 (2s, 3H, N=C(CH )ꢀAr);

2 3

2

13

δ 169.58, 165.09, 141.95, 140.86, 138.92, 134.83, 133.26,

C NMR (101 MHz, DMSOꢀd6) δ 170.66, 164.95, 157.10,

1

3

31.35, 130.83, 130.35, 129.94, 129.43, 128.78, 128.38, 127.86,

27.83, 127.69, 125.81, 40.60; IR (KBr pellet, cmꢀ1): 3377,

153.87 150.17, 140.86, 134.90, 131.28, 130.13, 129.94, 129.43,

129.32, 129.21, 129.14, 128.95, 127.85, 127.78, 125.75, 120.34,

253, 1683; HRMS (ESI): m/z calcd for C H ClF N O S [M + 70 111.64, 55.51, 41.25, 17.57; HRMS (ESI): m/z calcd for

2

0

18

3

4

+

H] 477.0458, found 477.0441.

-(N-(2-chlorophenyl)sulfamoyl)-N-(2-oxo-2-(2-(piperazin-1-

ylmethylene)hydrazinyl) ethyl)benzamide (1v)

C H ClN O S [M + H] 515.1156, found 515.1155.

24 24 4 5

3

3-(N-(2-chlorophenyl)sulfamoyl)-N-(2-(2-(1-(4-methoxyphenyl)

ethylidene)hydrazinyl)-2-oxoethyl)benzamide (2c).

o

1

o

1

Yield: 76%; mp: 104ꢀ108 C; HNMR (400 MHz, DMSOꢀd6) δ =

Yield: 75%; mp: 218ꢀ222 C; H NMR (500 MHz, DMSOꢀd6) δ

1

1.24 and 11.20 (2s, 1H, CONHNCH), 10.15 (s, 1H, SO NHAr), 75 10.77 and 10.56 (2s, 1H, CONHNCH), 10.16 (s, 1H, SO NHAr),

2

9.07 and 8.87 (2t, J = 5.9 Hz, 1H, CONHCH ), 8.27 (s, 1H, Arꢀ

9.12 and 8.98 (t, J = 5.9 Hz, 1H, CONHCH ), 8.31 (s,1H, ArꢀH),

2

H), 8.14 (d, J = 7.8 Hz, 1H, ArꢀH), 7.84 (d, J = 7.8 Hz, 1H, Arꢀ

H), 7.70 (t, J = 7.8 Hz, 1H, ArꢀH), 7.41 (d, J = 8.0 Hz, 1H, ArꢀH),

8.16 (d, J = 8.0 Hz, 1H, ArꢀH), 7.86 (d, J = 7.9 Hz, 1H, ArꢀH),

7.70 (t, J = 7.8 Hz, 1H, ArꢀH), 7.42–7.22 (m, 7H, ArꢀH), 6.99 (d,

J = 7.9 Hz, 1H, ArꢀH), 4.47 and 4.12 (d, J = 5.7 Hz, 2H,

7

.31 – 7.20 (m, 4H, ArꢀH), 4.25 and 3.89 (2d, J = 5.7 Hz, 2H,

1

3

NHCH CO); C NMR (101 MHz, DMSOꢀd6) δ 169.54, 165.00, 80 NHCH CO), 3.79 (s, 3H), 2.28 and 2.26 (2s, 3H, N=C(CH )ꢀAr);

2

3

13

154.70, 149.62, 145.37, 140.87, 134.85, 133.27, 131.24, 129.95,

C NMR (126 MHz, DMSOꢀd6) δ 170.81, 165.02, 159.24,

1

29.44, 129.32, 127.84, 127.78, 127.69, 125.69, 78.97, 40.12; IR

147.75, 140.86, 139.61, 134.91, 134.72, 133.26, 131.28, 129.95,

129.44, 129.32, 129.23, 127.85, 127.79, 127.71, 125.76, 118.51,

(

KBr pellet, cmꢀ1): 3217, 2933, 1674; HRMS (ESI): m/z calcd

+

for C H ClN O S [M + H] 478.1190, found 478.1184.

114.54, 111.50, 55.09, 41.28, 13.61; HRMS (ESI): m/z calcd for

20

24

6

4

+

3

-(N-(2-chlorophenyl)sulfamoyl)-N-(2-(2-(cyclohexylmethylene

85

C

24

H24ClN

4

O

5

S [M + H] 515.1156, found 515.1144.

)hydrazinyl)-2-oxoethyl) benzamide (1w)

3-(N-(2-chlorophenyl)sulfamoyl)-N-(2-(2-(1-(3-hydroxyphenyl)

ethylidene)hydrazinyl)-2-oxoethyl)benzamide (2d)

o

1

Yield: 79%; mp: 232ꢀ236 C; H NMR (400 MHz, DMSOꢀd6) δ

o

1

9

1.04 and 11.02 (2s, 1H, CONHNCH), 10.14 (s, 1H, SO NHAr),

Yield: 78%; mp: 229ꢀ233 C; H NMR (400 MHz, DMSOꢀd6) δ

2

.05 and 8.86 (2t, J = 5.9 Hz, 1H, CONHCH ), 8.27 (s, 1H, Arꢀ

10.76 and 10.50 (2s, 1H, CONHNCH), 10.17 (s, 1H, SO NHAr),

2

H), 8.14 (d, J = 7.8 Hz, 1H, ArꢀH), 7.84(d, J = 7.8 Hz, 1H, ArꢀH), 90 9.51 (s, 1H), 9.11 and 8.97 (2t, J = 5.9 Hz, 1H, CONHCH ), 8.31

7.68 (t, J = 7.8 Hz, 1H, ArꢀH), 7.42ꢀ7.19 (m, 5H, ArꢀH), 4.25 and

2

(s, 1H, ArꢀH), 8.18 (d, J = 7.7 Hz, 1H, ArꢀH), 7.87 (d, J = 7.9 Hz,

1H, ArꢀH), 7.70 (t, J = 7.8 Hz, 1H, ArꢀH), 7.41 (d, J = 7.8 Hz,

1H, ArꢀH), 7.31ꢀ7.20 (m, 6H, ArꢀH), 6.80 (d, J = 6.3 Hz, 1H, Arꢀ

3

1

.89 (2d, J = 5.7 Hz, 2H, NHCH CO), 2.23ꢀ2.19 (m, 1H), 1.78ꢀ

2

.60 (m, 5H), 1.33ꢀ1.16 (m, 5H); C NMR (101 MHz, DMSOꢀ

1

3

d6) δ 169.44, 164.95, 154.53, 151.27, 140.85, 134.88, 133.27,

H), 4.47 and 4.12 (d, J = 5.7 Hz, 2H, NHCH CO), 2.24 and 2.22

2

13

1

31.23, 129.93, 129.40, 129.31, 129.26, 129.19, 127.82, 127.77, 95 (2s, 3H, N=C(CH )ꢀAr); C NMR (101 MHz, DMSOꢀd6) δ

3

127.67, 125.71, 40.73, 29.61, 25.49, 24.91; IR (KBr pellet, cmꢀ

170.75, 165.04, 157.28, 147.88, 140.88, 139.34, 134.91, 133.28,

131.29, 129.95, 129.45, 129.32, 129.25, 127.85, 127.79, 127.71,

1

): 3414, 3267, 2918, 1674; HRMS (ESI): m/z calcd for

+

C H ClN O S [M + H] 477.1363, found 477.1374.

125.75, 117.33, 116.24, 112.54, 41.30, 13.50; HRMS (ESI): m/z

2

26

4

+

3

-(N-(2-chlorophenyl)sulfamoyl)-N-(2-(2-(1-(4-fluorophenyl)et

calcd for C23

H22ClN

4

O

5

S [M + H] 501.0999, found 501.1035.

hylidene)hydrazinyl)-2-oxoethyl)benzamide (2a)

100 3-(N-(2-chlorophenyl)sulfamoyl)-N-(2-(2-(1-(4-hydroxyphenyl)

o

1

Yield: 88%; mp: 200ꢀ204 C; H NMR (400 MHz, DMSOꢀd6) δ

ethylidene)hydrazinyl) -2-oxoethyl)benzamide (2e)

1

9

0.79 and 10.56 (2s, 1H, CONHNCH), 10.16 (s, 1H, SO NHAr),

Yield: 85%; mp: Charing; H NMR (400 MHz, DMSOꢀd6) δ

2

.12and 8.91 (2t, J = 5.9 Hz, 1H, CONHCH ), 8.31 (s, 1H, Arꢀ

10.55 (s, 1H, CONHNCH), 10.19 (s, 1H, SO NHAr), 9.16 and

2

H), 8.18 (d, J = 7.0 Hz, 1H, ArꢀH), 7.87ꢀ7.85 (m, 3H, ArꢀH), 7.70

8.98 (2t, J = 5.9 Hz, 1H, CONHCH ), 8.31 (s, 1H, ArꢀH), 8.16 (d,

2

(t, J = 7.5 Hz, 1H, ArꢀH), 7.41 (d, J = 8.0 Hz, 1H, ArꢀH), 7.35 – 105 J = 6.0 Hz, 1H, ArꢀH), 8.11 and 7.92 (2s, 1H), 7.85 (d, J = 6.8

7.20 (m, 5H, ArꢀH), 4.47and 4.12 (2d, J = 5.5 Hz, 2H,

Hz, 1H, ArꢀH), 7.71 (t, J = 7.8 Hz, 1H, ArꢀH), 7.52 (d, J = 8.0

Hz, 2H, ArꢀH), 7.40 (d, J = 7.8 Hz, 1H, ArꢀH), 7.31 ꢀ7.23 (m, 3H,

ArꢀH), 6.82 (d, J = 8.0 Hz, 2H, ArꢀH), 4.40 and 3.99 (2d, J = 5.7

13

NHCH CO), 2.29 and 2.26(2s, 3H, N=C(CH )ꢀAr); C NMR

2

3

(101 MHz, DMSOꢀd6) δ 170.82, 165.03, 162.68, 147.00, 140.88,

1

3

1

34.91, 133.29, 131.29, 129.96, 129.46, 129.33, 129.25, 128.46,

28.29, 128.22, 127.85, 127.80, 127.72, 125.77, 120.34, 115.31, 110 NMR (101 MHz, DMSOꢀd6) δ 169.65, 164.94, 159.32, 143.83,

Hz, 2H, NHCH CO), 2.21 and 2.19 (2s, 3H, N=C(CH )ꢀAr); C

2 3

41.32, 13.51; HRMS (ESI): m/z calcd for C H ClFN O S [M +

140.85, 134.82, 133.35, 131.45, 131.33, 130.06, 129.45, 129.33,

128.82, 128.56, 127.84, 125.85, 125.15, 125.13, 115.62, 40.83,

2

3

21

4

+

H] 503.0956, found 503.0921.

Journal Name, [year], [vol], 00–00 |15

New Journal of Chemistry

Page 16 of 141

View Article Online

DOI: 10.1039/C7NJ03332J

+

1

3.46; HRMS (ESI): m/z calcd for C H ClN O S [M + H]

m/z calcd for C H ClN O S [M + H] 526.1456, found

526.1442.

2

3

22

4

5

26 28

4

+

5

01.0999, found 501.0988.

-(N-(2-chlorophenyl)sulfamoyl)-N-(2-oxo-2-(2-(1-(4-(trifluoro

methoxy)phenyl) ethylidene)hydrazinyl)ethyl)benzamide (2f)

3

60 3-(N-(2-chlorophenyl)sulfamoyl)-N-(2-oxo-2-(2-(1-(4-(pyrrolidi

n-1-yl)phenyl) ethylidene)hydrazinyl)ethyl)benzamide (2j)

Yield: 76%; mp: 244ꢀ248 C; H NMR (500 MHz, DMSOꢀd6) δ

o

1

o

1

5

0

5

0

5

0

5

0

5

0

5

Yield: 82%; mp: 190ꢀ194 C; H NMR (500 MHz, DMSOꢀd6) δ

1

8

0.86 and (2s, 1H, CONHNCH), 10.17 (s, 1H, SO NHAr), and

10.51 and 10.48 (2s, 1H, CONHNCH), 10.26 (s, 1H, SO NHAr),

2

.98 (t, J = 5.9 Hz, 1H, CONHCH ), 8.30 (s, 1H, ArꢀH), 8.18 (d,

9.25 and 9.01 (2t, J = 5.9 Hz, 1H, CONHCH ), 8.32 (s, 1H, Arꢀ

2

J = 7.5 Hz, 1H, ArꢀH), 7.94–7.88 (m, 2H, ArꢀH), 7.86 (d, J = 7.9 65 H), 8.20ꢀ8.17 (m, 1H, ArꢀH), 7.86 (d, J = 7.9 Hz, 1H, ArꢀH),

Hz, 1H, ArꢀH), 7.70 (t, J = 7.8 Hz, 1H, ArꢀH), 7.41 (d, J = 8.0

Hz, 3H, ArꢀH), 7.31ꢀ7.19 (m, 3H, ArꢀH), 4.47 and 4.13 (d, J =

7.69ꢀ7.63 (m, 3H, ArꢀH), 7.39 (d, J = 7.5 Hz, 1H, ArꢀH), 7.27–

7.17 (m, 3H, ArꢀH), 6.54 (d, J = 8.7 Hz, 2H, ArꢀH), 4.42 and 4.09

1

2

3

4

5

.8 Hz, 2H, NHCH CO), 2.31 and 2.28 (2s, 3H, N=C(CH )ꢀAr);

(2d, J = 5.8 Hz, 2H, NHCH CO), 3.25 (t, J = 6.2 Hz, 4H), 2.22

2

3

2

1

3

13

C NMR (126 MHz, DMSOꢀd6) δ 170.88, 165.02, 148.74,

46.59, 140.87, 137.26, 134.89, 133.26, 131.28, 129.94, 129.45, 70 NMR (126 MHz, DMSO) δ 170.33, 165.13, 149.45, 148.14,

29.24, 128.23, 128.01, 127.84, 127.78, 127.71, 125.75, 121.02,

and 2.18 (2s, 3H, N=C(CH )ꢀAr), 1.91 (t, J = 6.2 Hz, 4H);

C

3

1

141.25, 135.79, 134.85, 133.89, 131.16 129.90, 129.33, 127.69,

127.50, 127.13, 126.26, 126.06, 125.79, 111.14, 47.20, 41.28,

24.92, 13.11; HRMS (ESI): m/z calcd for C H ClN O S [M +

120.80, 118.98, 41.32, 13.48; HRMS (ESI): m/z calcd for

C H ClF N O S [M + H] 569.0873 found 569.0854.

3

phenyl)ethylidene) hydrazinyl)-2-oxoethyl)benzamide (2g)

Yield: 88%; mp: 309ꢀ312 C; H NMR (500 MHz, DMSOꢀd6) δ

10.55 and 10.35 (2s, 1H, CONHNCH), 9.10 and 8.92 (2t, J = 5.9

Hz, 1H, CONHCH ), 8.31 (s, 1H, ArꢀH), 8.17 (d, J = 6.0 Hz, 1H,

ArꢀH), 7.86 (d, J = 7.8 Hz, 1H, ArꢀH), 7.69ꢀ7.64 (m, 3H, ArꢀH),

+

2

4

21

3

4

5

27 29

5

4

+

-(N-(2-chlorophenyl)sulfamoyl)-N-(2-(2-(1-(4-(dimethylamino)

H] 554.1629, found 554.1626.

75 3-(N-(2-chlorophenyl)sulfamoyl)-N-(2-oxo-2-(2-(1-(4-(piperazin

o

1

-1-yl)phenyl)ethylidene)hydrazinyl)ethyl)benzamide (2k)

o

1

Yield: 80%; mp: 221ꢀ225 C; H NMR (500 MHz, DMSOꢀd6) δ

10.62 and 10.40 (2s, 1H, CONHNCH), 9.02 and 8.84 (2t, J = 5.9

2

Hz, 1H, CONHCH ), 8.29 (s, 1H, ArꢀH), 8.00 (d, J = 7.6 Hz, 1H,

2

7

1

.38 (d, J = 7.5 Hz, 1H, ArꢀH), 7.26ꢀ7.21 (m, 2H, ArꢀH), 7.14 (m, 80 ArꢀH), 7.85 (d, J = 7.8 Hz, 1H, ArꢀH), 7.69 (d, J = 8.9 Hz, 2H,

H, ArꢀH), 6.72 (d, J = 7.8 Hz, 2H, ArꢀH), 4.44 and 4.08 (d, J =

ArꢀH), 7.56 (t, J = 7.7 Hz, 1H, ArꢀH), 7.23 (d, J = 7.8 Hz, 1H,

ArꢀH), 7.18 (d, J = 8.0 Hz, 1H, ArꢀH), 7.03 – 6.97 (m, 3H, ArꢀH),

6.77 (t, J = 7.5 Hz, 1H, ArꢀH), 4.43 and 4.08 (d, J = 5.7 Hz, 2H,

5.7 Hz, 2H, NHCH CO), 2.9 (brs, , 6H), 2.21 and 2.19 (2s, 3H,

N=C(CH )ꢀAr); C NMR (126 MHz, DMSOꢀd6) δ 170.89,

1

calcd for C H ClN O S [M+H] 528.1472, found 528.1440.

3

phenyl)ethylidene)hydrazinyl)-2-oxoethyl)benzamide (2h)

Yield: 83%; mp: 243ꢀ247 C; H NMR (500 MHz, DMSOꢀd6) δ 90 569.1738, found 569.1760.

2

13

3

65.56, 151.34, 148.93, 142.02, 140.93, 135.37, 135.18, 131.47,

30.34, 129.80, 129.68, 129.45, 128.16, 127.85, 127.50, 126.21, 85 2.22 and 2.21(2s, 3H, N=C(CH )ꢀAr); C NMR (126 MHz,

NHCH CO), 3.29 (t, J = 5.0 Hz, 4H), 3.09 (t, J = 5.0 Hz, 4H),

2

13

3

25.86, 125.76, 112.02, 41.79, 14.26, 13.61; HRMS (ESI): m/z

DMSOꢀd6) δ 172.11, 170.63, 165.55, 151.08, 147.88, 144.74,

140.93, 134.41, 130.11, 129.39, 129.27, 128.99, 128.67, 127.32,

127.01, 125.42, 123.49, 121.58, 114.75, 46.38, 43.75, 41.29,

+

25

27

5

4

-(N-(2-chlorophenyl)sulfamoyl)-N-(2-(2-(1-(4-(methylsulfonyl)

13.19; HRMS (ESI): m/z calcd for C27H30ClN O S [M + H]

6 4

o

1

+

1

0.98 and 10.73 (2s, 1H, CONHNCH), 10.17 (s, 1H, SO NHAr),

3-(N-(2-chlorophenyl)sulfamoyl)-N-(2-(2-(1-(4-morpholinophe

nyl)ethylidene)hydrazinyl)-2-oxoethyl)benzamide (2l)

2

9.14 and 9.01 (t, J = 5.9 Hz, 1H, CONHCH ), 8.30 (s,1H, ArꢀH),

8

J = 7.8 Hz, 1H, ArꢀH), 7.58 (t, J = 7.8 Hz, 1H, ArꢀH), 7.41 (d, J =

7

2

o

1

.18 (d, J = 8.0 Hz, 1H, ArꢀH), 8.08ꢀ7.86 (m, 4H, ArꢀH), 7.70 (t,

Yield: 82%; mp: 226ꢀ230 C; H NMR (500 MHz, DMSOꢀd6) δ

10.62 and 10.40 (2s, 1H, CONHNCH), 10.17 (s, 1H, SO NHAr),

2

.9 Hz, 1H, ArꢀH), 7.30–7.22 (m, 3H, ArꢀH), 4.50 and 4.15 (2d, J 95 9.10 and 8.94 (2t, J = 5.9 Hz, 1H, CONHCH ), 8.31 (s, 1H, Arꢀ

2

=

5.7 Hz, 2H, NHCH CO), 3.44(s, 3H), 2.20 and 2.19 (2s, 3H,

H), 8.17 (d, J = 6.0 Hz, 1H, ArꢀH), 7.86 (d, J = 7.5 Hz, 1H, Arꢀ

H), 7.71ꢀ7.68 (m, 3H, ArꢀH), 7.41 (d, J = 8.0 Hz, 1H, ArꢀH),

7.31ꢀ7.20 (m, 3H, ArꢀH), 6.95 (d, J = 7.5 Hz , 2H, ArꢀH), 4.54

2

13

N=C(CH )ꢀAr); C NMR (126 MHz, DMSOꢀd6) δ 171.07,

3

1

65.09, 146.36, 142.76, 140.89, 134.87, 133.27, 131.31, 129.97,

29.49, 129.34, 129.03, 127.88, 127.81, 127.75, 127.34, 127.09,

and 4.09 (2d, J = 5.7 Hz, 2H, NHCH CO), 3.74 (brs, 4H), 3.16

2

13

26.87, 125.77, 43.50, 41.37, 13.54; HRMS (ESI): m/z calcd for 100 (brs, 4H), 2.22 and 2.21(2s, 3H, N=C(CH )ꢀAr); C NMR (126

3

+

C H ClN O S [M + H] 563.0826, found 563.0827.

MHz, DMSOꢀd6) δ 172.48, 165.10, 151.51, 148.06, 140.88,

134.95, 133.30, 131.26, 129.94, 129.42, 129.20, 128.34, 127.80,

127.77, 127.65, 127.24, 126.93, 125.75, 114.14, 65.93, 47.72,

41.29, 13.16; HRMS (ESI): m/z calcd for C H ClN O S [M +

2

4

24

4

6 2

3-(N-(2-chlorophenyl)sulfamoyl)-N-(2-(2-(1-(4-isopropylphenyl

ethylidene)-hydrazinyl)-2-oxoethyl)benzamide (2i)

)

o

1

Yield: 72%; mp: 243ꢀ247 C; H NMR (400 MHz, DMSOꢀd6) δ

1

9

H), 8.16 (d, J = 7.6 Hz, 1H, ArꢀH), 7.86 (d, J = 7.9 Hz, 1H, Arꢀ

H), 7.73–7.66 (m, 3H, ArꢀH), 7.40 (d, J = 7.9 Hz, 1H, ArꢀH),

7

NHCH CO), 2.94ꢀ2.88 (m, 1H), 2.27 and 2.25 (2s, 3H, 110 9.12 and 8.96 (2t, J = 5.9 Hz, 1H, CONHCH ), 8.30 (s, 1H, Arꢀ

N=C(CH )ꢀAr), 1.21 (d, J = 6.9 Hz, 6H); C NMR (101 MHz,

DMSO) δ 170.71, 165.03, 149.48, 148.02, 141.15, 135.73,

1

27

29

5

+

0.72 and 10.49 (2s, 1H, CONHNCH), 10.16 (s, 1H, SO NHAr), 105 H] 570.1578, found 570.1604.

2

.10 and 8.94 (2t, J = 5.9 Hz, 1H, CONHCH ), 8.31 (s, 1H, Arꢀ

3-(N-(2-chlorophenyl)sulfamoyl)-N-(2-(2-(1-(4-(4-fluorophenox

y)phenyl)ethylidene) hydrazinyl)-2-oxoethyl)benzamide (2m)

2

o

1

Yield: 75%; mp: 214ꢀ217 C; H NMR (400 MHz, DMSOꢀd6) δ

.29 – 7.16 (m, 5H, ArꢀH), 4.46 and 4.16 (d, J = 5.8 Hz, 2H,

10.76 and 10.52 (2s, 1H, CONHNCH), 10.17 (s, 1H, SO NHAr),

2

1

3

H), 8.18 (d, J = 7.7 Hz, 1H, ArꢀH), 7.90 – 7.77 (m, 4H, ArꢀH),

3

7.70 (t, J = 7.8 Hz, 1H, ArꢀH), 7.41 (d, J = 7.8 Hz, 1H, ArꢀH),

7.34 – 7.19 (m, 5H, ArꢀH), 7.13 – 7.07 (m, 2H, ArꢀH), 7.01 (d, J

= 8.8 Hz, 2H, ArꢀH), 4.46 and 4.11 (2d, J = 5.8 Hz, 2H,

34.88, 133.83, 131.13, 129.89, 129.37, 129.15, 127.71, 127.38,

26.26, 126.06, 125.73, 41.30, 33.16, 23.68, 13.48; HRMS (ESI):

1

6

|

Journal Name, [year], [vol], 00–00

Page 17 of 141

New Journal of Chemistry

View Article Online

DOI: 10.1039/C7NJ03332J

1

3

NHCH CO), 2.28 and 2.26 (2s, 3H, N=C(CH )ꢀAr); C NMR

(

1

Invivo antiꢀinflammatory Activity

Antiꢀinflammatory activity was evaluated by carrageenan induced

52.07, 147.33, 140.87, 134.91, 133.27, 131.27, 129.93, 129.43, 60 paw edema test in rats (Winter et al. 1962). Ibuprofan 10 and 20

2

3

101 MHz, DMSOꢀd6) δ 170.71, 165.00, 159.57, 157.96, 157.19,

29.31, 129.22, 128.15, 127.89, 127.82, 127.77, 127.68, 125.74,

120.93, 117.61, 116.75, 41.31, 13.43; HRMS (ESI): m/z calcd

for C H ClFN O S [M + H] 595.1218, found 595.1225.

-(N-(2-chlorophenyl)sulfamoyl)-N-(2-(2-(1-(2,5-difluoropheny

mg kgꢀ1 was administered as standard drug for comparison. The

test compounds were administered at two dose levels of 10 and

20 mg kgꢀ1. The paw volumes were measured using the mercury

displacement technique with the help of plethysmo graph

65 immediately before and 30 min, 1, 2 and 3 h after carrageenan

injection. The percent inhibition of paw edema was calculated

according to the following formula, percent inhibition I = 100[1ꢀ

(a ꢀ x)/(b ꢀ y)] where x is the mean paw volume of rats before the

administration of carrageenan and test compounds or reference

5

0

5

0

5

0

5

0

5

0

5

+

29

25

4

5

3

l) ethylidene) hydrazinyl)-2-oxoethyl)benzamide(2n)

o

1

Yield: 78%; mp: 238ꢀ242 C; H NMR (400 MHz, DMSOꢀd6) δ

10.92 and 10.69 (2s, 1H, CONHNCH), 10.16 (s, 1H, SO NHAr),

.12 and 8.95 (2t, J = 5.9 Hz, 1H, CONHCH ), 8.30 (s, 1H, Arꢀ

2

H), 8.17 (d, J = 7.8 Hz, 1H, ArꢀH), 7.85 (d, J = 7.6 Hz, 1H, Arꢀ

1

2

3

4

5

2

9

H), 7.70 (t, J = 7.8 Hz, 1H, ArꢀH), 7.48ꢀ7.47 (m, 1H, ArꢀH), 7.41 70 compound (test group), a is the mean paw volume of rats after the

(

d, J = 7.9 Hz, 1H, ArꢀH), 7.37 – 7.19 (m, 6H, ArꢀH), 4.41 and

administration of carrageenan in the test group (drug treated), b is

the mean paw volume of rats after the administration of

carrageenan in the control group, y is the mean paw volume of

rats before the administration of carrageenan in the control group.

4.13 (2d, J = 5.7 Hz, 2H, NHCH CO), 2.28 and 2.26 (2s, 3H,

N=C(CH )ꢀAr); C NMR (101 MHz, DMSOꢀd6) δ 170.99,

1

2

13

3

65.02, 157.94, 156.10, 144.57, 140.87, 134.87, 133.27, 131.27,

29.94, 129.43, 129.32, 129.23, 127.83, 127.77, 127.69, 125.75,

75

18.08, 117.75, 115.85, 41.25, 16.44; HRMS (ESI): m/z calcd for

DPPH (2, 2ꢀdiphenylꢀ1ꢀpicrayl hydrazyl) Antioxidant assay

+

C H ClF N O S [M + H] 521.0862, found 521.0829.

2

3

20

2

4

3

-(N-(2-chlorophenyl)sulfamoyl)-N-(2-(2-(1-(2,4-dimethoxyphe

Linoleic Acid, TMPD (NꢀTetra Methyl Phenylene Diamine),

hematin and Tween 20 were purchased from Sigma, Arachidonic

Yield: 68%; mp: 172ꢀ176 C; H NMR (400 MHz, DMSOꢀd6) δ 80 acid purchased from Nuꢀcheck Prep, Inc (MN, USA) and

nyl)ethylidene) hydrazinyl)-2-oxoethyl)benzamide(2o)

o

1

0.57 and 10.35 (2s, 1H, CONHNCH), 10.15 (s, 1H, SO NHAr),

Dimethyl sulfoxide (DMSO) of HPLC grade, DPPH (2,2ꢀ

diphenylꢀ1ꢀpicryl hydrazyl). All solutions were prepared in

deionised distilled water. All other reagents were of standard

quality commercially available. The DPPH (2, 2ꢀdiphenylꢀ2ꢀ

2

9.08 and 8.85 (2t, J = 5.6 Hz, 1H, CONHCH ), 8.29 (s, 1H, Arꢀ

H), 8.16 (d, J = 8.0 Hz, 1H, ArꢀH), 7.85 (d, J = 7.2 Hz, 1H, Arꢀ

H), 7.68 (t, J = 7.8 Hz, 1H, ArꢀH), 7.40 (d, J = 7.9 Hz, 1H, ArꢀH),

2

7

.30 – 7.19 (m, 4H, ArꢀH), 6.61 (s, 1H, ArꢀH), 6.55 (d, J = 8.4 85 picrylhydrazyl) radical scavenging effect was carried out

Hz, 1H, ArꢀH), 4.34 and 4.08 (2d, J = 5.8 Hz, 2H, NHCH CO),

according to the method of (Burits and Bucar 2000). Antioxidants

react with DPPH and convert it to α,αꢀdiphenyl,ꢀβꢀpicryl

hydrazine. Compounds of different concentrations were prepared

in methanol, 1 mL of each compound solutions having different

2

3.81 (s, 3H, OCH ), 3.79 (s, 3H, OCH ), 2.16 and 2.15 (2s, 3H,

3

1

N=C(CH )ꢀAr); C NMR (101 MHz, DMSOꢀd6) δ 170.55,

3

1

64.94, 161.17, 158.33, 153.88, 150.00, 140.85, 134.92, 133.27,

31.27, 129.95, 129.42, 129.20, 127.84, 127.79, 127.69, 125.75, 90 concentrations (20, 40, 60, 80 and 100 µM) were taken in

21.68, 104.88, 98.65, 55.57, 55.31, 41.25, 17.56; HRMS (ESI):

different test tubes; 4 mL of a 0.1 mM Methanol solution of

DPPH was added and shaken vigorously. The tubes were then

incubated in the dark room at RT for 20 min. A DPPH blank was

prepared without compound, and Methanol was used for the

95 baseline correction. Changes (decrease) in the absorbance at 517

nm were measured using a UVꢀvisible spectrophotometer and the

remaining DPPH was calculated. The percent decrease in the

absorbance was recorded for each concentration, and percent

quenching of DPPH was calculated on the basis of the observed

+

m/z calcd for C H ClN O S [M + H]

545.1262, found

2

5

26

4

6

5

45.1288.

Biology

In vitro COXꢀ1 and COXꢀ2 Assay

COXꢀ1 was isolated from ram seminal vesicles as described by

4

(

Hemler et al., 1976) . The enzyme COXꢀ2 was isolated

according to the method of (Reddy et al., 2000) with slight 100 decreased in absorbance of the radical. The radical scavenging

modiﬁcations. Enzymatic activities of COXꢀ1 and COXꢀ2 were

activity was expressed as the inhibition percentage and was

calculated using the formula: Radical scavenging activity = [(A₀

– A )/A ] ×100 (%), Where A is the absorbance of the control

4

5

measured as given by (Copeland et al.,1994) , with slight

modifications using a chromogenic assay based on the oxidation

of N,N,N,Nꢀtetraꢀmethylꢀpꢀphenyl diamine, (TMPD) during the

1

0

(blank, without compound) and A is the absorbance of the test

1

reduction of prostaglandin G2 (PGG2) to prostaglandin H2 105 compound. The radical scavenging activity of ascorbic acid

(

PGH2). The reaction mixture contained TrisꢀHCl buffer (100

(Standard) was also measured and compared with that of the test

compounds.

Determination of antibacterial activity

mM, pH 8.0), hematin (15 ꢁM), EDTA (3 ꢁM), enzyme (100 ꢁg)

and test compound. The mixture was pre incubated at 25ºC for 15

min and then the reaction was initiated by the addition of

A collection of three organisms including Gramꢀpositive and

Arachidonic acid (AA) and TMPD in total volume of 2 ml. The 110 Gramꢀnegative organisms were used for this study of clinical

enzyme activity was measured by estimating the initial velocity

of TMPD oxidation followed by the increase in absorbance at 610

nm

isolates such as Escherichia Coli (ꢀve), Klebsiella Species (+ve),

Pseudomonas Species (+ve) were obtained from Microbiology

laboratory of Global Hospital, Hyderabad. All strains were tested

for purity by standard microbiological methods. The bacterial

Journal Name, [year], [vol], 00–00 |17

New Journal of Chemistry

Page 18 of 141

View Article Online

DOI: 10.1039/C7NJ03332J

stock cultures were maintained on Mueller Hinton Agar (MHA)

slants and stored at 4°C.An agarꢀwell diffusion method was

employed for evaluation of antibacterial activity. The bacterial

strains were reactivated from stock cultures by transferring into

Mueller Hinton Broth (MHB) and incubating at 37°C for 18 h. A

final inoculums containing 106 colony forming units (1 x 106

CFU/ml) was added aseptically to MHA medium and poured into

sterile Petri dishes. Different test compounds at a concentration of

14. J. Cotter and E. Wooltorton, Can Med Assoc J, 2005, 172, 1299ꢀ

299.

15. R. B. Silverman and M. W. Holladay, The Org Chem of drug design

and drug action, Academic press, 2014.

16. J. E. Lesch, The first miracle drugs: how the sulfa drugs transformed

medicine, Oxford University Press, USA, 2007.

1

6

7

0

5

0

5

1

7. D. K Patel, S. K. Prasad, R. Kumar, and S. Hemalatha, Asian Pac J

Trop Biomed, 2(4), 320ꢀ330.

18. L. J. De Groot and J. L. Jameson, Endocrinology adult and pediatric:

the thyroid gland, Elsevier Health Sciences, 2013.

1

2

9. G. Der, Gastroenterol Nurs, 2003, 26, 182ꢀ190.

0. A. Ward and R. N. Brogden, Drugs, 1988, 36, 732ꢀ753.

1

.0mg/50ꢁL was added to wells (8mm in diameter) punched on

10

agar surface. Plates were incubated overnight at 37°C and

diameter of inhibition zone (DIZ) around each well was measured

in mm. Experiments were performed in triplicates. Antibiotic

such as Ciprofloxacin at a concentration of 1mg/50ꢁL were used

as positive reference to determine sensitivity of microorganisms

21. R. L. Vigdahl and R. H. Tukey, Biochem Pharmacol, 1977, 26, 307ꢀ

311.

2

2. C. GundogduꢀHizliates, H. Alyuruk, M. Gocmenturk, Y. Ergun and L.

Cavas, Bioorg. Chem, 2014, 52, 8ꢀ15.

3. T. T. Tok, Ö. Ozasik, D. Sarigol and A. U. Baran, Turk J Chem, 2015,

39, 54ꢀ83.

4. R. Šink, A. Kovač, T. Tomašić, V. Rupnik, A. Boniface, J. Bostock,

I. Chopra, D. Blanot, L. P. Mašič, S. Gobec and A. A. Zega,

ChemMedChem, 2008, 3, 1362ꢀ1370.

75

80

85

4

6ꢀ49

15

tested. DMSO was used as a negative control

.

Molecular docking protocol

2

5. G. Rajitha, K. V. Prasad, A. Umamaheswari, D. Pradhan and K.

Bharathi, Med Chem Res, 2014, 23, 5204ꢀ5214.

6. D. Tzeli, P. Kozielewicz, M. Zervou, C. Potamitis, K. Kokkotou, B.

Rak, A. Petrou, E. Tsolaki, A. Gavalas and A. Geronikaki,

ChemistrySelect, 2016, 1, 2426ꢀ2438.

The Xꢀray threeꢀdimensional structures of human cyclooxyegenas

e –II along with reference ligand mefenamic acid (PDB: 5IKR)

and active site of flurbiprofen with prostaglandin H2 synthaseꢀ1

20

(PDB: 1CQE) were retrieved from protein data bank. Prepared

2

7. T. R. F. de Melo, R. C. Chelucci, M. E. L. Pires, L. A. Dutra, K. P.

Barbieri, P. L. Bosquesi, G. H. G. Trossini, M. C. Chung and J. L.

dos Santos, Int. J. Mol. Sci, 2014, 15, 5821ꢀ5837.

and energy wasminimized by protein preparation wizard, receptor

grid was generated employing active site of Mefanamic acid and f

lurbiprofen respectively. The extra precision mode Glide 5.0

dockingwas employed for the present protein ligand interactions.

The ADME properties were calculated using Quickprop module

of Schrodinger LLC.

8. O. ÜnsalꢀTan, K. Özden, A. Rauk and A. Balkan, Eur. J. Med. Chem,

2

010, 45, 2345ꢀ2352.

25

29. B. J. Orlando and M. G. Malkowski, J. Biol. Chem, 2016, 291,

9

0

5

15069ꢀ15081.

3

0. D. Picot, P. J. Loll, and R. M. Garavito, Nature, 1994, 367, 243ꢀ249.

1. A. P. Lill, C. B. Rödl, D. Steinhilber, H. Stark and B. Hofmann, Eur.

J. Med. Chem, 2015, 89, 503ꢀ523.

3

2. C. Lowe, H. Dyke, A. Haughan, F. Galvin, T. Morgan and C. Picken,

WO0174786, 2001.

3. G. Palla, G. Predieri, P. Domiano, C. Vignali and W. Turner,

Tetrahedron, 1986, 42, 3649ꢀ3654.

4. V. V. Syakaev, S. N. Podyachev, B. I. Buzykin, S. K. Latypov, W. D.

Habicher and A. I. Konovalov, J Mol Struct, 2006, 788, 55ꢀ62.

Acknowledgements

We thank Andhra and GITAM Universities for their continuous

support and encouragement to carry out innovative research. We

also thank GVK Biosciences for their support in providing

synthesis and analytical services. We would like to thank Dr

Sasikumar Kuttappan, Dr. Ramarao.G and Gajendra B. Raolji,for

their critical comments in preparing the manuscript.

30

1

00 35. A. Kotali, D. A. Nasiopoulou, C. A. Tsoleridis, P. A. Harris, C. A.

Kontogiorgis and D. J. HadjipavlouꢀLitina, Molecules, 2016, 21, 138.

3

6. Nithinchandra, B. Kalluraya, S. Shetty and M. Babu, J Chem Pharm

Res, 2013, 5, 307ꢀ313.

7. K. Salat, A. Moniczewski and T. Librowski, Mini. Rev. Med. Chem,

2013, 13, 335ꢀ352.

8. M. Singhal, A. Paul, H. P. Singh, S. K. Dubey and R. K. Songara,

Inter. J. Pharm. Sci. Drug Res., 2011, 3, 150ꢀ154.

9. P. K. Godhaviya, P. K. Patel and D. S. Kundariya, Eur J Biomed

Pharm Sci, 2015, 2, 440ꢀ451

35

The authors have declared that no conflict of interest.

05

References

1

.

A. M. Elliott, B. H. Smith, K. I. Penny, W. C. Smith, and W. A.

Chambers, Lancet, 1999, 354 1248ꢀ1252.

10 40. R. Zoraghi, R. H. See, P. AxerioꢀCilies, N. S. Kumar, H. Gong, A.

Moreau, M. Hsing, S. Kaur, R. D. Swayze and L. Worrall,

Antimicrob. Agents Chemother., 2011, 55, 2042ꢀ2053.

2

.

C. Phillips, Anaesthesia, 2001, 56, 1031ꢀ1033.

4

0

5

3. R. Kuan, R. J. Holt, K. E. Johnson, J. D. Kent, D. A. Peura and D.

Malone, Clin. Ther, 2013, 35, 321ꢀ332.

4

1. E. Tatar, S. Senkardes, H.E.Sellitepe, S. G. Kucukguzel, S.

A.Karaoglu, A. Bozdeveci, E. De Clercq, C. Pannecouque, T. B.

Hadda and Đ. Kucukguzel, Turk J Chem, 2016, 40, 510ꢀ534.

2. X.ꢀL. Wang, Y.ꢀB. Zhang, J.ꢀF. Tang, Y.ꢀS. Yang, R.ꢀQ. Chen, F.

Zhang and H.ꢀL. Zhu, Eur. J. Med. Chem, 2012, 57, 373ꢀ382.

3. J.ꢀY. Lee, K.ꢀW. Jeong, J.ꢀU. Lee, D.ꢀI. Kang and Y. Kim, Bioorg.

Med. Chem, 2009, 17, 1506ꢀ1513.

4

.

C. P. Landrigan, J. M. Rothschild, J. W. Cronin, R. Kaushal, E.

Burdick, J. T. Katz, C. M. Lilly, P. H. Stone, S. W. Lockley and D.

W. Bates, N Engl J Med, 2004, 351, 1838ꢀ1848.

15

4

5. J. Vane and R. Botting, Scand J Rheumatol, 1996, 25, 9ꢀ21.

6

7

8

9

. B. Cryer and M. Feldman, Am. J. Med, 1998, 104, 413ꢀ421.

.

F. Fitzpatrick, Curr. Pharm. Des, 2004, 10, 577ꢀ588.

C. S. Williams, M. Mann and R. N. DuBois, Oncogene, 1999, 18.

E. A. Meade, W. L. Smith and D. L. Dewitt, J. Biol. Chem, 1993,

268, 6610ꢀ6614.

120 44. M. Hemler and W. Lands, J. Biol. Chem., 1976, 251, 5575ꢀ5579.

45. R. A. Copeland, J. M. Williams, J. Giannaras, S. Nurnberg, M.

Covington, D. Pinto, S. Pick and J. M. Trzaskos, Proc. Natl. Acad.

Sci., 1994, 91, 11202ꢀ11206.

5

0

5

1

0. H. Suleyman, B. Demircan and Y. Karagoz, Pharmacol Rep, 2007,

9, 247ꢀ258.

1. J.ꢀM. Dogné, C. T. Supuran and D. Pratico, J. Med. Chem, 2005, 48, 125

251ꢀ2257.

5

46. S. S. Kumar and M. Kamaraj, Am Eurasian J Agric Environ Sci,

2010, 7, 176ꢀ178.

47. F. Kavanagh, Analytical microbiology (vol II), Acedemic press, New

York and London, 1972.

48. A. Miles, S. Misra and J. Irwin, J Hyg, 1938, 38, 732ꢀ749.

49. S. Satish, K. Raveesha and G. Janardhana, Lett Appl Microbiol, 1999,

2

5

12. C. Sostres, C. J. Gargallo, M. T. Arroyo and A. Lanas, Best Pract Res

Clin Gastroenterol, 2010, 24, 121ꢀ132.

1

3. M. Bäck, L. Yin and E. Ingelsson, Eur Heart J, 2011, 33, 1928ꢀ33.

130

28, 145ꢀ147.

1

8|

Journal Name, [year], [vol], 00–00

Article Doi

Molecular hybrid design, synthesis and biological evaluation of N-phenyl sulfonamide linked N-acyl hydrazone derivatives functioning as COX-2 inhibitors: New anti-inflammatory, anti-oxidant and anti-bacterial agents

DOI: 10.1039/c7nj03332j

Source and publish data:

Authors:

Article abstract of DOI:10.1039/c7nj03332j

Full text of DOI:10.1039/c7nj03332j

Products guided by the article

R&D Labs maybe for 4025-64-3

Relevant to this article

Hot Product