Design and Bioevaluation of Novel Hydrazide-Hydrazones Derived from 4-Acetyl-N-Substituted Benzenesulfonamide

ISSN 1068-1620, Russian Journal of Bioorganic Chemistry, 2020, Vol. 46, No. 5, pp. 702–714. © Pleiades Publishing, Ltd., 2020.

Design and Bioevaluation of Novel Hydrazide-Hydrazones Derived

from 4-Acetyl-N-Substituted Benzenesulfonamide

E. Bozkurt^a, Y. Sıcak^b, E. E. Oruç-Emre^{a, 1}, A. Karaküçük Iyidoğan^a, and M. Öztürk^c

^aDepartment of Chemistry, Faculty of Arts and Sciences, Gaziantep University, Gaziantep, 27410 Turkey

^bDepartment of Medicinal and Aromatic Plants, Köyceğiz Vocational School, Muğla Sıtkı Koçman University,

Muğla, 48800 Turkey

^cDepartment of Chemistry, Faculty of Sciences, Muğla Sıtkı Koçman University, Muğla, 48800 Turkey

Received January 1, 2020; revised March 18, 2020; accepted March 22, 2020

Abstract—In this research, a series of hydrazine-hydrazone derivatives (Ia–g), (IIa–h) were synthesized to

discover new antioxidant and anticholinesterase agents. The structures of synthesized compounds were char-

acterized by spectroscopic data using UV, IR, ¹H, ¹³C NMR, mass spectroscopy, and elemental analysis. The

bio-evaluation of the synthesized compounds (Ia–g), (IIa–h) were evaluated according to in vitro activity

assays. The results of β-carotene/linoleic acid assay showed that among the synthesized compounds, the (Ib),

(Ie), (IIb–IIe), and (IIh) compound exhibited higher activity for the lipid peroxidation inhibitory activity. In

the DPPH free scavenging activity and the cation radical scavenging activity in ABTS^•+activity, compound

(IIb) was found to be more active. In the CUPRAC reduced power assay, the A_0.5values of all synthesized

compounds were better than α-TOC. In AChE assay, compound (IIb) exhibited the most activity with IC₅₀

=

11.12 0.74 μM, while the compounds (Ib–g) and (IIb–h), exhibited excellent activity than the positive stan-

dard galantamine (IC₅₀= 46.06 0.10 μM) in the BChE assay.

Keywords: sulfonamide, hydrazone, antioxidant activity, anticholinesterase inhibitory activity, Lipinski’s

rules

DOI: 10.1134/S1068162020050052

INTRODUCTION

niazid (antimicrobial), nifuroxazide (intestinal anti-

septic), nitrofurantoin, and nifuratel (urine antisep-

tic), iproniazid and isocarboxazid (antidepressants)

[11]. In the literature, it has been reported that hydra-

zide-hydrazone derivatives exhibit antioxidant and

anticholinesterase activity [12–15].

In protecting the organism’s health status, the bal-

ance between the antioxidant systems of the body with

free radicals is essential [16]. Extreme reactive oxygen

species (ROS) production eventuate oxidative stress

that may be the reason for fatal damage to living cell

structures [17]. Oxidative stress has also related some

of the common diseases such as cancer, neurodegen-

erative, cardiovascular, inflammatory, and autoim-

mune. It is associated with the pathology of Alzhei-

mer’s disease, as well [18].

Alzheimer’s disease is degeneration of the central

nervous system, also is known as the most common

form of dementia. As a progressive neurologic disor-

der, it is characterized mainly by premature senile

mental deterioration that results in behavioral abnor-

malities in the patient [19]. The acetylcholinesterase

(AChE) inhibitory compounds were used to treat Alz-

heimer’s disease due to the deficiency of the insuffi-

Sulfonamides (sulfa drugs) are significant bioactive

synthetic medicines. Over the last decades, many sulfa

drugs have been developed and began using in the

treatment. [1]. The brinzolamide, which is a carbonic

anhydrase inhibitor, has been used to reduce intraoc-

ular pressure in patients with open-angle glaucoma or

ocular hypertension [2]. An anti-glaucoma agent, dor-

zolamide, is used to decrease the production of aque-

ous humor [3]. Another sulfonamide drug sultiame

having anticonvulsant activity is reported for the cure

of West syndrome and epilepsy [4]. Besides, studies

have shown that sulfonamides exhibit antioxidant and

anticholinesterase activities [5–9].

Another essential organic compound class, hydra-

zones (–CONHN=CH–) are formed by the reaction

of hydrazine and ketones/aldehydes [10]. Hydrazones

can be used as intermediates to synthesize coupling

products using the active hydrogen of the azomethine

group. Besides, they are very effective organic com-

pounds and used as drugs in the treatment such as iso-

¹Corresponding author: phone: + (903) 423-17-29-98; fax:

+ (903) 423-60-10-32; e-mail: oruc@gantep.edu.tr.

702

DESIGN AND BIOEVALUATION

703

cient amount of acetylcholine (ACh). However, these absorption bands accompanied by the C=N absorp-

drugs have undesired side effects. Therefore, the tion band between the 1591–1607 cm^–1region that

was good evidence for the presence of an azomethine

linkage. An additional strong band in the 1637–

1671 cm^–1region, attributed to a carbonyl stretching,

confirmed the hydrazone feature of all the compounds

[21–24]. The asymmetric and symmetric stretching

bands of the SO₂NH group of the synthesized mole-

improvement of novel effective antioxidants and

AChE inhibitory compounds having fewer side effects

are desired. According to some literature, using anti-

oxidants may decrease the progression of Alzheimer’s

disease and reduce neuronal degeneration [20].

In our body, which is under oxidative stress, oxygen

is divided into two atoms that do not have a paired

electron. These atoms that travel alone and have miss-

ing electrons are called free radicals. However, elec-

trons like to go around in pairs. That’s why free radi-

cals in our bodies travel our entire body to find another

electron. During this circulation, cells, proteins, and

DNA are damaged. Free radicals can cause many dis-

eases. It can lead to diseases such as diabetes, Alzhei-

mer’s, and Parkinson’s disease, vascular occlusion. In

recent years, free radicals formed in our body have

become a severe health problem with the increase of

oxidation-related diseases. It is an advantage for an

antioxidant compound if it inhibits or minimizes sev-

eral diseases related to oxidative stress. Thus, the novel

hydrazide-hydrazones, combined with the sulfon-

amide group to increase the pharmacological activi-

ties, were designed herein. These compounds (Ia–g),

(IIa–h), derived from 4-acetyl-N-substituted benzene-

sulfonamide, were synthesized and evaluated for their

in vitro antioxidant and anticholinesterase activities.

cules were in the range of 1335–1347 cm^–1and 1144–

1166 cm^–1, respectively [25–28]. The absorption

bands associated with substituents connected to the

hydrazide-hydrazone skeleton appeared in the

expected regions [29].

1

In the H NMR spectra of the hydrazide-hydra-

zone derivatives, the proton of –CONHN= group res-

onated as a singlet at 10.49–11.19 ppm. The disappear-

ance of the proton peaks of the free amino group is evi-

dence of hydrazide-hydrazone synthesis. These data

were compatible with the literature records [30–33].

Moreover, resonating of the proton of –SO₂NH group

as a singlet at the range of 10.32–10.92 ppm was

another proof of the hydrazide-hydrazone group for-

mation. In the structure of compounds i and ii, the

protons of –CH₃had resonance at 2.59 ppm as the

electron density, after the formation of imine

(‒N=C–) resonated at 2.28–2.38 ppm. In the struc-

ture of compounds (Ia–h), the protons in ortho and

meta positions relative to the sulfonamide group in the

A ring resonated in the range of 7.03–7.24 ppm. In the

structure of compounds (IIa–h), however, they dis-

played a peak at 7.83 ppm due to the electron-with-

drawing property of the carboxylic acid. Chemical

shifts of the protons belonging to the rings C and D of

the compounds (If), (IIf) were observed in the range

of 7.56–8.00 ppm, and the amide proton was observed

in the range of 10.80–10.81 ppm [34]. The protons of

the C and D rings of the compounds (Ig), (IIg) reso-

nated in the range of 7.29–7.44 ppm, and the tertiary

hydroxyl proton was detected in the range of 7.23–

7.24 ppm [35, 36].

RESULTS AND DISCUSSION

In this work, the new hydrazide-hydrazones (Ia–

g), (IIa–h) derivated from 4-acetyl-N-substituted

benzenesulfonamide were synthesized. In the first

step, the substituted benzoylhydrazine derivatives

were prepared by the treatment of substituted benzoyl-

chloride with hydrazine hydrate. In the second step,

sulfonamide compounds were synthesized via the

treatment of 4-acetylbenzenesulfonylchloride with

substituted aromatic amines. In the last step, substi-

tuted hydrazide-hydrazone derivatives were obtained

by interacting substituted benzoylhydrazine with sul-

fonamide compounds in methanolic solution. The

synthetic route followed for the preparation of the tar-

get molecules was shown outlined in Scheme 1.

In this research, the ultraviolet and visible (UV-

Vis) spectra of all hydrazide-hydrazones derivatives

were carried out (dissolved) in DMSO. In the UV-Vis

spectra of hydrazone groups (Ia–g), (IIa–h), the K

bands caused by transitions of n → σ* and π → π* of nitro-

gen in –C=N– group were detected at 274–285 nm.

Also, characteristic R bands originating from the n →

π* transition, containing the carbonyl moiety of the

hydrazide group (C=O), were at 295–315 nm.

In the ¹³C NMR spectrum of the compound i and

ii, it was found that the –CH₃carbon in the acetyl

group resonated at 27.44–27.45 ppm, the aromatic

carbons resonated in the range 118.86–143.58 ppm,

the carbonyl carbons in the acetyl group were detected

at 197.63–197.68 ppm, carbonyl carbon of COOH in

the structure of compound ii was at 167.15 ppm, and

the values herein were consistent with the literature

data [27]. The resonance of the imine bond (–C=N)

carbon in the range of 152.72–154.94 ppm was com-

patible with the literature data [37]. The methyl

(‒CH₃) carbon of hydrazones was a resonance in the

range of 13.80–15.47 ppm, and the aromatic carbons

were resonance in the range of 115.58–133.10 ppm,

the carboxylic acid carbonyl carbon was a resonance in

the range of 167.18–167.74 ppm, the carbonyl (‒C=O)

carbon bound to the hydrazone group was found to have

The IR spectra of hydrazide-hydrazones (Ia–g),

(IIa–h) provided the 3137–3354 cm^–1absorption as

the weak NH band. Both weak NH and C–H bending resonance in the range of 163.23–169.37 ppm.

RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 46 No. 5 2020

704

BOZKURT et al.

O

R

+

R

Cl

O

HO

O

S

O

NaOH

R₁

NH₂

+

Cl

C CH₃

O

NH₂NH₂· H₂O

O

S

O

H

O

C CH₃

R₁

N

NH₂

O

R

N

H

iii

i = R₁: -H

ii = R₁: -COOH

H_F

C₈

H_G

H_D

H_E

H_C

H_A

O

H_H

C₁

H

R₁

N S

C N N C R

O ^C

CH₃

C₃

C₇

C₁₀

C₉

6

C₁₂

C₁₁

C₅

C₄

C₂

H_B

C₁₄

C₁₅

H_J

C₁₄

C₁₃

C₁₅

C₁₄

C₁₃

C₁₅

C₁₆

C₁₄

C₁₃

C₁₅

C₁₆

C₁₆C₁₇

C₁₃

C₁₆

C₁₅

N

F

Cl

C₁₄

H_I

H_J

H_I

H_J

H_I

H_J

C₁₃

OH_H

a

b

c

d

I

R

H_K

C₁₄

C₁₅

C₁₄

C₁₅

C₁₉

C₁₈

C₁₇

C₂₀

C₂₁

H_N

C₁₄

C₁₅

C₁₆

H_J

O

C₁₃

C₁₆

C₁₃

C₁₆

C₁₃

H

N

NO₂

Br

H_K

H_L

H_I

H_J

H_I

H_J

H_L

H_M

H_I

H_J

e

f

h

g

O

N S

H O

C N N C R

CH₃

H

(Ia−g) series

O

HOOC

N S

C N N C R

H O

CH₃

H

(IIa−h) series

Scheme 1. Synthetic pathway of substituted hydrazide-hydrazones (Ia–g), (IIa–h).

The mass spectra of the synthesized compounds (I, IIg) bearing the nonsubstituted phenyl ring in the

II, Ia–g, IIa–h) were run using ESI (+) and (–) tech-

nique. According to the results, the compounds (Ib,

Ic, Id, Ig, IIa–d, IIf, and IIh) exhibited [M⁺¹] molec-

ular ion peaks while compounds (II, Ie, IIe) [M^–1],

and the compounds (I, Ia) [M⁺²], and the compounds

structure, the ions formed as a result of the fragmenta-

tion of the phenyl ring and the cleavage ions of the

phenyl ring were detected. Compounds (IIa–h) bear-

ing acid groups have been generally found to form ions

resulting from the cleavage of the α-cleavage relative to

(If and IIg) [M^–2]. The compounds (I, Ia–g, IIa, IIf, the acid carbonyl, –COOH (m/z 45). Formed ions

RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY

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DESIGN AND BIOEVALUATION

705

with cleavage of the pyridine ring (m/z 78) in com- the DPPH, which resulted in the decrease of absorp-

pounds (Ib) and (IIb) and the cleavage products of this tion at 517 nm [39–42, 44]. The lower absorbance at

ring were detected. In general, when the mass spectra 517 nm indicates higher DPPH free radical scavenging

of all synthesized compounds were examined, it, activity. In the DPPH free scavenging activity, com-

unlike the molecular ion, has been found that the deg- pounds (IIb) (IC₅₀= 26.77 0.31 μM) demonstrated the

radation proceeds from 8 points. In Scheme 2, frag-

mentation points on the skeletal structure of the syn-

thesized compounds were indicated.

best activity. Moreover, all series (Ia–g), (IIa–h) exhibited

more activity than BHT (IC₅₀= 53.80 0.92 μM).

ABTS (2,2′-azino-di-[3-ethylbenzthiazoline sul-

fonate) cation radical scavenging activity method is

based on the neutralizes of ABTS cation radical by an

antioxidant. The ABTS cation radical is produced by

the oxidation of ABTS molecule with strong oxidizing

agents, such as K₂S₂O₇in water. The produced green-

ish radical absorbs at 734 nm. The advantage of this

radical is the solubility in inorganic and organic sol-

vents. Therefore, using this assay, both hydrophilic

and hydrophobic compounds can be tested [45].

Another advantage of the ABTS assay is that the bulky

compounds can approach this molecule to transfer

electrons easily when compared with the DPPH mol-

ecule. In this assay, lower absorbance exhibits the

higher ABTS cation radical scavenging activity [39–

O

8

7

6

²H

N

1

5

4

3

O

S

N

R

N

C

CH₃

H

O

Scheme 2. Fragmentation points

on the skeletal structure of the synthesized compounds.

Biological Activity

Antioxidant activity evaluation. The synthesized

compounds (Ia–g, IIa–h) were screened for their anti-

oxidant activity using four different assays (Table 1).

The α-tocopherol and BHT (butylated hydroxyl tolu-

ene) were used as positive standards to compare the

activity. In general, among the synthesized molecules

(Ia–g), (IIa–h) series, the antioxidant activity of

compounds (IIa–h) series were founded to be active

than compounds (Ia–g) derivatives. β-carotene-lin-

oleic acid assay is based on the discoloration of the yel-

lowish color of a β-carotene having an absorption

band at 470 nm. The singlet oxygen oxidizes the dou-

ble bonds of linoleic acid added to the oxygenated

media, which resulted in the lipid peroxyl radicals (L^•

or LOO^•). The produced radicals attach the β-caro-

tene to degrade it. The antioxidant in the media neu-

tralizes the radicals or stops the radicalic degradation

radicals by transferring Hydrogen radical or scavenge

the singlet oxygen, which accelerates the radicalic deg-

radation [38–42]. Therefore, the higher absorbance at

470 nm indicates the higher antioxidant activity.

According to the β-carotene/linoleic acid assay results,

the compounds (IIb) (IC₅₀= 10.21 0.12 μM), (Ib)

42, 46]. In ABTS assay, compound (IIb) (IC₅₀

4.13 0.54 μM) was the most active compound

among the tested compounds (Ia–g), (IIa–h). Com-

=

pounds (Ib) (IC₅₀= 7.08 0.45 μM), (IIe) (IC₅₀

=

7.45 0.50 μM), (Ie) (IC₅₀= 9.69 0.28 μM), (IIc)

(IC₅₀= 10.88 0.63 μM), (Ic) (IC₅₀= 11.85 0.18 μM),

(IId) (IC₅₀= 13.51

0.49 μM), and (Id) (IC₅₀=

14.41 1.13 μM) indicated good ABTS^•+cation radi-

cal scavenging activity.

The CUPRAC (Cupric Reducing Antioxidant

Capacity) assay tests the electron giving power of the

antioxidant. The antioxidant reduces the Cupric to

Cuprous. The reduction potential is monitored by

using the neocuproine ligand. The neocuproine ligand

and cuprous can occur complex molecule which

absorbs at 450 nm. Therefore, the amount of reduc-

tion of Cupric to cuprous indicates the power of anti-

oxidants. Accordingly, the higher absorbance at

450 nm suggests the higher Cupric reducing antioxi-

dant capacity [40–42, 47, 48]. In the CUPRAC assay,

compound (IIb) (A_0.5= 8.88 0.01 μM) possessed the

highest activity. The cupric reducing the antioxidant

capacities of synthesized compounds (Ia–g), (IIa–h)

were better than α-TOC (A_0.5= 40.41 0.03 μM).

In this study, according to the antioxidant activity

assay results of the synthesized compounds, they

exhibit better antioxidant activity than other com-

pounds with the potential of forming free radicals by

weakening the NH bond in the hydrazone group of the

compounds (Ib) and (IIb) containing the heteroatom

in the ring and compound (Ic), (Id), (IIc) and (IId)

containing the halogen group bound to the ring.

(IC₅₀= 12.83

0.19 μM), (IIc) (IC₅₀= 14.75

0.48 μM), (IId)

0.44 μM), (IIe) (IC₅₀= 16.20

(IC₅₀= 18.83 0.19 μM), (Ie) (IC₅₀= 20.16 0.35 μM),

and (IIh) (IC₅₀= 20.16 0.37 μM) exhibited higher

lipid peroxidation inhibitory activity among the syn-

thesized compounds. The compounds (IIb), (Ib),

(IIc), (IIe), (IId), (Ie), and (IIh) exhibiting high lipid

peroxidation inhibitory activity sadi that they have the

abilities of radical hydrogen transfer.

DPPH (2,2-diphenyl-1-picryl-hydrazyl-hydrate)

free radical scavenging activity method is based on the

neutralizes of DPPH radical by an antioxidant. The

DPPH is a stable free radical absorbing at 517 nm

wavelength. When the DPPH radical get an electron

from an antioxidant, the absorption at 517 nm

decreases [43]. This free radical is stable at room tem-

Acetyl- and butyryl-cholinesterase inhibitory activi-

perature. Therefore, it can be said that the antioxidant, ties evaluation. The only known hypothesis to treat

if approaches DPPH molecule, transfers electrons to Alzheimer’s disease is to inhibit the acetylcholinester-

RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 46 No. 5 2020

706

BOZKURT et al.

Table 1. Antioxidant activity results of synthesized compounds^a

DPPH^•assay IC₅₀, ABTS^•+assay IC₅₀,

Sample

code

β-Carotene/linoleic acid assay IC₅₀, μM

CUPRAC A_0.50, μM

μM

(I)

(II)

(Ia)

(Ib)

(Ic)

(Id)

(Ie)

(If)

(Ig)

(IIa)

(IIb)

(IIc)

(IId)

(IIe)

(IIf)

(IIg)

(IIh)

44.18 0.42

39.56 0.90

35.47 0.54

12.83 0.19

22.77 0.33

27.14 0.60

20.16 0.35

33.82 0.66

30.49 0.76

29.14 0.88

10.21 0.12

14.75 0.44

18.36 0.61

16.20 0.48

25.88 0.68

22.84 0.52

20.16 0.37

58.19 0.54

54.93 0.71

52.06 0.18

30.36 0.85

33.99 1.14

36.76 0.53

32.01 0.17

49.40 0.44

44.26 0.68

50.65 0.94

26.77 0.31

33.24 0.55

35.73 0.26

30.29 0.75

45.74 0.59

43.52 0.36

39.44 0.58

53.80 0.92

40.11 0.22

36.77 0.34

34.17 0.03

7.08 0.45

11.85 0.18

14.41 1.13

9.69 0.28

29.16 0.40

30.49 0.07

33.41 0.89

4.13 0.54

10.88 0.63

13.51 0.49

7.45 0.50

25.37 1.08

29.70 0.44

17.30 0.67

2.81 0.43

42.08 0.00

38.45 0.01

33.66 0.03

8.88 0.00

18.77 0.04

21.64 0.01

16.47 0.02

28.30 0.02

24.11 0.00

20.35 0.01

8.40 0.01

9.73 0.01

10.04 0.00

14.26 0.00

16.27 0.00

13.90 0.04

13.15 0.03

3.84 0.00

BHT^b

α-TOC^b

2.44

4.63

0.07

0.11

12.16 0.16

4.93 0.39

40.41 0.03

a

b

Values expressed are means SD of three parallel measurements. p < 0.05, significantly different with student’s t-test. Reference

compounds.

ase (AChE) and butyrylcholinesterase (BChE), which respectively, which were lower than 25 μM. The said

are the chief enzymes of Alzheimer’s disease. There- compounds they were exhibited better activity among

fore, acetylcholinesterase inhibitory drugs are used for synthesized compounds (Ia–g), (IIa–h). In the BChE

the treatment of patients. The inhibition of both assay, however, the IC₅₀of all compounds (Ia–g),

enzymes lessens the symptoms of Alzheimer’s disease

by increasing the communication between nerve end-

ings and the activities in cholinergic pathways in the

brain [49]. Accordingly, the anticholinesterase activity

method is based on the inhibition of AChE and BChE

enzymes. In a control test, where there is no testing

compound, the enzyme hydrolyzes the acetylthiocho-

line or butyrylthiocholine to give thiocholine. The lat-

ter reacts with the DTNB to give a yellow color which

can be measured at 412 nm. When any inhibitory com-

pound added to the medium to be tested for its activity,

the compound inhibits the enzymes; thus, thiocholine

occurs a lesser amount, which resulted in lower absor-

bances. Therefore, the lower absorbance indicates

higher activity. In other words, lower absorbance indi-

cates higher acetylcholinesterase and butyrylcholines-

terase inhibitory activity of the compound.

(IIa–h) except compounds (Ia) and (IIa), were lower

than galantamine used as a drug in mild Alzheimer

patients. The compounds (IIb), (Ib), (IIe), (IIc),

(IId), (Ie), (Ic), (Id), (IIh), (IIg), (Ig), (IIf), and (If)

from synthesis series exhibited excellent activity with

IC₅₀values of 14.26 0.68, 17.25 0.37, 20.74 0.62,

21.88 0.82, 26.65 0.49, 26.65 0.54, 31.19 0.84,

35.20 0.68, 36.35 0.40, 40.72 0.43, 43.34 0.60,

and 45.51 0.61 μM, respectively. The galantamine

possessed 46.06 0.10 μM IC₅₀value in the same con-

ditions. As a result, the compounds (IIb) and (Ib) the

AChE and BChE against show better activity at low

absorbance by inhibiting both enzymes better than

other compounds.

Druglikeness Properties

The in vitro anticholinesterase activity of synthe-

sized compounds (Ia–g), (IIa–h) against AChE and

BChE were given in Table 2. In AChE inhibitory

assay, the IC₅₀values of compounds (IIb), (Ib), (IIe),

According to Lipinski’s rules of five, our results

showed that the molecular weights of compounds

except for (If), (IIf–g) were not greater than 500 at the

range of 393.47–499.59 Da. The logP values of all

(IIc), and (IId) were 11.12

0.74, 15.28

0.33, hydrazones were smaller than 5 at the range of 2.49–

18.23 0.64, 20.42 0.71, and 23.19

0.56 μM, 4.67. The number of groups that accepted hydrogen

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DESIGN AND BIOEVALUATION

707

Table 2. Acetyl-, and butyryl-cholinesterase inhibitory

pounds. According to the antioxidant activity results,

these two compounds may have a significant impact

on the prevention of radical-induced oxidative stress.

In anticholinesterase activity, compounds (IIb), (Ib),

(IIe), (IIc), (IId), (Ic), and (Id) showed considerable

activity against both AChE and BChE enzymes. Nota-

bly, the BChE activity of the compounds containing

the heteroatom in the ring, the halogen, and nitro

groups in the phenyl ring were was found to be more

excellent from the galantamine used as standard.

According to the data in Table 3, suggested that com-

pounds (IIb) and (Ib) from novel synthesized hydra-

zide-hydrazone derivatives with tertiary amine groups

can be evaluated as both AChE and BChE enzyme

inhibitors, which may have promising features for the

treatment of Alzheimer’s disease.

activities of synthesized compounds^a

Anticholinesterase inhibitory activity

Sample

AChE assay IC₅₀,

μM

BChE assay IC₅₀,

μM

(I)

(II)

(Ia)

(Ib)

(Ic)

(Id)

(Ie)

(If)

(Ig)

(IIa)

(IIb)

(IIc)

(IId)

(IIe)

(IIf)

(IIg)

(IIh)

49.30 0.67

47.79 0.44

45.05 0.26

15.28 0.33

28.09 0.33

33.70 0.56

25.07 0.85

41.23 0.82

38.04 0.55

44.52 0.28

11.12 0.74

20.42 0.71

23.19 0.56

18.23 0.64

40.14 0.40

36.18 0.83

30.49 0.50

4.50 0.09

54.47 0.06

51.73 0.19

48.76 0.49

17.25 0.37

31.19 0.84

35.20 0.68

26.65 0.54

45.51 0.61

40.72 0.43

48.36 0.79

14.26 0.68

21.88 0.82

26.65 0.49

20.74 0.62

43.34 0.60

40.52 0.78

36.35 0.40

46.06 0.10

EXPERIMENTAL

All chemicals were purchased from Sigma-Aldrich

(St. Louis, MO, USA), Alfa Aesar, Fluka, and Merck.

The reactions and the purities of the compounds were

monitored by thin-layer chromatography (TLC) on

silica gel 60 F254 aluminum sheets purchased from

Merck (Darmstadt, Germany). Melting points were

recorded by open capillaries on the Stuart melting

point SMP30 apparatus and are uncorrected. C, H, N,

S percent of the compounds were detected by Thermo

Scientific Flash 2000 (Finnegan MAT, USA) elemen-

tal analyzer. UV spectra, PG Instruments brand T80 +

UV/Vis Spectrometer spectrometry was in the range

of 190 to 1100 nm wavelengths. FTIR spectra were

recorded on Perkin Elmer Frontier spectrometer by

attenuated total reflectance (ATR) apparatus

(Waltham, Massachusetts, USA). Mass spectra were

recorded on Ab-SciEx 3200 Q-Trap MSMS detector

with an electrospray ionization probe (Framingham,

MA, USA). NMR spectra were recorded on Brucker

Avance-400 MHz spectrometer (Billerica, MA, USA)

by using DMSO-d₆as a solvent and TMS as an inter-

nal standard. Bioactivity measurements were carried

out on a 96-well microplate reader, SpectraMax

340PC³⁸⁴, Molecular Devices (USA), at the Depart-

ment of Chemistry, Mugla Sıtkı Kocman University.

Galantamine^b

a

Values expressed are means

SD of three parallel measure-

b

ments. p < 0.05, significantly different with student’s t-test.

Reference compounds.

atoms (n-ON) was less than 10 except compounds

(IIe) and (IIf), and the number of groups that donated

hydrogen atoms (n-OHNH) was less than 5, which

were within the Lipinski’s rules. All data for the calcu-

lation of absorption (%ABS), according to Zhao et al.

[50] and TPSA values were shown in Table 3.

CONCLUSIONS

Novel hydrazide-hydrazones (Ia–g), (IIa–h) deri-

vatized from 4-acetyl-N-substituted benzenesulfon-

amide were synthesized. The structures of synthesized

Synthesis of 4-acetyl-N-phenyl benzenesulfonamide

compounds were confirmed by spectroscopy methods (i or I). To a solution of 4-acetylbenzenesulfonyl chlo-

1

as UV-Vis, IR, H NMR, ¹³C NMR, mass spectros-

copy, and elemental analysis (C, H, N, S). Antioxi-

dant and anticholinesterase activities of the synthe-

sized compounds (Ia–g), (IIa–h) were reported for

the first time in this study. The (Ia–g) and (IIa–h)

hydrazone series in both activity assays were found to

be more active than the starting materials. Fifteen dif-

ferent hydrazone derivatives tested for their antioxi-

dant potency by in vitro antioxidant and anticholines-

terase activities. Compound (IIb) and (Ib), bearing

heteroatom on the aromatic ring, were found to be the

ride (1 mmol) in acetone, 5 g of silicagel was added.

2 mmol of aniline was added dropwise to the stirred

mixture at room temperature. After the reaction has

been completed (as indicated by TLC), methanol was

added and the silica gel was removed by filtration. The

methanol solution was taken in a beaker and then puri-

fied water was added dropwise to crystallize the prod-

uct by precipitation. The crystalline product was

washed with water and filtered and dried [51]. This

compound was previously synthesized by Gioiello

[52]. Yield: 83%; orange solid, mp 99–101°C; IR

most potent antioxidant agents among all tested com- (ν, cm^–1): 3273 (N–H); 3092, 3042 (aromatic C–H);

RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 46 No. 5 2020

708

BOZKURT et al.

1

Table 3. Druglikenees properties of hydrazones (Ia–g,

IIa–h)*

2962, 2885 (aliphatic C–H); 1687 (C=O); H NMR

(400 MHz) (DMSO-d₆/TMS) δ (ppm): 2.59 (s, 3H,

H_B); 7.04 (t, 1H, J₁= 6.8 Hz, J₂= 6.8 Hz, H_H); 7.10 (d,

2H, J = 8.4 Hz, H_F); 7.24 (t, 2H, J₁= 8.0 Hz, J₂=

8.0 Hz, H_G); 7.88 (d, 2H, J = 8.4 Hz, H_D); 8.08 (d,

Compound LogP TPSA

MW

87.63 393.47

2.49 100.52 394.46

nOH nOHNH

(Ia)

3.78

6

7

2

3

2

3

4

3

4

(Ib)

2H, J = 8.4 Hz, H_C); 10.47 (s, 1H, H_E); ¹³C NMR

(100 MHz) (DMSO-d₆/TMS) δ (ppm): 27.44 (C₂);

120.74, 124.87, 127.50, 129.48, 129.72 (C₄, C₅, C₈, C₉,

C₁₀); 137.75, 140.20, 143.58 (C₃, C₆, C₇); 197.68 (C₁);

(Ic)

(Id)

3.94

4.46

87.63 411.46

87.63 427.91

6

9

8

(Ie)

(If)

3.74 133.46 438.46

4.67 116.73 512.59

MS (m/z) (%): 277 [M⁺²]; UV-Vis (DMSO, λ_max

,

nm): 296, 280; Anal. calc. for C₁₄H₁₃NO₃S: C, 61.07;

H, 4.76; N, 5.09; S, 11.65%; found: C, 61.09; H, 4.85;

N, 5.00; S, 11.09%.

(Ih)

(Ig)

4.59

87.63 472.36

6

7

8

9

4.06 107.86 499.59

3.69 124.93 437.48

2.40 137.82 438.46

3.85 124.93 455.47

4.37 124.93 471.92

3.65 170.75 482.47

4.58 154.03 556.60

4.50 124.93 516.37

3.97 145.16 543.60

(IIa)

(IIb)

(IIc)

(IId)

(IIe)

(IIf)

(IIh)

(IIg)

Synthesis of 4-(4-acetylphenylsulfonamido)benzoic

acid (ii or II). 7.3 mmol of 4-aminobenzoic acid was

added to 10 mL of purified water and the pH of the

reaction mixture was maintained to 9 with aqueous

NaHCO₃solution. 7.3 mmol of 4-acetylbenzenesulfo-

nyl chloride was then added in small portions to the

reaction mixture and the reaction was stirred at room

temperature. After the reaction has been completed (as

indicated by TLC), the pH of the reaction mixture was

changed to 2 with 1M HCl. The resulting precipitate

was filtered off with water and dried. The crude prod-

uct was purified by crystallization from methanol [53],

this compounds was previously synthesized by Deng

and Mani [27]. Yield: 84%; cream solid, mp 251–

8

11

10

8

9

* These parameters were determined with Molinspiration calcula-

tion software and Molsoft software.

acetic acid was added to the reaction mixture. The

253°C; IR (ν, cm^–1): 3259 (N–H); 3110 (aromatic C– mixture was refluxed on a water bath for 2 h. After

1

cooling the mixture, the precipitate was filtered, dried,

and recrystallized from ethanol [55].

H); 2836 (aliphatic C–H); 1677 (C=O); H NMR

(400 MHz) (DMSO-d₆/TMS) δ (ppm): 2.60 (s, 3H,

H_B); 7.22 (d, 2H, J = 8.4 Hz, H_F); 7.82 (d, 2H, J = 8.8

Hz, H_G); 7.95 (d, 2H, J = 8.4 Hz, H_D); 8.11 (d, 2H,

J = 8.4 Hz, H_C); 10.99 (s, 1H, H_E); 12.81 (s, 1H, H_H);

4-(1-(2-Benzoylhydrazinylidene)ethyl)-N-phenyl-

benzenesulfonamide (Ia). Yield: 47%; white solid, mp

222–225°C; IR (ν, cm^–1): 3378, 3137 (N–H); 3024

(aromatic C–H); 2953, 2882 (aliphatic C–H); 1687

(C=O); 1600 (C=N); ¹H NMR (400 MHz) (DMSO-

d₆/TMS) δ (ppm): 2.36 (s, 3H, H_B); 7.04 (t, 1H, J₁=

8.0 Hz, J₂= 6.8 Hz, H_H); 7.10 (d, 2H, J = 7.2 Hz, H_F);

7.24 (t, 2H, J₁= 7.6 Hz, J₂= 8.0 Hz, HG); 7.52 (t, 2H,

J₁= 6.8 Hz, J₂= 6.8 Hz, H_J); 7.59 (d, 1H, J = 6.4 Hz,

H_K); 7.80–7.97 (m, 6H, H_C, H_D, H_I); 10.33 (s, 1H,

¹³C NMR (100 MHz) (DMSO-d₆/TMS) δ (ppm):

27.45 (C₂); 118.86, 126.42, 127.54, 129.64, 131.28 (C₄,

C₅, C₈, C₉, C₁₀); 140.42, 142.02, 143.24 (C₃, C₆, C₇);

167.15 (C₁₁); 197.68 (C₁); MS (m/z): 317.7 [M^–1]; UV-

Vis (DMSO, λ_max, nm): 293, 275; Anal. calc. for

C₁₅H₁₃NO₅S: C, 56.42; H, 4.10; N, 4.39; S, 10.04%;

found: C, 55.96; H, 3.87; N, 4.36; S, 9.91%.

H_E); 10.89 (s, 1H, H_A); ¹³C NMR (100 MHz)

(DMSO-d₆/TMS) δ (ppm): 14.86 (C₂); 120.72,

Synthesis of the substituted hydrazide derivatives

(iii). Firstly 4-substituted aroyl chloride (10 mmol)

was reacted with phenol (10 mmol in 100 mL of 10% 124.69, 127.28, 127.47, 128.72, 129.65, 132.07, 134.37

sodium hydroxide solution) to form 4-substituted (C₄, C₅, C₈, C₉, C₁₀, C₁₄, C₁₅, C₁₆); 137.40, 138.02,

phenyl benzoate. The crude product was washed with

water and recrystallized from ethanol. Then the 4-sub-

stituted phenyl benzoate (5 mmol) was reacted with

hydrazine hydrate (10 mmol) in methanol. The mix-

ture was refluxed and monitored by TLC. The crude

product was washed with water and recrystallized from

ethanol [54].

Synthesis of substituted hydrazide-hydrazone deriv-

atives (Ia–g), (IIa–h). To a solution of 1 mmol hydra-

zide derivatives (iii) in 10 mL, methanol was added a

solution of 1 mmol acetylbenzenesulfonamide deriva-

tives (i or ii) in 10 mL methanol. A few drops of glacial

140.20, 142.59 (C₃, C₆, C₇, C₁₃); 147.7 (C₁), 163.2

(C₁₂); MS (m/z) (%): 394.7 [M⁺²]; UV-Vis (DMSO,

λ

_max, nm): 305, 279; Anal. calc. for C₂₁H₁₉N₃O₃S: C

64.10; H 4.87; N 10.68; S 8.15%; found: C 63.42; H

4.72; N 10.77; S 8.23%.

N-Phenyl-4-[1-[2-(pyridine-4-carbonyl)hydraz-

inylidene]ethyl]benzenesulfonamide (Ib). Yield 46%;

white solid, mp 232–235°C; IR (ν, cm^–1): 3284 (N–

H); 3067 (aromatic C–H); 2870, 2815 (aliphatic C–

1

H); 1671 (C=O); 1598 (C=N); H NMR (400 MHz)

(DMSO-d₆/TMS) δ (ppm): 2.38 (s, 3H, H_B); 7.04–

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Vol. 46

No. 5

2020

DESIGN AND BIOEVALUATION

709

7.24 (m, 5H, H_F, H_G, H_H); 7.81–7.82 (m, 4H, H_D, (aromatic C–H); 2962, 2891 (aliphatic C–H); 1665

(C=O); 1600 (C=N); 1521 (NO₂asymmetric stretch-

ing band); 1341 (SO₂asymmetric stretching band);

1158 (SO₂symmetric stretching band); H NMR

H_I); 8.00 (d, 2H, J = 7.6 Hz, H_C), 8.78 (d, 2H, J = 7.6

Hz, H_J); 10.36 (s, 1H, H_E); 11.13 (s, 1H, H_A); ¹³C

NMR (100 MHz) (DMSO-d₆/TMS) δ (ppm): 15.17

(C₂); 120.75, 122.41, 124.72, 127.31, 127.69, 129.67,

150.59 (C₄, C₅, C₈, C₉, C₁₄, C₁₅); 133.58 (C₁₀); 137.99

(C₇); 140.49 (C₃); 141.41 (C₁₃); 142.31 (C₆); 154.94

(C₁); 163.28 (C₁₂); MS (m/z) (%): 395.1 [M⁺²]; UV-

Vis (DMSO, λ_max, nm): 305, 279; Anal. calc. for

C₂₀H₁₈N₄O₃S: C 60.90; H 4.60; N 14.20; S 8.13%;

found: C 60.30; H 4.46; N 14.37; S 8.27%.

4-(1-(2-(4-Fluorobenzoyl)hydrazono)ethyl)-N-

phenylbenzenesulfonamide (Ic). Yield 56%; cream

solid, mp 225–227°C; IR (ν, cm^–1): 3317 (N–H);

3073 (aromatic C–H); 2944, 2876, 2811 (aliphatic C–

H); 1666 (C=O); 1603 (C=N); ¹H NMR (400 MHz)

(DMSO-d₆/TMS) δ (ppm): 2.36 (s, 3H, H_B); 7.03 (t,

1H, J₁= 7.6 Hz, J₂= 7.2 Hz, H_H); 7.11 (d, 2H, J = 7.2 Hz,

H_F); 7.24 (t, 2H, J₁= 7.6 Hz, J₂= 7.2 Hz, H_G); 7.35 (t,

2H, J₁= 8.8 Hz, J₂= 8.8 Hz, H_J); 7.80 (d, 2H, J = 8.0 Hz,

H_C); 7.96 (m, 4H, H_D, H_I); 10.33 (s, 1H, H_E); 10.91 (s,

1

(400 MHz) (DMSO-d₆/TMS) δ (ppm): 2.39 (s, 3H,

H_B); 7.04 (t, 1H, J₁= 6.8 Hz, J₂= 6.8 Hz, H_H); 7.11 (d,

2H, J = 8.0 Hz, H_F); 7.24 (t, 2H, J₁= 7.6 Hz, J₂=

8.0 Hz, H_G); 7.82–8.13 (m, 6H, H_C, H_Dand H_I); 8.35

(d, 2H, J = 6.8 Hz, H_J); 10.34 (s, 1H, H_E); 11.19 (s,

1H, H_A); ¹³C NMR (100 MHz) (DMSO-d₆/TMS) δ

(ppm): 15.19 (C₂); 120.73, 123.90, 124.71, 127.31,

129.66, 130.04, 130.98 (C₄, C₅, C₈, C₉, C₁₄, C₁₅); 135.11,

137.97, 140.08, 140.44, 142.32 (C₃, C₆, C₇, C₁₀, C₁₃);

151.38 (C₁₆); 154.83 (C₁); 163.23 (C₁₂); MS (m/z) (%):

436.6 [M^–1]; UV-Vis (DMSO, λ_max, nm): 300; Anal.

calc. for C₂₁H₁₈N₄O₅S: C, 57.53; H, 4.14; N, 12.78; S,

7.31%; found: C 56.99; H, 4.01; N, 12.79; S, 7.42%.

N-(4-(2-(1-(4-(N-Phenylsulfamoyl)phenyl)-ethyliden)-

hydrazinocarbonyl)phenyl)benzamide (If). Yield 77%;

white solid, mp 259–261°C; IR (ν, cm^–1): 3345,

3280 (N–H); 3029 (aromatic C–H); 2918, 2846 (ali-

1H, H_A); ¹³C NMR (100 MHz) (DMSO-d₆/TMS) δ phatic C–H); 1654 (C=O); 1591 (C=N); 1339

(SO₂asymmetric stretching band); 1161 (SO₂sym-

(ppm): 14.78 (C₂); 115.67, 120.71, 124.73, 127.40,

129.67, 131.29 (C₄, C₅, C₈, C₉, C₁₄, C₁₅); 130.75, metric stretching band); ¹H NMR (400 MHz)

(DMSO-d₆/TMS) δ (ppm): 2.38 (s, 3H, H_B); 7.04 (t,

1H, J₁= 7.2 Hz, J₂= 7.6 Hz, H_H); 7.11 (d, 2H, J =

8.4 Hz, H_F); 7.24 (t, 2H, J₁= 8.4 Hz, J₂= 7.2 Hz, H_G);

7.56 (t, 2H, J₁= 6.8 Hz, J₂= 7.6 Hz, H_M); 7.63 (t, 1H,

J₁= 7.6, J₂= 7.2 Hz, H_N); 7.80 (d, 2H, H_C); 7.93–8.00

(m, 8H, H_D, H_I, H_Jand H_L); 10.33 (s, 1H, H_E); 10.51

135.82, 137.97, 140.21, 142.53 (C₃, C₆, C₇, C₁₀, C₁₃);

153.53 (C₁); 164.27 (C16), 166.35 (C₁₂); MS (m/z)

(%): 411.9 [M⁺¹]; UV-Vis (DMSO, λ_max, nm): 305,

282; Anal. calc. for C₂₁H₁₈FN₃O₃S: C 61.30; H 4.41; N

10.21; S 7.79%; found: C 60.25; H 4.25; N 10.12; S

7.65%.

(s, 1H, H_K); 10.80 (s, 1H, H_A); ¹³C NMR (100 MHz)

(DMSO-d₆/TMS) δ (ppm): 14.73 (C₂); 119.83,

120.72, 121.35, 124.70, 127.29, 127.45, 128.06, 128.78,

129.66 (C₄, C₅, C₁₉, C₈, C₉, C₁₄, C₂₁, C₂₀, C₁₅); 132.31,

134.56, 135.11, 136.60, 138.03, 140.14, 140.71 (C₃, C₆,

C₇, C₁₀, C₁₃, C₁₆, C₁₈); 142.67 (C₁); 164.22 (C₁₂);

4-(1-(2-(4-Chlorobenzoyl)hydrazono)ethyl)-N-

phenylbenzenslfonamide (Id). Yield 47%; white solid,

mp 210–213°C; IR (ν, cm^–1): 3313, 3156 (N–H);

3078, 3029 (aromatic C–H); 2944, 2968, 2898 (ali-

phatic C–H); 1637 (C=O); 1598 (C=N); 1347 (SO₂

asymmetric stretching band); 1156 (SO₂symmetric

165.84 (C₁₇); MS (m/z) (%): 510.7 [M^–2]; UV-Vis

(DMSO, λ_max, nm): 315, 278; Anal. calc. for

C₂₈H₂₄N₄O₄S: C, 65.61; H, 4.72; N, 10.93; S, 6.26%;

found: C, 64.76; H, 4.59; N, 11.04; S, 6.10%.

1

stretching band); H NMR (400 MHz) (DMSO-

d₆/TMS) δ (ppm): 2.36 (s, 3H, H_B); 7.03 (t, 1H, J₁=

7.2 Hz, J₂= 7.2 Hz, H_H); 7.11 (d, 2H, J = 8.0 Hz, H_F);

7.24 (t, 2H, J₁= 7.6 Hz, J₂= 8.0 Hz, H_G); 7.59 (d, 2H,

J = 8.0 Hz, H_J); 7.80 (d, 2H, J = 7.6 Hz, H_C); 7.92–

7.98 (m, 4H, H_Dand H_I); 10.34 (s, 1H, H_E); 10.96 (s,

1H, H_A); ¹³C NMR (100 MHz) (DMSO-d₆/TMS) δ

(ppm): 14.97 (C₂); 120.71, 124.69, 127.40, 128.00,

4-(1-(2-(2-Hydroxy-2,2-diphenylacetyl)hydrazono)-

ethyl)-N-phenylbenzensulfon-amide (Ig). Yield 85%;

orange solid, mp 228–231°C; IR (ν, cm^–1): 3268

(N‒H); 3082, 3020 (aromatic C-H); 2972 (aliphatic

129.66, 133.10 (C₄, C₅, C₈, C₉, C₁₄, C₁₅); 130.55, C–H); 1650 (C=O); 1600 (C=N); 1342 (SO₂asym-

136.95, 138.01, 139.04, 140.36, 142.47 (C₃, C₆, C₇, C₁₀, metric stretching band); 1166 (SO₂symmetric stretch-

ing band); ¹H NMR (400 MHz) (DMSO-d₆/TMS) δ

C₁₃, C₁₆); 149.63 (C₁); 162.27 (C₁₂); MS (m/z) (%):

429 [M⁺²]; UV-Vis (DMSO, λ_max, nm): 305, 274; (ppm): 2.38 (s, 3H, H_B); 7.04 (t, 1H, J₁= 7.6 Hz, J₂=

Anal. calc. for C₂₁H₁₈ClN₃O₃S: C, 58.94; H, 4.24; N, 7.6 Hz, H_H); 7.09 (d, 2H, J = 8.0 Hz, H_F); 7.23 (t, 2H,

9.82; S, 7.49%; found: C, 58.24; H, 4.11; N, 9.88; S, J₁= 7.2 Hz, J₂= 7.2 Hz, H_G); 7.29–7.38 (m, 10H, H_L,

7.22%.

H_L', H_K, H_K', H_Jand H_J'); 7.80 (d, 2H, J = 8.0 Hz,

H_C); 7.94 (d, 2H, J = 8.0 Hz, H_D); 10.32 (s, 1H, H_E);

10.49 (s, 1H, H_A); ¹³C NMR (100 MHz) (DMSO-

d₆/TMS) δ (ppm): 13.83 (C₂); 81.16 (C₁₃); 120.83,

4-(1-(2-(4-Nitrobenzoyl)hydrazono)ethyl)-N-phen-

ylbenzensulfonamide (Ie). Yield 70%; yellow solid,

mp 239–241°C; IR (ν, cm^–1): 3311 (N–H); 3083

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BOZKURT et al.

124.75, 127.30, 127.53, 127.85, 127.99, 128.23, 129,64 (ppm): 2.36 (s, 3H, H_B); 7.22 (d, 2H, J = 8.4 Hz, H_F);

(C₄, C₅, C₈, C₉, C₁₅, C₁₆, C₁₇); 135.83, 137.97, 140.32,

142.40, 143.87 (C₃, C₆, C₇, C₁₀, C₁₄); 152.85 (C₁);

7.34 (t, 2H, J₁= 8.8 Hz, J₂= 8.8 Hz, H_J); 7.82 (d, 2H,

J = 8.4 Hz, H_G); 7.87 (d, 2H, J = 8.4 Hz, H_C); 7.94–

169.36 (C₁₂); MS (m/z) (%): 500.6 [M⁺¹]; UV-Vis 7.96 (m, 4H, H_Dand H_I); 10.84 (s, 2H, H_Aand H_E);

12.73 (s, 1H, H_H); ¹³C NMR (100 MHz) (DMSO-

d₆/TMS) δ (ppm): 14.78 (C₂); 115.58, 118.75, 118.88,

126.23, 127.33, 127.65, 129.64, 131.24 (C₄, C₅, C₈, C₉,

C₁₀, C₁₄, C₁₅); 130.90, 139.91, 142.39, 142.86 (C₃, C₆,

C₇, C₁₃); 145.52 (C₁); 164.17 (C₁₆); 166.50 (C₁₂); 167.18

(C₁₁); MS (m/z) (%): 457.1 [M⁺²]; UV-Vis (DMSO,

(DMSO, λ_max, nm): 295; Anal. calc. for C₂₈H₂₅N₃O₄S:

C, 67.32; H, 5.04; N, 8.41; S, 6.42%; found: C, 66.36;

H, 5.00; N, 8.48; S, 6.12%.

4-(4-(1-(2-Benzoylhydrazono)ethyl)phenylsulfon-

amido)benzoic acid (IIa). Yield 48%; white solid, mp

244–246°C; IR (ν, cm^–1): 3327 (N–H); 3042 (aro-

matic C–H); 2931, 2864 (aliphatic C–H); 1688, 1652

(C=O); 1606 (C=N); 1335 (SO₂asymmetric stretch-

λ

_max, nm): 305, 279; Anal. calc. for C₂₂H₁₈FN₃O₅S: C,

58.02; H, 3.98; N, 9.23; S, 7.04%; found: C, 57.81; H,

3.91; N, 8.51; S, 6.92%.

1

ing band); 1158 (SO₂symmetric stretching band); H

NMR (400 MHz) (DMSO-d₆/TMS) δ (ppm): 2.36 (s,

3H, H_B); 7.21 (d, 2H, J = 8.4 Hz, H_F); 7.52 (t, 2H,

J₁= 7.2 Hz, J₂= 8.0 Hz, H_J); 7.59 (t, 1H, J₁= 7.6 Hz,

J₂= 7.6 Hz, H_K); 7.81 (d, 2H, J = 8.4 Hz, H_G); 7.88–

8.11 (m, 6H, H_C, H_Dand H_I); 10.90 (s, 2H, H_Aand

H_E); 12.77 (s, 1H, H_H); ¹³C NMR (100 MHz)

(DMSO-d₆/TMS) δ (ppm): 14.75 (C₂); 118.76, 127.31,

127.64, 128.71, 129.6, 131.23, 132.05 (C₄, C₅, C₈, C₉,

C₁₄, C₁₅, C₁₆); 126.23, 134.40, 139.90, 142.31, 142.91

(C₃, C₆, C₇, C₁₀, C₁₃); 146.78 (C₁); 1623.44 (C₁₂);

167.18 (C₁₁); MS (m/z) (%): 438.0 [M⁺¹]; UV-Vis

(DMSO, λ_max, nm): 305, 279; Anal. calc. for

C₂₂H₁₉N₃O₅S: C, 60.40; H, 4.38; N, 9.61; S, 7.33%;

found: C, 60.15; H, 4.37; N, 9.18; S, 7.39%.

4-(4-(1-(2-(4-Chlorobenzoyl)hydrazono)ethyl)phe-

nylsulfonamido)benzoic acid (IId). Yield 45%; white

solid, mp 276–278°C; IR (ν, cm^–1): 3260 (N–H);

3080 (aromatic C–H); 2953, 2829 (aliphatic C–H);

1674, 1663 (C=O); 1607 (C=N); 1336 (SO₂asymmet-

ric stretching band); 1160 (SO₂symmetric stretching

1

band); H NMR (400 MHz) (DMSO-d₆/TMS) δ

(ppm): 2.36 (s, 3H, H_B); 7.22 (d, 2H, J = 8.4 Hz, H_F);

7.59 (d, 2H, J = 8.4 Hz, H_J); 7.81 (d, 2H, J = 8.8 Hz,

H_G); 7.88–8.09 (m, 6H, H_C, H_Dand H_I); 10.92 (s,

2H, H_Aand H_E); 12.78 (s, 1H, H_H); ¹³C NMR

(100 MHz) (DMSO-d₆/TMS) δ (ppm): 15.47 (C₂);

119.31, 126.77, 127.90, 128.23, 129.35, 131.07 (C₄, C₅,

C₈, C₉, C₁₀, C₁₄, C₁₅); 131.79, 140.60, 142.81, 143.34

(C₃, C₆, C₇, C₁₃); 146.09 (C₁); 167.74 (C₁₁); MS (m/z)

4-(4-(1-(2-Isonicotinoylhydrazono)ethyl)phenylsul-

fonamido)benzoic acid (IIb). Yield 41%; white solid,

mp 288–290°C; IR (ν, cm^–1): 3364 (N–H); 3075

(aromatic C–H); 2966 (aliphatic C–H); 1687, 1656

(C=O); 1606 (C=N); 1338 (SO₂asymmetric stretch-

(%): 473.0 [M⁺¹]; UV-Vis (DMSO, λ_max, nm): 305,

284; Anal. calc. for C₂₂H₁₈ClN₃O₅S: C, 55.99; H,

3.84; N, 8.90; S, 6.79%; found: C, 55.43; H, 3.71; N,

8.87; S, 6.87%.

1

ing band); 1161 (SO₂symmetric stretching band); H

4-(4-(1-(2-(4-Nitrobenzoyl)hydrazono)ethyl)phe-

nylsulfonamido)benzoic acid (IIe). Yield 49%; yellow

solid, mp 281–283°C; IR (ν, cm^–1): 3325 (N–H);

3108, 3047 (aromatic C–H); 2935, 2869 (aliphatic C–

H); 1682, 1665 (C=O); 1603 (C=N); 1336 (SO₂asym-

metric stretching band); 1157 (SO₂symmetric stretch-

NMR (400 MHz) (DMSO-d₆/TMS) δ (ppm): 2.38 (s,

3H, H_B); 7.22 (d, 2H, J = 7.6 Hz, H_F); 7.81–7.83 (m,

4H, H_Gand H_C); 7.89 (d, 2H, J = 8.0 Hz, H_D); 8.03

(d, 2H, J = 8.0 Hz, H_I); 8.78 (d, 2H, J = 8.0 Hz, H_J);

10.90 (s, 1H, H_E); 11.14 (s, 1H, H_A); 12.79 (s, 1H,

H_H); ¹³C NMR (100 MHz) (DMSO-d₆/TMS) δ

(ppm): 15.11 (C₂); 118.79, 122.43, 123.39, 126.24,

127.35, 127.87, 131.25, (C₄, C₅, C₈, C₉, C₁₀, C₁₄);

140.20, 141.42, 142.62, 142.94 (C₃, C₆, C₇, C₁₃); 147.68

(C₁); 150.57 (C₁₅); 163.37 (C₁₂); 167.20 (C₁₁); MS

ing band); ¹H NMR (400 MHz) (DMSO-d₆/TMS) δ

(ppm): 2.38 (s, 3H, H_B); 7.22 (d, 2H, J = 7.6 Hz, H_F);

7.81 (d, 2H, J = 7.6 Hz, H_G); 7.89–8.13 (m, 6H, H_C,

H_Dand H_I); 8.35 (d, 2H, J = 8.4 Hz, H_J); 10.87 (s, 1H,

H_E); 11.19 (s, 1H, H_A); ¹³C NMR (100 MHz)

(DMSO-d₆/TMS) δ (ppm): 15.15 (C₂); 118.78,

123.89, 126.23, 127.35, 127.53, 127.82, 129.63, 130.05,

131.23 (C₄, C₅, C₈, C₉, C₁₀, C₁₄, C₁₅); 140.20, 142.29,

142.62 (C₃, C₆, C₇); 149.66 (C₁₆); 154.66 (C₁); 163.26

(m/z) (%): 439.0 [M⁺¹]; UV-Vis (DMSO, λ_max, nm):

305, 279; Anal. calc. for C₂₁H₁₈N₄O₅S: C, 57.53; H,

4.14; N, 12.78; S, 7.31%; found: C, 56.85; H, 3.94; N,

12.71; S, 7.25%.

(C₁₂); 167.17 (C₁₁); MS (m/z) (%): 480.6 [M^–1]; UV-

Vis (DMSO, λ_max, nm): 354, 319, 285; Anal. calc. for

C₂₂H₁₈N₄O₇S: C, 54.77; H, 3.76; N, 11.61; S, 6.65%;

found: C, 54.12; H, 3.81; N, 11.27; S, 6.55%.

4-(4-(1-(2-(4-Fluorobenzoyl)hydrazono)ethyl)phe-

nylsulfonamido)benzoic acid (IIc). Yield 69%; white

solid, mp 239–241°C; IR (ν, cm^–1): 3264 (N–H);

3073 (aromatic C–H); 2824 (aliphatic C–H); 1675,

1657 (C=O); 1604 (C=N); 1336 (SO₂asymmetric

stretching band); 1160 (SO₂symmetric stretching

band); 1H NMR (400 MHz) (DMSO-d₆/TMS) δ

4-(4-(1-(2-(4-Benzamidobenzoyl)hydrazono)-

ethyl)phenylsulfonamido)benzoic acid (IIf). Yield 78%;

white solid, mp 291–293°C; IR (ν, cm^–1): 3354,

RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY

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DESIGN AND BIOEVALUATION

711

516.6 [M⁺¹]; UV-Vis (DMSO, λ_max, nm): 305, 279;

Anal. calc. for C₂₂H₁₈BrN₃O₅S: C, 51.17; H, 3.51; N,

8.14; S, 6.21%; found: C, 50.63; H, 3.39; N, 8.20; S,

3308 (N–H); 3029 (aromatic C–H); 2918 (aliphatic

C–H); 1680, 1656 (C=O); 1607 (C=N); 1347 (SO₂

asymmetric stretching band); 1163 (SO₂symmetric

1

stretching band); H NMR (400 MHz) (DMSO- 6.12%.

d₆/TMS) δ (ppm): 2.38 (s, 3H, H_B); 7.22 (d, 2H, J =

8.8 Hz, H_F); 7.56 (t, 2H, J₁= 7.6 Hz, J₂= 7.2 Hz, H_M);

7.63 (t, 1H, J₁= 7.2 Hz, J₂= 7.2 Hz, H_N); 7.82 (d, 2H,

Biological Activity

Determination of antioxidant activity. The antioxi-

dant activity was measured using four complementary

assays. The β-carotene-linoleic acid assay differs from

the others in that the antioxidant gives to media the

hydrogen radical. In this assay, the antioxidant com-

pound also scavenges the singlet oxygen and also

transfers electrons to stop the radicalic degradation.

Therefore, β-carotene-linoleic acid assay, lipid perox-

J = 8.4 Hz, H_J); 7.88 (d, 2H, J = 8.0 Hz, H_G); 7.93–

8.00 (m, 8H, H_C, H_D, H_Iand H_L); 10.52 (s, 1H, H_E);

10.81 (s, 1H, H_A); ¹³C NMR (100 MHz) (DMSO-

d₆/TMS) δ (ppm): 14.73 (C₂); 118.74, 119.82, 120.72,

126.21, 127.33, 127.61, 128.24, 128.92, 131.25 (C₄, C₅,

C₈, C₉, C₁₀, C₁₄, C₁₅, C₁₉, C₂₀); 132.31, 133.14, 135.10,

135.17, 139.95, 142.32, 142.97 (C₃, C₆, C₇, C₁₃, C₁₆,

C₁₈, C₂₁); 145.99 (C₁); 164.33 (C₁₇); 166.34 (C₁₂); idation inhibitory activity, is called total antioxidant

167.19 (C₁₁); MS (m/z) (%): 556.8 [M⁺¹]; UV-Vis

(DMSO, λ_max, nm): 315, 279; Anal. calc. for

C₂₉H₂₄N₄O₆S: C, 62.58; H, 4.35; N, 10.07; S, 5.76%;

found: C, 61.75; H, 4.27; N, 10.16; S, 5.88%.

activity. In the DPPH, ABTS, and CUPRAC assays,

however, the antioxidant can transfer only electrons to

neutralize the radical.

The lipid peroxidation inhibitory activity of the

compounds was evaluated using the β-carotene-lin-

oleic acid assay [56]. For this test, 25 L of linoleic acid,

and 200 mg of Tween 40 emulsifier were added to 1 mL

of chloroform containing 0.5 mg β-carotene. The

chloroform solvent was evaporated under vacuum,

and 100 mL of distilled water saturated with oxygen

was added by vigorous shaking. One hundred and sixty

microliters of this mixture were delivered into each

well containing 40 μL of different concentrations of

the compounds dissolved in DMSO. The zero-time

absorbance was measured at 470 nm after the said

emulsion was added to each well in a microplate

reader. The emulsion system was kept at 50°C in an

oven. The absorbance was read until the color disap-

peared in control wells by controlling in every 30 min-

utes. A blank, devoid of β-carotene, was prepared for

background subtraction. BHT and α-tocopherol were

used as positive standards to compare the activity.

4-(4-(1-(2-(2-Hydroxy-2,2-diphenylacetyl)hydra-

zono)ethyl)phenylsulfonamido)benzoic acid (IIg). Yield

78%; orange solid, mp 111–113°C; IR (ν, cm^–1):

3345 (N–H); 3057 (aromatic C–H); 2952 (aliphatic

C–H); 1682, 1606 (C=O); 1606 (C=N); 1335 (SO₂

asymmetric stretching band); 1156 (SO₂symmetric

1

stretching band); H NMR (400 MHz) (DMSO-

d₆/TMS) δ (ppm): 2.38 (s, 3H, H_B); 7.19–7.24 (m,

3H, H_Fand H_I); 7.29–7.44 (m, 10H, H_L, H_L', H_K, H_K',

H_Jand H_J'); 7.80 (d, 2H, J = 8.4 Hz, H_G); 7.86 (d, 2H,

J = 8.4 Hz, H_C); 7.97 (d, 2H, J = 8.4 Hz, H_D); 10.49

(s, 1H, H_E); 10.86 (s, 1H, H_A); ¹³C NMR (100 MHz)

(DMSO-d₆/TMS) δ (ppm): 13.80 (C₂); 118.84,

126.27, 127.33, 127.71, 127.84, 127.99, 128.23, 131.22

(C₄, C₅, C₈, C₉, C₁₀, C₁₅, C₁₆, C₁₇); 140.10, 142.25,

142.49, 143.86 (C₃, C₆, C₇, C₁₃); 152.72 (C₁); 167.17

(C₁₂); 169.37 (C₁₁); MS (m/z) (%): 541.8 [M^–2]; UV-

Vis (DMSO, λ_max, nm): 295, 278; Anal. calc. for

C₂₉H₂₅N₃O₅S: C, 64.08; H, 4.64; N, 7.73; S, 5.90%;

found: C, 61.46; H, 4.59; N, 7.58; S, 5.81%.

The bleaching rate (R) of β-carotene was calcu-

lated according to the following equation:

Bleaching rate R : ln a b t ,

( )

(

)

where, ln = natural log, a = absorbance at time zero,

b = absorbance at time t (120 min). The antioxidant

activity (AA) was calculated in terms of percent inhibi-

tion relative to the control, using the following equa-

tion:

4-(4-(1-(2-(4-Bromobenzoyl)hydrazono)ethyl)phe-

nylsulfonamido)benzoic acid (IIh). Yield 70%; white

solid, mp 287–289°C; IR (ν, cm^–1): 3262 (N–H);

3073 (aromatic C–H); 2951, 2829 (aliphatic C–H);

1674, 1662 (C=O); 1607 (C=N); 1336 (SO₂asymmet-

ric stretching band); 1160 (SO₂symmetric stretching

Antioxidant activity AA :

(

)

1

band); H NMR (400 MHz) (DMSO-d₆/TMS) δ

A

− A_compoundA_control× 100.

(

[

)

]

control

(ppm): 2.36 (s, 3H, H_B); 7.22 (d, 2H, J = 7.6 Hz, H_F);

7.73 (d, 2H, J = 6.8 Hz, H_J); 7.81–8.01 (m, 8H, H_C,

H_D, H_Iand H_G); 10.92 (s, 2H, H_Aand H_E); 12.77 (s,

1H, H_H); ¹³C NMR (100 MHz) (DMSO-d₆/TMS) δ

(ppm): 14.90 (C₂); 118.77, 126.25, 126.54, 127.34,

127.66, 130.68, 131.24 (C4, C₁₆, C₅, C₈, C₉, C₁₀, C₁₄,

C₁₅); 131.7, 139.99, 142.29, 142.80 (C₃, C₆, C₇, C₁₃);

148.02 (C₁); 164.01 (C₁₂); 167.18 (C₁₁); MS (m/z) (%):

Then results were given as IC₅₀μg/mL corresponding

the concentration which protects 50% of β-carotene

amount [39–42, 57].

The ABTS cation radical scavenging activity was

determined spectrophotometrically [46] with slight

modifications [39–42, 57]. The ABTS^•+was obtained

by the reaction of 7 mM ABTS dissolved in H₂O with

2.45 mM potassium persulfate. The mixture was

RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 46 No. 5 2020

712

BOZKURT et al.

stored in the dark at room temperature for 12 h. The prine, and NH₄Ac buffer (1 M, pH 7.0) solutions were

radical cation was stable in this form for more than

2 days if stored in the dark at room temperature. To

test the activity of the compounds, the prepared radi-

cal solution was diluted to get an absorbance of

0.700 0.025 at 734 nm with ethanol for one cm cell

length. Then, 160μL of the radical solution was added

to 40 μL of compound solution dissolved in DMSO at

different concentrations (5–50 μg/mL). After 10 min,

the percentage inhibition at 734 nm was calculated for

each concentration relative to a blank absorbance

(methanol). Lower absorbance of the reaction mixture

indicated higher free radical-scavenging activity. A

blank, devoid of ABTS solution was prepared for back-

ground subtraction. BHT and α-tocopherol were used

as positive standards to compare the activity.

added to 40 μL ml of compound solutions dissolved in

DMSO at different concentrations. The 96 well plates

were kept at room temperature for one hour. Then the

absorbance at 450 nm was recorded against a blank.

BHT and α-tocopherol were used as positive stan-

dards to compare the activity.

Then results of CUPRAC assay were given as

A

_0.50μg/mL corresponding to the concentration of

0.500 absorbances at graph drawn absorbance versus

concentration.

Determination of anticholinesterase activity. The

Ellman method was used to measure acetylcholines-

terase (AChE) and butyrylcholinesterase (BChE)

inhibitory activity [57, 58]. The commercial AChE

from electric eel and BChE from horse serum were

employed. As substrates of the enzymes, acetylthio-

choline iodide and butyrylthiocholine chloride were

utilized. 5,5′-dithio-bis(2-nitrobenzoic)acid (DTNB)

was made use of for measurement of activity as a col-

oring reagent. To dissolve the compounds, ethanol

solvent was used. To test the activity, 10 μL of sample

solution dissolved in ethanol at different concentra-

tions and 20 μL AChE (5.32 × 10^–3U) or BChE

(6.85 × 10^–3U) enzyme dissolved in buffer were added

to 150 μL of 100 mM sodium phosphate buffer

(pH 8.0). Then incubated for 15 min at 25°C. After

incubation, 10 μL of 0.5 mM DTNB were added, and

the reaction was started by addition of 10 μL of acet-

ylthiocholine iodide (0.71 mM) or butyryl-thiocho-

line chloride (0.2 mM). The measurement was moni-

tored spectrophotometrically by the formation of yel-

low 5-thio-2-nitrobenzoate anion, as the result of the

reaction of DTNB with thiocholine at 412 nm wave-

length using a 96-well microplate reader (SpectraMax

PC340, Molecular Devices, USA). Percentage of

inhibition of AChE or BChE was determined by com-

parison of reaction rates of samples relative to blank

sample (ethanol in phosphate buffer, pH 8) using the

formula (E – S)/E × 100, where E is the activity of

enzyme without test compound, and S is the activity of

the enzyme with a test compound. Galantamine was

used as a reference compound [58].

The ability to scavenge the ABTS cation radical was

calculated by using the following equation:

ABTS cation radical scavenging activity AA :

(

)

A

− A_compoundA_control× 100.

(

[

)

]

control

Then results ABTS assay was given as IC₅₀μg/mL cor-

responding to the concentration, which scavenges

50% of ABTS cation radical.

DPPH free radical-scavenging activity of the

extracts of compounds was determined using the

DPPH radical [39, 44]. DPPH absorbs at 517 nm in its

radical form. However, if reduced by an antioxidant

transfer electron, its absorption at 517 nm decreases.

To test the compounds in this assay, 0.1 mM DPPH

solution was prepared in ethanol. 160 μL of this solu-

tion was added to 40 μL of compound solutions dis-

solved in DMSO at different concentrations. The 96

well plates were kept in the dark place. Thirty minutes

later, the absorbance was measured at 517 nm. Lower

absorbance of the reaction mixture indicated higher

free radical-scavenging activity. A blank, devoid of

DPPH solution was prepared for background subtrac-

tion. BHT and α-tocopherol were used as positive

standards to compare the activity.

The ability to scavenge the DPPH radical was cal-

culated by using the following equation:

DPPH free radical scavenging activity AA :

(

)

A

− A_compoundA_control× 100.

(

[

)

]

control

Then results of DPPH assay were given as IC₅₀μg/mL

corresponding to the concentration, which scavenges

50% of DPPH free radical.

COMPLIANCE WITH ETHICAL STANDARDS

The cupric reducing antioxidant capacity of the

compounds was determined to see the reduction

potential of the compounds. This method is based on

the measurement of absorbance at 450 nm by the for-

mation of a stable complex between neocuproine and

copper (I), which is formed by the reduction of copper

(II) in the presence of antioxidant [39, 48]. To test the

cupric reducing antioxidant capacity of the com-

pounds, 40 μL each of 10 mM Cu (II), 7.5 mM neocu-

This article does not contain any studies involving

human participants performed by any of the authors and

does not contain any studies involving animals performed

by any of the authors.

Conflict of Interests

The authors declare that they have no conflicts of interests.

RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY

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DESIGN AND BIOEVALUATION

713

SUPPLEMENTARY MATERIALS

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Article Doi

Design and Bioevaluation of Novel Hydrazide-Hydrazones Derived from 4-Acetyl-N-Substituted Benzenesulfonamide

DOI: 10.1134/S1068162020050052

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