Novel azole-functionalited flouroquinolone hybrids: Design, conventional and microwave irradiated synthesis, evaluation as antibacterial and antioxidant agents

46

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Letters in Drug Design & Discovery, 2018, 15, 46-64

RESEARCH ARTICLE

ISSN: 1570-1808

eISSN: 1875-628X

Novel Azole-Functionalited Flouroquinolone Hybrids: Design, Conven-

tional and Microwave Irradiated Synthesis, Evaluation as Antibacterial

and Antioxidant Agents

Impact

Factor:

1.17

BENTHAM

S

CIENCE

Meltem Mentese^a, Neslihan Demirbas^a,*, Arif Mermer^a, Serpil Demirci^b, Ahmet Demirbas^aand

Faik Ahmet Ayaz^c

b

^aDepartment of Chemistry, Karadeniz Technical University, 61080 Trabzon, Turkey; Department of Medical Services

c

and Techniques, Giresun University, Vocational High School of Health Service, 28100 Giresun Turkey; Department of

Biology, Karadeniz Technical University, 61080, Trabzon, Turkey

Abstract: Background: The synthesis of new hybrid molecules consisting of several heterocyclic

pharmacophores namely fluoroquinolone, 1,2,4-triazole, 1,3,4-oxadiazole and piperazine was car-

ried out by conventional and successfully optimized microwave mediated techniques.

A R T I C L E H I S T O R Yꢀ

Methods: The structures of new compounds were confirmed using spectroscopic techniques. These

compounds were screened for their antibacterial activity against E. coli, P. aeruginosa, Y. pseudo-

tuberculosis, S. aureus, E. faecalis, B. cereus and M. smegmatis.

Received: February 07, 2017

Revised: June 08, 2017

Accepted: August 08, 2017

DOI:

Results and Conclusion: Fourteen of these hybrids exhibited excellent antibacterial activities on

10.2174/1570180814666170823163540

the test microorganisms when compared with ampicillin with the mic values varying between 0.03-

0.25 μg/mL.

Keywords: Fluoroquinolone, 1,2,4-triazole, 1,3,4-oxadiazole, piperazine, antibacterial activity, antioxidant activity,

microwave.

1. INTRODUCTION

reasons of this undesirable situation are the increasing ex-

penses of antibacterial resistant drugs, strict legal require-

ments and high prices of antibiotics. In order to overcome

this situation, the collaboration of all sectors including regu-

lations, society and researchers is necessary [6]. In order to

overcome the drug resistance, the mostly implemented ap-

proach aiming the development of new antibacterial agents is

to improve the pharmacodynamics of the existing drugs by

changing their structural units or producing new derivatives.

This approach has been accepted as an attractive strategy by

scientific communities since this method does not require the

discovery of new antibacterial scaffolds or validation of

novel biological targets, which has proven to be an ex-

tremely difficult and time consuming task [7].

The increasing community- and hospital- acquired infec-

tious diseases caused by resistant bacteria to most classes of

antibacterial drugs resulted in a pressing and urgent need for

designing of new antibiotic candidates. The declaration of

The European Centre for Disease Prevention and Control

(ECDC) reporting “Every year, the infections caused by re-

sistant bacteria gives rise to 25,000 deaths with a cost of over

1.5 billion Eur because of healthcare spending and labor

losses in the Europa” reveals that this is a public health prob-

lem with also socio-economic loses [1-5]. Mortality in these

patients infected by resistant bacteria was reported as two

times higher than the patients infected by nonresistant bacte-

ria [2]. It is clear that pharmaceutical industry today is not

able to meet the urgent need for discovery of new and effec-

tive antibiotics, despite much efforts aiming to deal with

resistance problem by development of new class of antibac-

terial agents with different mode of action. Some of the main

More recently, the concept of hybrid molecules, which

contain two or more pharmacophore groups binding together

covalently in one molecular framework, has been introduced

in the medicinal chemistry field. These compounds that are

obtained by molecular hybridization of several pharma-

cophore groups, act by inhibiting two or more conventional

targets simultaneously, and this multiple target strategy has

resulted in the development of a number of bioactive hybrid

molecules [8].

*Address correspondence to this author at the Karadeniz Technical Univer-

sity, Department of Chemistry, 61080 Trabzon, Turkey;

E-mail: neslihan@ktu.edu.tr

1875-628X/18 $58.00+.00

Novel Azole-Functionalited Flouroquinolone Hybrids

Letters in Drug Design & Discovery, 2018, Vol. 15, No. 1 47

DNA gyrase and topoisomerase IV are known as essen-

tial and immanent enzymes responsible for bacterial cell

growth and division [9]. Fluoroquinolones, proceeding as

DNA gyrase and bacterial topoisomerase IV inhibitors,

which can inhibit DNA synthesis by forming complexes with

DNA gyrase or topoisomerase II enzyme, were discovered as

broad-spectrum antibiotics in 1980s. Since their introduction

to clinical use, they were extensively applied for the treat-

ment of infectious diseases. But unfortunately, the wide use

of fluoroquinolones in clinical settings resulted in the emer-

gence of resistant bacterial strains. The resistance problem

along with the decline of the antibiotic discovery and devel-

opment studies made mandatory the design of new antibiot-

ics [8, 10, 11].

antioxidant capacity and antibacterial activity are currently

continuing in our laboratory [31, 32].

In this context, we reported here the conventional and

microwave irradiated green synthesis, antimicrobial and an-

tioxidant activity screening studies of novel fluoroquinolone-

azole hybrids by the molecular hybridization strategy. The

rational design of the targeted compounds was depicted in

Fig. (1).

2. EXPERIMENTEL

2.1. General

All the chemicals were purchased from Fluka Chemie

AG Buchs (Switzerland) and used without further purifica-

tion. Microwave-assisted syntheses were carried out using

monomode CEM-Discover microwave apparatus. Reactions

were monitored by thin-layer chromatography (TLC) on

silica gel 60 F254 aluminium sheets. Melting points of the

synthesized compounds were determined in open capillaries

on a Büchi B-540 melting point apparatus and are uncor-

rected. The mobile phase was ethyl acetate:diethyl ether

(1:1), and detection was made using UV light. FT-IR spectra

were recorded using a Perkin Elmer 1600 series FTIR spec-

Several successful syntheses of ﬂuoroquinolone hybrids

including arylfuran [8], benzofuroxan [12], piperazine [13,

14], thiadiazole [15], triazole [16] or quinolone [17] unit

have been reported, most of which were obtained by substi-

tution on piperazine ring at C-7 position of the basic struc-

ture of quinolones.

Since some preferable properties including flexibility,

convergence and economic nature, multicomponent reactions

have received considerable attention in organic, combinato-

rial and medicinal chemistry leading to the formation of sev-

eral compounds possessing elaborate biological activities

[18-20]. Moreover, the growing emphasis of “green chemis-

try techniques” in new drug discovery protocols has in-

creased the popularity of the scope of microwave assisted

organic synthesis due to some superior properties such as

mild reaction conditions, shortened reaction times, increased

reaction yields, relatively less decomposition, less formation

of by-products etc [21-23]. Thus, the development of new

strategies including a combination of multicomponent reac-

tions and microwave irradiation techniques without any

harmful organic solvent and catalyst has become one of the

most important strategies of synthetic organic chemistry.

1

trometer. H NMR and ¹³C NMR spectra were registered in

DMSO-d₆on a BRUKER AVENE II 400 MHz NMR Spec-

trometer (400.13 MHz for ¹H and 100.62 MHz for ¹³C). The

chemical shifts are given in ppm relative to Me₄Si as an in-

ternal reference, J values are given in Hz. The elemental

analysis was performed on a Costech Elemental Combustion

System CHNS-O elemental analyzer. All the compounds

gave C, H and N analysis within 0.4% of the theoretical

values. The Mass spectra were obtained on a Quattro LC-MS

(70 eV) Instrument.

2.1.1. Ethyl 2-[4-(4-nitrophenyl)piperazin-1-yl]acetate (2)

Method 1

Discovery of new agents with antioxidant properties has

become another extraordinary active area of preventive me-

dicinal chemistry [24-26] and some fluoroquinolones and

related compounds were reported as antioxidant capacity in

addition to antimicrobial activity [27-30]. Moreover, synthe-

sizing some fluoroquinolone hybrid compounds with their

Ethyl bromoacetate (10 mmol) was added to the solution

of 1-(4-nitrophenyl) piperazine (10 mmol) in tetrahydrofuran

drop wise and the mixture was stirred at room temperature in

the presence of triethylamine (30 mmol) for 3 h. The solid

formed was removed by filtration, and the solvent was

O

COOH

F

N

R

N

N N

O₂N

N

X'

X

fluoroquinolone

core

lipophilic group with

polar substituent

piperazinylazole

moiety

Fig. (1). The rational design of the new fluoroquinolone-azole hybrids.

48 Letters in Drug Design & Discovery, 2018, Vol. 15, No. 1

Mentese et al.

evaporated under reduced pressure. The yellow solid ob-

tained was purified by crystallization from ethyl acetate to

afford the desired compound. Yield 84%.

fied to pH 6 with 37 % HCl. On cooling the mixture in cold

overnight, a solid obtained. This was recrystallized from

acetone to give the title compound 4 as a white solid. Yield:

76%.

Method 2

The mixture of ethyl bromoacetate (10 mmol), triethy-

lamine (30 mmol) and 1-(4-nitrophenyl)piperazine (10

mmol) was irradiated in monomode microwave reactor in

closed vessel with pressure control at 80 W maximum power

for 8 min. The formed yellow product was washed with wa-

ter and purified by crystallization from ethyl acetate. Yield

99%. mp.115-116°C.

FT-IR (υ_max,cm^-1): 3080 (ar-H), 1742 (C=O), 1313 and

1587 (NO₂), 1207 (C-O). ¹H NMR (DMSO-d₆, δ ppm): 1.24

(t, 3H, CH_3,J= 8.0 Hz), 2.69 (s, 4H, 2CH₂), 3.34 (s, 2H,

CH₂), 3.50 (s, 4H, 2CH₂), 4.14 (q, 2H, CH₂, J= 8.0 Hz), 7.06

(d, 2H, ar-H, J= 8.0 Hz), 8.09 (d, 2H, ar-H, J=8.0 Hz). ¹³C

NMR (DMSO-d₆, δ ppm): 14.70 (CH₃), 46.90 (2CH₂), 52.00

(2CH₂), 58.64 (CH₂), 60.48 (CH₂), arC: [113.20 (CH),

113.24 (CH), 126.28 (CH), 126.30 (CH), 137.44 (C), 155.29

(C)], 170.41 (C=O). LC-MS m/z (%): 316.12 ([M+ Na]⁺, 6),

188.16 (100). Elemental Anal. Calcd. for C₁₄H₁₉N₃O₄(%):C,

57.33; H, 6.53; N, 14.33, Found (%): C, 57.34; H, 6.52; N,

14.33.

The mixture of compound 3 (10 mmol), KOH (10 mmol)

and CS₂(20 mmol) in ethanol was irradiated in the mono-

mode microwave reactor in closed vessel at 200 W for 12

min. Then, it was acidified to pH 6 with 37 % HCl. On cool-

ing the mixture in cold overnight, a solid obtained. This was

recrystallized from acetone to give the title compound 4 as a

white solid. Yield: 97%, mp. 184-186°C.

FT-IR (υ_max,cm^-1): 3373 (NH), 1587-1314 (NO₂). ¹H

NMR (DMSO-d₆, δ ppm): 2.58-2.61 (m, 4H, 2CH₂), 2.70 (t,

2H, CH₂, J= 8.0 Hz)3.44-3.48 (m, 4H, 2CH₂), 7.00 (d, 2H,

ar-H, J= 4.0 Hz), 8.02 (d, 2H, ar-H, J= 4.0 Hz) 8.04 (s, 1H,

NH). ¹³C NMR (DMSO-d₆, δ ppm): 46.40 (CH₂), 46.65

(CH₂), 51.46 (CH₂), 51.85 (CH₂), 58.37 (CH₂), arC: [113.10

(CH), 113.16 (CH), 126.14 (2CH), 137.40 (C), 155.05 (C)],

161.05 (oxadiazole C-5), 178.51 (oxadiazole C-2). LC-MS

m/z (%): 322.24 ([M+1]⁺, 10), 294.34 (100). Elemental

Anal. Calcd. for C₁₃H₁₅N₅O₃S (%): C, 48.59; H, 4.70; N,

21.79, Found (%): C, 48.59; H, 4.70; N, 21.78.

2.1.2. [4-(4-Nitrophenyl)piperazin-1-yl]acetohydrazide (3)

Method 1

2.1.4. General Method for The Synthesis of Compounds

5a-b

Method 1

Hydrazine hydrate (30 mmol) was added to the solution

of compound 2 (10 mmol) in absolute ethanol and the mix-

ture was refluxed for 5 h. On removing the solvent under

reduced pressure, a solid obtained. This was recrystallized

from ethanol to give the target compound. Yield 75%.

The solution of ciprofloxacin (for 5b) or norfloxacin (for

5a) (10 mmol) in dimethyl formamide was stirred at room

temperature in the presence of formaldehyde (30 mmol) for

15 min. Then, compound 4 was added into it and stirred at

room temperature for additional 24 h. The reaction mixture

was poured into ice-water and a solid obtained. This crude

product was collected by filtration and recrystallized from

dimethyl sulfoxide to afford the desired product.

Method 2

The mixture of hydrazine hydrate (30 mmol) and com-

pound 2 (10 mmol) was irradiated in monomode microwave

reactor in closed vessel with pressure control at 120 W for 5

min. The crude product obtained was recrystallized from

ethanol to give the pure compound. Yield: 97%. Mp, 163-

164°C.

FT-IR (υ_max,cm^-1): 3328 and 3248 (NH, NH₂), 3006 (ar-

H), 1631 (C=O), 1474 and 1322 (NO₂). ¹H NMR (DMSO-d₆,

δ ppm): 2.58-2.63 (m, 4H, 2CH₂+DMSO), 3.06 (s, 2H, CH₂),

3.55 (s, 4H, 2CH₂), 4.32 (s, 2H, NH₂), 7.09 (s, 2H, ar-H),

8.11 (s, 2H, ar-H), 9.06 (s, 1H, NH). ¹³C NMR (DMSO-d₆, δ

ppm): 46.88 (2CH₂), 52.89 (2CH₂), 60.16 (CH₂), arC:

[113.22 (2CH), 126.36 (2CH), 137.39 (C), 155.31 (C)],

168.65 (C=O). LC-MS m/z (%): 303.11 ([M+1+ Na]⁺, 15),

302.11 ([M+ Na]⁺, 100). Elemental Anal. Calcd. For

C₁₂H₁₇N₅O₃(%):C, 51.60; H, 6.14; N, 25.08, Found (%): C,

51.61; H, 6.13; N, 25.08.

Method 2

The mixture of ciprofloxacin (for 5b) or norfloxacin (for

5a) (10 mmol), compound 4 and formaldehyde (30 mmol)

was irradiated in monomode microwave reactor in closed

vessel with pressure control at 80 W for 15 min. The solid

obtained was recrystallized from dimethyl sulfoxide to

afford the desired product.

1-Ethyl-6-fluoro-7-{4-(5-([4-(4-nitrophenyl)piperazin-1-

yl]methyl)-2-thioxo-1,3,4-oxadiazol-3(2H)-yl)methyl]

piperazin-1-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylic

acid (5a)

mp.: 220-221°C, Yield: 70% (Method 1), 88% (Method

2). FT-IR (υ_max,cm^-1): 3365 (COOH), 3071 (ar-H), 2829

(C=S), 1724 (C=O), 1626 (C=O), 1496 and 1329 (NO₂),

1

2.1.3.

5-{[4-(4-Nitrophenyl)piperazin-1-yl]methyl}-1,3,4-

1224 (C-O). H NMR (DMSO-d₆, δ ppm): 1.39- 1.43 (m,

oxadiazole-2-thiol (4)

Method 1

3H, CH₃), 2.64-92 (m, 8H, 4CH₂), 3.34-3.50 (m, 8H, 4CH₂+

H₂O), 3.79 (s, 2H, CH₂), 4.58 (s, 2H, CH₂), 5.05 (s, 2H,

CH₂), 7.01 (d, 2H, ar-H, J= 8.0 Hz), 7.17 (d, 1H, ar-H, J=

8.0 Hz), 7.90-7.97 (m, 1H, ar-H), 8.01-8.11 (m, 2H, ar-H),

8.95 (s, 1H, quinolone =CH), 15.36 (s, 1H, COOH). ¹³C

NMR (DMSO-d₆, δ ppm): 14.79 (CH₃), 43.30 (CH₂), 45.60

(CH₂), 45.31 (CH₂), 46.68 (2CH₂), 48.36 (CH₂), 49.54

The solution of KOH (10 mmol) in water was added to

the solution of compound 3 (10 mmol) in ethanol and the

mixture was refluxed in the presence of CS₂(20 mmol) for

10 hours. Then, it was cooled to room temperature and acidi-

Novel Azole-Functionalited Flouroquinolone Hybrids

Letters in Drug Design & Discovery, 2018, Vol. 15, No. 1 49

(CH₂), 49.79 (2CH₂), 51.98 (CH₂), 69.92 (CH₂), arC:

[113.19 (2CH), 126.15(2CH), 137.71 (C), 154.59 (C),],

106.26 and 106.45 (d, CH, J= 9.0 Hz), 107.54 (C), 111.80

(CH), 119.81 (C), 137.45(C), 145.85 (C), 148.99 (CH),

152.65 (C), 155.59 (oxadiazole C-5), 166.63 (C=O), 173.99

(oxadiazole C-2), 176.86 (C=O). LC-MS m/z (%):653,22

H₂O), 3.70 (s, 4H, 2CH₂), 7.02 (d, 2H, ar-H, J= 8.0 Hz),

7.06-7.43 (m, 5H, ar-H), 8.05 (d, 2H, ar-H, J= 8.0 Hz), 9.59

(bs, 2H, 2NH), 9.94 (bs, 1H, NH). ¹³C NMR (DMSO-d₆, δ

ppm): 46.73(2CH₂), 51.88 (CH₂), 52.72 (2CH₂), 59.99

(CH₂), arC: [113.10 (4CH), 126.19 (4CH), 128.62 (CH),

137.28 (C), 139.58 (2C)], 155.15 (C=O), 181.34 (C=S).LC-

MS m/z (%): 430.16 ([M+2]⁺, 24), 429.16 ([M+1]⁺, 94),

220.10 (100). Elemental Anal. Calcd. forC₂₀H₂₄N₆O₃S

(%):C, 56.06; H, 5.65; N, 19.61, Found (%): C, 56.05; H,

5.67; N, 19.61.

+

([M+1] , 100). Elemental Anal. Calcd. for C₃₀H₃₃FN₈O₆S

(%): C, 55.21; H, 5.10; N, 17.17, Found (%): C, 55.28; H,

5.17; N, 17.21.

1-Cyclopropyl-6-fluoro-7-{4-(5-[4-(4-nitrophenyl)piperazin-1-

yl]methyl)-2-thioxo-1,3,4-oxadiazol-3(2H)-yl]methyl)

piperazin-1-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylic

acid (5b)

N-Benzyl-2-{[4-(4-nitrophenyl)piperazin-1-yl]acetyl}

hydrazincarboxamide (6b)

mp. 203-204°C Yield: 78% (Method 1), 97% (Method 2).

FT-IR (υ_max,cm^-1): 3298, 3231, 3183 (NH), 1697 (C=O).¹H

NMR (DMSO-d₆, δ ppm): 2.62 (s, 4H, 2CH₂), 3.09 (s, 2H,

CH₂), 3.48 (s, 4H, 2CH₂+ H₂O), 4.25 (s, 2H, CH₂), 6.97 (d,

3H, ar-H, J= 32.0 Hz), 7.28 (s, 4H, ar-H), 7.91 (s, 1H, NH),

8.05 (s, 2H, ar-H), 9.53 (s, 2H, 2NH).¹³C NMR (DMSO-d₆, δ

ppm): 43.13(CH₂), 50.36 (2CH₂), 51.54 (2CH₂), 57.67

(CH₂), arC: [112.41 (2CH), 126.40 (2CH), 126.92 (CH),

127.59 (2CH), 128.43 (CH), 138.88 (C), 139.85 (C), 158.23

(C)], 156.89 (C=O), 171.95 (C=O).LC-MS m/z (%): 412.19

([M]⁺, 100), 413.19 ([M+1]⁺, 22.1). Elemental Anal. Calcd.

ForC₂₀H₂₄N₆O₄(%): C, 58.24; H, 5.87; N, 20.38, Found (%):

C, 57.85; H, 5.67; N, 19.44.

mp.: 215-216°C, Yield: 75% (Method 1), 89% (Method

2). FT-IR (υ_max,cm^-1): 3333 (COOH), 3022 (ar-H), 1718

1

(C=O), 1679 (C=O), 1491 and 1356 (NO₂), 1229 (C-O). H

NMR (DMSO-d₆, δ ppm): 1.18 (s, 2H, CH₂), 1.31 (d, 2H,

CH₂, J= 4.0 Hz), 2.65-2.73 (m, 4H, 2CH₂), 2.89-2.94 (m,

4H, 2CH₂), 3.32 (bs, 6H, 3CH₂+ H₂O), 3.47 (s, 3H, CH +

CH₂), 3.80 (s, 2H, CH₂), 5.06 (s, 2H, CH₂), 7.05 (d, 2H, ar-

H, J= 12.0 Hz), 7.54-7.60 (m, 1H, ar-H), 7.87-7.95 (m, 2H,

ar-H), 8.03 (d, 1H, ar-H, J= 8.0 Hz), 8.65 (s, 1H, quinolone

=CH), 15.17 (bs, 1H, COOH). ¹³C NMR (DMSO-d₆, δ ppm):

8.04 (2CH₂), 36.30 (CH), 46.68 (2CH₂), 48.35 (CH₂), 49.73

(2CH₂), 51.06 (CH₂), 51.47 (CH₂), 51.96 (2CH₂), 69.91

(CH₂), arC: [113.18 (2CH), 126.12 (2CH), 139.59 (C),],

107.03 (CH), 107.22 (C), 111.31 and 111.54 (d, CH, J= 23.0

Hz), 119.09 and 119.17 (d, C, J= 8.0 Hz), 137.43 (C), 145.41

(C), 148.45 (CH), 152.19 and 154.67 (d, C-F, J_C-F= 248.0

Hz), 155.06 (oxadiazole C-5), 166.37 (C=O), 176.82 (C=O),

178.53 (oxadiazole C-2). LC-MS m/z (%): 665,22 ([M+1] ⁺,

100). Elemental Anal. Calcd. for C₃₁H₃₃FN₈O₆S (%):C, 56.02;

H, 5.00; N, 16.86, Found (%): C, 56.08; H, 5.07; N, 16.91.

N-Ethyl-2-{[4-(4-nitrophenyl)piperazin-1-yl]acetyl}

hydrazincarbothioamide (6c)

mp.124-125°C Yield: 75% (Method 1), 96% (Method 2).

FT-IR (υ_max,cm^-1): 3286, 3228, 3202, 3120 (NH), 1743

(C=O), 1485 and 1319 (NO₂).¹H NMR (DMSO-d₆, δ ppm):

1.19 (t, 3H, CH₃, J= 8.0 Hz), 2.63-2.65 (m, 4H, 2CH₂), 3.29

(s, 2H, CH₂), 3.45-3.49 (m, 4H, 2CH₂), 4.09 (q, 2H, CH₂, J=

8.0 Hz), 7.01-7.04 (m, 2H, ar-H, J= 8.0 Hz), 7.85 (bs, 1H,

NH), 8.03-8.08 (m, 2H, ar-H), 9.12 (bs, 1H, NH), 9.68 (bs,

1H, NH).¹³C NMR (DMSO-d₆, δ ppm): 14.58 (CH₃),

46.79(2CH₂), 51.87 (2CH₂), 58.54 (CH₂), 60.36 (CH₂), arC:

[113.08 (CH), 113.11 (CH), 126.16 (2CH), 137.32 (2C)],

155.16 (C=O), 170.30 (C=S). LC-MS m/z (%): 367.16

([M+1]⁺, 100). Elemental Anal. Calcd. for C₁₅H₂₂N₆O₃S

(%):C, 49.17; H, 6.05; N, 22.93, Found (%): C, 49.14; H,

6.08; N, 22.96.

2.1.5. General Method for The Synthesis of Compounds

6a-f

Method 1

A mixture of compound 3 (10 mmol) and the correspond-

ing iso(thio)cyanate (10 mmol) was stirred in dichloro-

methane at room temperature for 12 h (for 6b), 21 h (for 6d

and 6e) or 20 h (for 6a, 6c and 6f). On evaporating the solvent

under reduced pressure, a solid obtained. The crude product

was recrystallized from ethanol (for 6a, 6c, 6d and 6f) or

ethyl acetate (for 6b and 6e) to afford the desired product.

N-Phenyl-2-{[4-(4-nitrophenyl)piperazin-1-yl]acetyl}

hydrazincarbothioamide (6d)

Method 2

mp.192-194°C Yield: 73% (Method 1), 92% (Method 2).

FT-IR (υ_max,cm^-1): 3314, 3277, 3216 (NH), 3053 (ar-H),

1744 (C=O). ¹H NMR (DMSO-d₆, δ ppm): 2.48 (s, 4H,

2CH₂), 3.29 (s, 2H, CH₂), 3.44 (s, 4H, 2CH₂), 6.92 (d, 2H,

ar-H, J= 4.0 Hz), 7.13 (m, 1H, ar-H), 7.22 (m, 2H, ar-H),

7.34 (m, 2H, ar-H), 7.99 (d, 2H, ar-H, J= 4.0 Hz), 8.03 (bs,

1H, NH), 8.84 (bs, 2H, NH). ¹³C NMR (DMSO-d₆, δ ppm):

52.00 (2CH₂), 54.90 (2CH₂), 61.84 (CH₂), arC: [112.30

(2CH), 124.80 (2CH), 126.56 (2CH),128.41 (CH), 129.35

(2CH), 137.42 (C), 138.54 (C), 155.76 (C)], 170.33 (C=O),

181.12 (C=S). LC-MS m/z (%): 415.15 ([M+1]⁺, 100),

223.18 (32). Elemental Anal. Calcd. For C₁₉H₂₂N₆O₃S (%):

C, 55.06; H, 5.35; N, 20.28; Found (%): C, 54.14; H, 5.02;

N, 19.98.

A mixture of compound 3 (10 mmol) and the correspond-

ing iso(thio)cyanate (20 mmol) was irradiated in monomode

microwave reactor in closed and vessel with pressure control

at 80 W for 12 min. The crude product obtained was recrys-

tallized from ethanol to (for 6a, 6c, 6d and 6f) or ethyl ace-

tate (for 6b and 6e) to give the pure compound.

N-Benzyl-2-{[4-(4-nitrophenyl)piperazin-1-yl]acetyl}

hydrazincarbothioamide (6a)

mp. 209-210°C Yield: 59% (Method 1), 73% (Method 2).

FT-IR (υ_max,cm^-1): 3285, 3268, 3231, 3119 (NH), 1743

(C=O), 1484 and 1307 (NO₂).¹H NMR (DMSO-d₆, δ ppm):

2.64 (s, 4H, 2CH₂), 3.15 (s, 2H, CH₂), 3.38 (s, 2H, CH₂+

50 Letters in Drug Design & Discovery, 2018, Vol. 15, No. 1

Mentese et al.

N-Phenyl-2-{[4-(4-nitrophenyl)piperazin-1-yl]acetyl}

hydrazincarboxamide (6e)

1.07 (m, 4H, 2CH₂), 2.50-3.46 (m, 6H, 3CH₂+ H2O), 5.34

(s, 2H, CH₂), 6.94-6.97 (m, 2H, ar-H), 6.98-7.57 (m, 5H, ar-

H), 8.03 (d, 2H, ar-H, J= 8.0 Hz), 13.88 (bs, 1H, SH). ¹³C

NMR (DMSO-d₆, δ ppm): 46.37 (CH₂), 46.67 (CH₂), 46.77

(CH₂), 51.88 (CH₂), 52.06 (CH₂), 52.24 (CH₂), arC: [113.09

(CH), 113.14 (CH), 126.14 (CH), 127.37 (CH), 127.79 (CH),

128.75 (CH), 128.85 (CH), 129.40 (CH), 129.65 (CH),

134.50 (C), 136.69 (C), 149.57 (C)], 155.05 (triazole C-5),

181.34 (triazole C-3). LC-MS m/z (%): 433.13 ([M+ Na]⁺,

10), 412.16 ([M+2]⁺, 22), 411.15 ([M+1]⁺, 100). Elemental

Anal. Calcd. forC₂₀H₂₂N₆O₂S (%):C, 58.52; H, 5.40; N,

20.47, Found (%): C, 58.57; H, 5.43; N, 20.49.

mp. 211-212°C Yield: 76% (Method 1), 93% (Method 2).

FT-IR (υ_max,cm^-1): 3258, 3223, 3199 (NH), 1689 (C=O),

1481 and 1332 (NO₂). ¹H NMR (DMSO-d₆, δ ppm): 2.62 (s,

4H, 2CH₂), 3.13 (s, 2H, CH₂), 3.49 (s, 4H, 2CH₂), 6.94-7.02

(m, 3H, ar-H), 7.26 (d, 2H, ar-H, J=4.0 Hz), 7.46-7.52 (m,

2H, ar-H), 8.05 (d, 2H, ar-H, J=16.0 Hz), 8.09 (s, 1H, NH),

8.82 (s,1H, NH), 9.66 (s, 1H, NH). ¹³C NMR (DMSO-d₆, δ

ppm): 52.16 (2CH₂), 53.89 (2CH₂), 60.80 (CH₂), arC:

[113.30 (2CH), 121.60 (2CH), 124.88 (2CH), 128.00 (CH),

128.90 (2CH), 136.92 (C), 139.40 (C), 155.70 (C)], 153.80

(C=O), 170.52 (C=O). LC-MS m/z (%): 398.17 ([M]⁺, 100),

400.19 ([M+2]⁺, 27). Elemental Anal. Calcd. For

C₁₉H₂₂N₆O₄(%):C, 57.28; H, 5.57; N, 21.09, Found (%): C,

56.67; H, 5.14; N, 20.84.

5-{[4-(4-Nitrophenyl)piperazin-1-yl]methyl}-4-benzyl-4H-

1,2,4-triazole-5-one (7b)

mp.242-243 °C, Yield: 73% (Method 1), 85% (Method

2). FT-IR (υ_max,cm^-1): 3164 (NH), 3027 (ar-CH), 1689

1

N-(4-fluorophenyl)-2-{[4-(4-nitrophenyl)piperazin-1-yl]

acetyl}hydrazincarbothioamide (6f)

(C=O), 1479 and 1313 (NO₂). H NMR (DMSO-d₆, δ ppm):

2.41 (d, 2H, CH₂, J=4.0 Hz), 2.50 (t, 2H, CH₂, J=4.0 Hz),

3.24 (s, 2H, CH₂), 3.32 (s, 2H, CH₂), 3.36 (s, 4H, 2CH₂

+H₂O), 4.89 (s, 2H, CH₂), 6.97 (d, 2H, ar-H, J=4.0 Hz), 7.26

(d, 3H, ar-H, J=8.0 Hz), 7.32 (d, 2H, CH₂, J=4.0 Hz), 8.03

mp.201-202°C Yield: 79% (Method 1), 94% (Method 2).

FT-IR (υ_max,cm^-1): 3329, 3254, 3221 (NH), 3081 (ar-H),

1736 (C=O), 1488 and 1311 (NO₂).¹H NMR (DMSO-d₆, δ

ppm): 2.51 (s, 2H, CH₂), 2.65 (s, 4H, 2CH₂), 3.34 (s, 4H,

2CH₂), 7.05 (d, 2H, ar-H, J= 8.0 Hz), 7.18 (m, 2H, ar-H),

7.42 (s, 2H, ar-H), 8.06 (d, 2H, ar-H, J= 8.0 Hz), 9.61 (bs,

2H, 2NH), 9.92 (bs, 1H, NH). ¹³C NMR (DMSO-d₆, δ ppm):

50.87 (2CH₂), 54.93 (2CH₂), 56.90 (CH₂), arC: [111.33

(2CH), 113.79 (2CH), 121.41 (2CH), 126.29 (2CH), 137.65

(C), 150.87 (C), 155.18 (C)], 168.75 (C=O), 181.10 (C=S).

LC-MS m/z (%): 433.14 ([M+1]⁺, 100), 434.15 (45), 220.18

(22). Elemental Anal. Calcd. For C₁₉H₂₁FN₆O₃S (%):C,

52.77; H, 4.89; N, 19.43, Found (%): C, 51.94; H, 4.32; N,

19.01.

(d, 2H, ar-H, J= 12.0 Hz), 11.75 (s, 1H, NH). ¹³C NMR

(DMSO-d₆, δ ppm): 42.43 (CH₂), 51.27 (2CH₂), 51.78

(2CH₂), 56.11 (CH₂), arC: [112.41 (2CH), 126.45 (2CH),

128.01 (CH), 128.53 (2CH), 128.76 (2CH), 137.06 (C),

138.88 (C), 146.90 (C)], 155.70 (triazole C-5), 158.23 (tria-

zole C-3). LC-MS m/z (%): 417.18 ([M+ Na]⁺, 43), 395.19

([M+1]⁺, 100). Elemental Anal. Calcd. For C₂₀H₂₂N₆O₃(%):

C, 60.90; H, 5.62; N, 21.31, Found (%): C, 59.97; H, 5.13;

N, 20.89.

5-{[4-(4-Nitrophenyl)piperazin-1-yl]methyl}-4-ethyl-4H-

1,2,4-triazole-3-thiol (7c)

2.1.6. General Method For The synthesis of Compounds (7a-f)

Method 1

mp.215-216°C, Yield: 75% (Method 1), 88% (Method 2).

FT-IR (υ_max,cm^-1): 3088 (ar-CH), 2830 (SH), 1589 and 1336

(NO₂). ¹H NMR (DMSO-d₆, δ ppm): 1.27 (t, 3H, CH₃, J= 8.0

Hz), 2.48-3.54 (m, 2H, CH₂+ DMSO), 2.63 (d, 2H, CH₂, J=

8.0 Hz), 3.12 (s, 2H, CH₂), 3.43-3.46 (m, 2H, CH₂+ H2O),

3.62 (s, 2H, CH₂), 4.02 (q, 2H, CH₂, J= 8.0 Hz), 6.99 (d, 2H,

ar-H, J= 12.0 Hz), 8.02 (d, 2H, ar-H, J= 12.0 Hz), 13.60 (bs,

1H, SH). ¹³C NMR (DMSO-d₆, δ ppm): 13.75 (CH₃), 46.65

(CH₂), 46.73 (CH₂), 51.89 (2CH₂), 52.07 (CH₂), 58.68

(CH₂), arC: [113.09 (CH), 113.19 (CH), 126.14 (CH),

126.16 (CH), 137.29 (C), 149.26 (C)], 155.11 (triazole C-5),

171.78 (triazole C-3). LC-MS m/z (%): 389.43 ([M+ K+2]⁺,

100), 375.47 ([M+ Na+4]⁺, 85). Elemental Anal. Calcd.

forC₁₅H₂₀N₆O₂S (%):C, 51.71; H, 5.79; N, 24.12, Found (%):

C, 51.75; H, 5.82; N, 24.10.

A solution of corresponding carbo(thio)amide 6 (10

mmol) in ethanol/water (1:1) was refluxed in the presence of

2N NaOH (20 mmol) for 7 h (for 7a), 8 h (for 7b), 12 h (for

7c) or 13 h (for 7d and 7e). The resulting solution was then

cooled to room temperature and acidified to pH 5 with 37%

HCl. The precipitate formed was collected by filtration,

washed with water, and recrystallized from dimethylforma-

mide to give the target compounds.

Method 2

A solution of corresponding carbo(thio)amide 6 (10

mmol) and 2N NaOH (20 mmol) in ethanol/water (1:1) was

irradiated in monomode microwave reactor in open vessel at

150 W for 14 min. The resulting solution was then acidified

to pH 5 with 37% HCl. The precipitate formed was collected

by filtration, washed with water, and recrystallized from di-

methylformamide to give the target compounds.

5-{[4-(4-Nitrophenyl)piperazin-1-yl]methyl}-4-phenyl-4H-

1,2,4-triazole-3-thiol (7d)

mp.198-200 °C, Yield: 81% (Method 1), 92% (Method

Benzyl-5-{[4-(4-nitrophenyl)piperazin-1-yl]methyl}-4H-

1,2,4-triazole-3-thiol (7a)

2). FT-IR (υ_max,cm^-1): 3109 (NH), 3018 (ar-CH), 2850 (SH),

1

1480 and 1310 (NO₂). H NMR (DMSO-d₆, δ ppm): 2.37 (t,

4H, 2CH₂, J=12.0 Hz), 3.28 (t, 4H, 2CH₂, J=12.0 Hz), 3.36

(s, 2H, CH₂), 6.97 (d, 2H, ar-H, J=8.0 Hz), 7.36-7.41 (m, 3H,

ar-H), 7.53-7.57 (m, 2H, ar-H), 8.03 (d, 2H, ar-H, J= 8.0

mp.218-220 °C, Yield: 87% (Method 1), 95% (Method

2). FT-IR (υ_max,cm^-1): 3113 (NH), 3035 (ar-CH), 2821 (SH),

1

1482 and 1305 (NO₂). H NMR (DMSO-d₆, δ ppm): 1.04-

Novel Azole-Functionalited Flouroquinolone Hybrids

Letters in Drug Design & Discovery, 2018, Vol. 15, No. 1 51

Hz), 13.90 (s, 1H, SH). ¹³C NMR (DMSO-d₆, δ ppm): 48.84

(CH₂), 50.50 (2CH₂), 52.19 (2CH₂), arC: [113.35 (2CH),

126.29 (2CH), 127.21 (2CH), 129.35 (2CH), 132.60 (CH),

137.65 (C), 143.18 (C), 143.18 (C)], 156.79 (triazole C-5),

174.33 (triazole C-3). LC-MS m/z (%): 419.14 ([M+ Na]⁺,

100), 420.15 ([M+2]⁺, 31). Elemental Anal. Calcd. For

C₁₉H₂₀N₆O₂S (%): C, 57.56; H, 5.08; N, 21.20, Found (%):

C, 57.02; H, 4.89; N, 20.79.

microwave reactor in closed vessel with pressure control at

80 W for 15 min. The solid obtained was recrystallized from

dimethyl sulfoxide to afford the desired product.

1-Ethyl-6-fluoro-7-{4-[(3-{[4-(4-nitrophenyl)piperazin-1-

yl]methyl}-4-benzyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazole-

1-yl)methyl]piperazin-1-yl}-4-oxo-1,4-dihydroquinoline-3-

carboxylic acid (8a)

mp. 216 °C (dec.), Yield: 87% (Method 1), 94% (Method

5-{[4-(4-Nitrophenyl)piperazin-1-yl]methyl}-4-phenyl-4H-

1,2,4-triazole-5-one (7e)

2). FT-IR (υ_max,cm^-1): 3060 (ar-CH), 1716 (C=O),

1

1630(C=O), 1447 and 1332 (NO₂), 1248 (C-O). H NMR

mp.242-243 °C, Yield: 68% (Method 1), 81% (Method

(DMSO-d₆, δ ppm): 1.43 (t, 3H, CH₃, J= 4.0 Hz) 2.44 (s, 4H,

2CH₂), 2.95 (s, 4H, 2CH₂), 3.21-3.24 (m, 4H, 2CH₂+H₂O),

3.37 (s, 4H, 2CH₂), 3.54 (s, 2H, CH₂), 4.58 (s, 2H, CH₂),

5.20 (s, 2H, CH₂), 5.42 (s, 2H, CH₂), 6.92 (d, 2H, ar-H, J=

8.0 Hz), 7.16-7.33 (m, 5H, ar-H), 7.91 (d, 2H, ar-H, J= 12.0

Hz), 8.01 (d, 2H, ar-H, J= 8.0 Hz), 8.91 (s, 1H, quinolone

=CH), 15.24 (s, 1H, COOH). ¹³C NMR (DMSO-d₆, δ ppm):

The spectrum could not be obtained, due to the slight solu-

bility in any NMR solvent. LC-MS m/z (%): 764.29

([M+Na]⁺, 10), 744.31 ([M+3]⁺, 15), 743.31 ([M+2]⁺, 45),

742.30 ([M+1]⁺, 100). Elemental Anal. Calcd. For

C₃₇H₄₀FN₉O₅S (%): C, 59.91; H, 5.43; N, 16.99, Found (%):

C, 59.94; H, 5.47; N, 17.03.

2). FT-IR (υ_max,cm^-1): 3184 (NH), 3046 (ar-CH), 1676

1

(C=O), 1475 and 1305 (NO₂). H NMR (DMSO-d₆, δ ppm):

2.64 (t, 4H, 2CH₂, J=12.0 Hz), 3.28 (t, 4H, 2CH₂, J=12.0

Hz), 3.35 (s, 2H, CH₂), 6.92-7.06 (m, 3H, ar-H), 7.23-7.25

(m, 1H, ar-H), 7.27-7.51 (m, 3H, ar-H), 8.03 (d, 2H, ar-H, J=

8.0 Hz), 9.62 (s, 1H, NH). ¹³C NMR (DMSO-d₆, δ ppm):

51.16 (2CH₂), 51.74 (2CH₂), 53.16 (CH₂), arC: [113.33

(2CH), 125.52 (2CH), 126.29 (2CH), 127.01 (CH), 129.21

(2CH), 133.28 (C), 137.65 (C), 151.98 (C)], 151.85 (triazole

C-3), 157.15 (triazole C-5). LC-MS m/z (%): 419.16 ([M+

K]⁺, 48), 381.17 ([M+1]⁺, 100). Elemental Anal. Calcd. For

C₁₉H₂₀N₆O₃(%): C, 59.99; H, 5.30; N, 22.09, Found (%): C,

59.18; H, 5.04; N, 21.88.

1-Ethyl-6-fluoro-7-{4-[(3-{[4-(4-nitrophenyl)piperazin-1-

yl]methyl}-4-benzyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1-

yl)methyl]piperazin-1-yl}-4-oxo-1,4-dihydroquinoline-3-

carboxylic acid (8b)

5-{[4-(4-Nitrophenyl)piperazin-1-yl]methyl}-4-(4-

fluorophenyl)-4H-1,2,4-triazole-3-thiol (7f)

mp.234-235 °C, Yield: 82% (Method 1), 93% (Method

2). FT-IR (υ_max,cm^-1): 3183 (NH), 3056 (ar-CH), 2831 (SH).

¹H NMR (DMSO-d₆, δ ppm): 2.37 (t, 4H, 2CH₂, J=12.0 Hz),

3.28 (t, 4H, 2CH₂, J=12.0 Hz), 3.42 (s, 2H, CH₂), 6.97 (d,

2H, ar-H, J=8.0 Hz), 7.36-7.41 (m, 2H, ar-H), 7.53-7.57 (m,

2H, ar-H), 8.03 (d, 2H, ar-H, J= 8.0 Hz), 13.90 (s, 1H, SH).

¹³C NMR (DMSO-d₆, δ ppm): 50.36 (2CH₂), 51.54 (2CH₂),

56.98 (CH₂) arC: [112.41 (2CH), 116.54 (2CH), 126.40

(2CH), 129.13 (2CH), 134.49 (C), 138.88 (C), 158.23 (C),

162.88 (d, J_C-F=42.0 Hz], 156.82 (triazole C-5), 174.45 (tria-

zole C-3). LC-MS m/z (%): 414.13 ([M+1]⁺, 100), 425.15

([M+2]⁺, 83), 436.13 ([M+Na]⁺, 24). Elemental Anal. Calcd.

For C₁₉H₁₉FN₆O₂S (%):C, 55.06; H, 4.62; F, 4.58; N, 20.28,

Found (%): C, 54.72; H, 4.13; N, 19.89.

mp. 235 °C, Yield: 88% (Method 1), 96% (Method 2).

FT-IR (υ_max,cm^-1): 3053 (ar-CH), 1744 (C=O), 1660(C=O),

1

1442 and 1328 (NO₂), 1241 (C-O). H NMR (DMSO-d₆, δ

ppm): 1.41 (t, 3H, CH₃, J= 12.0 Hz), 2.44 (s, 4H, 2CH₂),

2.51 (s, 4H, 2CH₂), 2.82 (s, 4H, 2CH₂), 3.23 (s, 4H, 2CH₂),

3.39 (s, 2H, CH₂), 4.58 (d, 2H, CH₂, J=4.0 Hz), 4.69 (s, 2H,

CH₂), 4.96 (s, 2H, CH₂), 6.94 (d, 2H, ar-H, J= 8.0 Hz), 7.17

(d, 1H, ar-H, J=8.0 Hz), 7.25-7.33 (m, 5H, ar-H), 7.91 (d,

1H, ar-H, J= 16.0 Hz), 8.02 (d, 2H, ar-H, J= 8.0 Hz), 8.94 (s,

1H, quinolone =CH), 15.33 (s, 1H, COOH). ¹³C NMR

(DMSO-d₆, δ ppm): 12.41 (CH₃), 42.69 (CH₂), 48.86 (CH₂),

50.36 (2CH₂), 50.76 (2CH₂), 51.43 (2CH₂), 51.54 (2CH₂),

56.37 (CH₂), 63.93 (CH₂), arC: [112.41 (2CH), 114.25 and

114.45 (d, CH, J=4.0 Hz), 126.43 (2CH), 128.01 (CH),

128.53 (2CH), 128.76 (2CH), 138.88 (C), 158.23 (C)],

102.55 (CH), 111.26 (C), 118.19 (C), 137.01 (C), 138.84

(triazole C-5), 146.55 and 146.90 (d, C, J= 9.0 Hz), 148.80

(CH), 150.10 and 152.20 (d, C-F, J_C-F= 105.0 Hz), 149.78

(C=O), 153.02 (triazole C-3), 167.02 (C=O), 176.57 (C=O).

LC-MS m/z (%): 748.31 ([M+Na]⁺, 23), 727.32 ([M+2]⁺,

39), 726.31 ([M+1]⁺, 100). Elemental Anal. Calcd. For

C₃₇H₄₀FN₉O₆(%): C, 61.23; H, 5.56; N, 17.37, Found (%):

C, 60.91; H, 5.17; N, 17.02.

2.1.7. General Method for The synthesis of Compounds (8a-l)

Method 1

The solution of ciprofloxacin (for 8g-l) or norfloxacin

(for 8a-f) (10 mmol) in dimethyl formamide was stirred at

room temperature in the presence of formaldehyde (37 %, 30

mmol) for 15 min. Then, the corresponding compound 7 was

added into it and stirred at room temperature for additional

24 h. The reaction mixture was poured to ice-water and a

solid obtained. This crude product was collected by filtration

and recrystallized from dimethyl sulfoxide to afford the

desired product.

1-Ethyl-6-fluoro-7-{4-[(3-{[4-(4-nitrophenyl)piperazin-1-

yl]methyl}-4-ethyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazole-

1-yl)methyl]piperazin-1-yl}-4-oxo-1,4-dihydroquinoline-3-

carboxylic acid (8c)

Method 2

The mixture of ciprofloxacin (for 8g-l), norfloxacin (for

8a-f) (10 mmol), the corresponding compound 7 and

formaldehyde (30 mmol) was irradiated in monomode

mp. 265-266 °C, Yield: 90% (Method 1), 97% (Method

2). FT-IR (υ_max,cm^-1): 3037 (ar-CH), 1708 (C=O), 1626

52 Letters in Drug Design & Discovery, 2018, Vol. 15, No. 1

Mentese et al.

1

(C=O), 1463 and 1363 (NO₂). H NMR (DMSO-d₆, δ ppm):

158.28 (C), 148.86 (CH), 150.31 (triazole C-3), 167.05

(C=O), 177.18 (C=O). LC-MS m/z (%): 734.30 ([M+Na]⁺,

1.30 (s, 3H, CH₃), 1.38 (s, 3H, CH₃), 2.48-2.55 (m, 8H,

4CH₂+ DMSO), 2.67-2.71 (s, 2H, CH₂), 2.86 (s, 2H, CH₂),

3.31-3.40 (m, 4H, 2CH₂+H₂O), 3.68 (s, 2H, CH₂), 4.08 (bs,

2H, CH₂), 4.56 (s, 2H, CH₂), 5.09 (s, 2H, CH₂), 6.97 (d, 2H,

ar-H, J= 8.0 Hz), 7.14 (s, 1H, ar-H), 7.89 (s, 1H, ar-H), 8.00

(d, 2H, ar-H, J= 8.0 Hz), 8.92 (s, 1H, quinolone =CH), 15.24

(s, 1H, COOH). ¹³C NMR (DMSO-d₆, δ ppm): The spectrum

could not be obtained, due to the slight solubility in any

NMR solvent. LC-MS m/z (%): 680.77 ([M+1]⁺, 100). Ele-

mental Anal. Calcd. For C₃₂H₃₈FN₉O₅S (%):C, 56.54; H,

5.63; N, 18.54, Found (%): C, 56.58; H, 5.67; N, 18.53.

+

28), 712.29 ([M+1] , 100), 666.28 (36). Elemental Anal.

Calcd. for C₃₆H₃₈FN₉O₆(%): C, 60.75; H, 5.38; N, 17.71;

Found (%): C, 60.11; H, 5.05; N, 16.96.

1-Ethyl-6-fluoro-7-{4-[4-(4-fluorophenyl)]-[(3-{[4-(4-

nitrophenyl)piperazin-1-yl]methyl}-5-thioxo-4,5-dihydro-

1H-1,2,4-triazol-1-yl)methyl]piperazin-1-yl}-4-oxo-1,4-

dihydroquinoline-3-carboxylic acid (8f)

mp. 242 °C, Yield: 83% (Method 1), 93% (Method 2).

FT-IR (υ_max,cm^-1): 3070 (ar-H), 1728 (C=O), 1656 (C=O),

1

1492 and 1323 (NO₂), 1228 (C-O). H NMR (DMSO-d₆, δ

1-Ethyl-6-fluoro-7-{4-[(3-{[4-(4-nitrophenyl)piperazin-1-

yl]methyl}-4-phenyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-

1-yl)methyl]piperazin-1-yl}-4-oxo-1,4-dihydroquinoline-3-

carboxylic acid (8d)

ppm): 1.42 (s, 3H, CH₃), 2.38 (s, 4H, 2CH₂), 2.51 (s, 4H,

2CH₂), 2.70 (s, 2H, CH₂), 2.99 (s, 2H, CH₂), 3.26 (s, 4H,

2CH₂), 4.59 (s, 4H, 2CH₂), 5.20 (s, 2H, CH₂), 6.95 (s, 2H,

ar-H), 7.19 (s, 1H, ar-H), 7.40 (s, 2H, ar-H), 7.58 (s, 2H, ar-

H), 7.92 (d, 1H, ar-H, J= 12.0 Hz), 8.02 (s, 2H, ar-H), 8.95

(s, 1H, quinolone =CH), 15.37 (bs, 1H, COOH). ¹³C NMR

(DMSO-d₆, δ ppm): 12.45 (CH₃), 48.05 (CH₂), 50.35

(2CH₂), 50.94 (2CH₂), 51.85 (2CH₂), 52.05 (2CH₂), 55.74

(CH₂), 63.51 (CH₂), arC: [112.41 (2CH), 114.25 and 114.48

(d, CH, J= 11.5 Hz), 115.85 and 116.07 (d, 2CH, J= 11.0

Hz), 126.40 (2CH), 129.84 (2CH), 133.36 (C), 138.75 (C),

158.23 (C), 161.32 and 163.41(d, C-F, J_C-F= 104.5 Hz)],

102.45 (CH), 111.38 (C), 118.19 (C), 138.45 (C), 146.77

(C), 148.81 (CH), 150.22 and 152.15 (d, C-F, J_C-F= 96.5

Hz), 154.35 (triazole C-5), 167.02 (C=O), 171.13 (triazole

mp. 248 °C, Yield: 84% (Method 1), 91% (Method 2).

FT-IR (υ_max,cm^-1): 3372 (OH), 3044 (ar-H), 1716 (C=O),

1

1625(C=O), 1494 and 1325 (NO₂), 1226 (C-O). H NMR

(DMSO-d₆, δ ppm): 1.37 (t, 3H, CH₃), 2.77 (s, 4H, 2CH₂),

2.93 (s, 4H, 2CH₂), 3.29 (s, 4H, 2CH₂), 3.36 (bs, 4H, 2CH₂+

H₂O), 4.22 (s, 2H, CH₂), 4.56 (s, 2H, CH₂), 5.20 (s, 2H,

CH₂), 5.85 (s, 1H, ar-H), 6.30-6.35 (m, 1H, ar-H), 6.73 (s,

3H, ar-H), 7.95 (s, 2H, ar-H), 7.40-7.46 (m, 3H, ar-H), 7.93

(d, 1H, ar-H, J= 8.0 Hz), 8.90 (s, 1H, quinolone =CH), 15.33

(bs, 1H, COOH). ¹³C NMR (DMSO-d₆, δ ppm): 14.36

(CH₃), 48.70 (2CH₂), 49.56 (2CH₂), 49.91 (2CH₂), 51.53

(2CH₂), 51.85 (2CH₂), 69.74 (CH₂), arC: [101.40 and 101.64

(d, CH, J= 24.0 Hz), 115. 76 (2CH), 115.72 (CH), 116.05

(CH), 119.54 (CH), 129. 13 (2CH), 129.25 (C), 130.81

(2CH), 144.67 (C), 149.69 (C)], 106. 97 (CH), 108.74 (C),

111.38 and 111.62 (d, CH, J= 24.0 Hz), 120. 95 (C), 139.94

(C), 144.51 (C), 148.49 (CH), 151.81 (triazole C-5), 152.53

and 155.01 (d, C-F, J_C-F= 248.0 Hz), 166.79 (C=O), 173.04

(triazole C-3), 176.79 (C=O). LC-MS m/z (%): 728,27

+

C-3), 178.41 (C=O). LC-MS m/z (%): 746.27 ([M+1] ,

+

100), 747.25 ([M+2] , 37). Elemental Anal. Calcd. For

C₃₆H₃₇F₂N₉O₅S (%):C, 57.98; H, 5.00; N, 16.90, Found (%):

C, 56.97; H, 4.83; N, 16.32.

1-Cyclopropyl-6-fluoro-7-{4-[(3-{[4-(4-nitrophenyl)

piperazin-1-yl]methyl}-4-benzyl-5-thioxo-4,5-dihydro-1H-

1,2,4-triazole-1-yl)methyl]piperazin-1-yl}-4-oxo-1,4-

dihydroquinoline-3-carboxylicacid (8g)

+

([M+1] , 100). Elemental Anal. Calcd. ForC₃₆H₃₈FN₉O₅S

(%): C, 59.41; H, 5.26; N, 17.32, Found (%):C, 59.38; H,

5.27; N, 17.31.

mp. 225-226 °C, Yield: 91% (Method 1), 97% (Method

2). FT-IR (υ_max,cm^-1): 3086 (ar-CH), 1732 (C=O),

1

1668(C=O), 1495 and 1322 (NO₂), 1256 (C-O). H NMR

1-Ethyl-6-fluoro-7-{4-[(3-{[4-(4-nitrophenyl)piperazin-1-

yl]methyl}-4-phenyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-

yl)methyl]piperazin-1-yl}-4-oxo-1,4-dihydroquinoline-3-

carboxylic acid (8e)

(DMSO-d₆, δ ppm): 1.16 (d, 2H, CH₂, J=8.0 Hz), 1.34 (d,

2H, CH₂, J= 8.0 Hz) 2.47 (s, 4H, 2CH₂), 2.98 (s, 4H, 2CH₂),

3.16 (s, 4H, 2CH₂), 3.38 (s, 4H, 2CH₂), 3.55 (s, 2H, CH₂),

3.81 (s, 1H, CH), 5.20 (s, 2H, CH₂), 5.43 (s, 2H, CH₂), 6.92

(d, 2H, ar-H, J= 8.0 Hz), 7.30 (s, 5H, ar-H), 7.55 (d, 1H, ar-

H, J= 4.0 Hz), 7.88 (d, 1H, ar-H, J= 12.0 Hz), 8.01 (d, 2H,

ar-H, J= 8.0 Hz), 8.66 (s, 1H, quinolone =CH), 15.01 (s, 1H,

COOH). ¹³C NMR (DMSO-d₆, δ ppm): 8.04 (2CH₂), 36.24

(CH), 46.57 (2CH₂), 47.97 (2CH₂), 49.99 (2CH₂), 50.26

(2CH₂), 52.13 (2CH₂), 69.22 (CH₂), arC: [109.37 (C), 113.17

(2CH), 126.01 (2CH), 127.35 (2CH), 127.87 (2CH), 128.87

(CH), 136.48 (C), 139.68 (C), 148.49 (C)], 106. 84 (CH),

107.52 (C), 111.39 and 111.62 (d, CH, J= 23.0 Hz), 119.22

(C), 137.77(C), 145.64 and 145.84 (d, C, J= 10.0 Hz),

148.29 (CH), 149.46 (triazole C-5), 152.53 and 155.01 (d, C-

F, J_C-F= 248.0 Hz), 166.20 (C=O), 170.47 (triazole C-3),

mp. 190-192 °C, Yield: 83% (Method 1), 92% (Method

2). FT-IR (υ_max,cm^-1): 3046 (ar-CH), 1748 (C=O), 1679

(C=O), 1492 and 1320 (NO₂), 1251 (C-O). ¹H NMR

(DMSO-d₆, δ ppm): 1.44 (s, 3H, CH₃), 2.44 (s, 4H, 2CH₂),

2.52 (s, 4H, 2CH₂), 2.72 (s, 4H, 2CH₂), 2.89 (s, 4H, 2CH₂),

3.26 (bs, CH₂+ H₂O), 4.61 (s, 2H, CH₂), 4.73 (s, 2H, CH₂),

6.96 (s, 2H, ar-H), 7.20 (s, 2H, ar-H), 7.55 (s, 4H, ar-H),

7.93 (s, 1H, ar-H), 8.03 (s, 2H, ar-H), 8.96 (s, 1H, quinolone

=CH), 15.36 (s, 1H, COOH). ¹³C NMR (DMSO-d₆, δ ppm):

12.42 (CH₃), 48.86 (CH₂), 50.36 (2CH₂), 50.76 (2CH₂),

51.44 (2CH₂), 51.56 (2CH₂), 55.68 (CH₂), 63.93 (CH₂), arC:

[112.41 (CH), 114.24 and 114.45 (d, CH, J=10.5 Hz), 118.19

(CH), 126.40 (2CH), 126.58 (2CH), 128.91 (2CH), 129.32

(CH), 134.33 (C),], 102.55 (CH), 111.26 (C), 138.74 (C),

138.89 (C), 148.43 (triazole C-5), 146.66 and 146.88 (d, C,

J= 11.0 Hz), 150.12 and 152.21 (d, C-F, J_C-F= 105.0 Hz),

176.87 (C=O). LC-MS m/z (%): 776.31 ([M+Na]⁺, 10),

+

754.33 ([M+1]

, 100). Elemental Anal. Calcd. for

C₃₈H₄₀FN₉O₅S (%):C, 60.54; H, 5.35; N, 16.72, Found (%):

C, 60.58; H, 5.37; N, 16.69.

Novel Azole-Functionalited Flouroquinolone Hybrids

Letters in Drug Design & Discovery, 2018, Vol. 15, No. 1 53

1-Cyclopropyl-6-fluoro-7-{4-[(3-{[4-(4-nitrophenyl)

piperazin-1-yl]methyl}-4-benzyl-5-oxo-4,5-dihydro-1H-

1,2,4-triazole-1-yl)methyl]piperazin-1-yl}-4-oxo-1,4-

dihydroquinoline-3-carboxylicacid (8h)

1.30 (d, 2H, CH₂, J= 8.0 Hz) 2.77 (s, 4H, 2CH₂), 2.95 (s, 4H,

2CH₂), 3.24 (s, 4H, 2CH₂), 3.40 (bs, 4H, 2CH₂+ H₂O), 3.76

(s, 1H, CH), 4.22 (s, 2H, CH₂), 5.20 (s, 2H, CH₂), 5.73 (d,

1H, ar-H, J= 8.0 Hz), 6.34-6.79 (m, 4H, ar-H), 7.95 (d, 2H,

ar-H, J= 8.0 Hz), 7.40-7.47 (m, 3H, ar-H), 7.95 (d, 1H, ar-H,

J= 8.0 Hz), 8.58 (s, 1H, quinolone =CH), 15.18 (bs, 1H,

COOH). ¹³C NMR (DMSO-d₆, δ ppm): 8.03 (2CH₂), 36.04

(CH), 48.77 (2CH₂), 49.06 (2CH₂), 49.96 (2CH₂), 51.35

(2CH₂), 51.58 (CH₂), 68.74 (CH₂), arC: [101.48 and 101.72

(d, CH, J= 24.0 Hz), 115.67 (2CH), 115.79 (CH), 116.72

(CH), 129.31 (2CH), 129.40 (C), 130.83 (2CH), 144.35 (C),

149.39 (C),], 106. 79 (CH), 108.64 (C), 111.36 and 111.60

(d, CH, J= 24.0 Hz), 119.45 and 120.59 (d, C, J=114.0 Hz),

139.49 (C), 144.46 (C), 148.24 (CH), 151.52 and 155.28 (d,

C-F, J_C-F= 376.0 Hz), 151.19 (triazole C-5), 166.43 (C=O),

mp. 151-153 °C, Yield: 88% (Method 1), 94% (Method

2). FT-IR (υ_max,cm^-1): 3046 (ar-CH), 1725 (C=O), 1674

(C=O), 1491 and 1319 (NO₂), 1251 (C-O). ¹H NMR

(DMSO-d₆, δ ppm): 1.20 (s, 2H, CH₂), 1.33 (s, 2H, CH₂)

2.44 (s, 4H, 2CH₂), 2.51 (s, 4H, 2CH₂), 2.73 (s, 2H, CH₂),

3.25 (s, 4H, 2CH₂), 3.39 (s, 4H, 2CH₂), 3.81 (s, 1H, CH),

4.94 (s, 2H, CH₂), 5.04 (d, 2H, CH₂,J=8.0 Hz), 6.96-6.98 (m,

2H, ar-H), 7.28-7.35 (m, 5H, ar-H), 7.56-7.60 (m, 1H, ar-H),

7.91 (d, 1H, ar-H, J= 12.0 Hz), 8.04 (d, 2H, ar-H, J= 8.0 Hz),

8.66 (s, 1H, quinolone =CH), 15.22 (s, 1H, COOH). ¹³C

NMR (DMSO-d₆, δ ppm): 9.15 (2CH₂), 37.62 (CH), 42.69

(CH₂), 50.35 (2CH₂), 50.78 (2CH₂), 51.44 (2CH₂), 51.58

(2CH₂), 57.38 (CH₂), 65.95 (CH₂), arC: [112.44 (CH),

114.67 (C), 126.43 (2CH), 128.11 (2CH), 128.53 (2CH),

128.76 (2CH), 136.30 (C), 138.85 (C), 158.23 (C)], 107.59

(CH), 109.37 (C), 113.23 and 113.33 (d, CH, J= 10.5 Hz),

137.06 (C), 147.79 (CH), 148.95 and 150.86 (d, C, J= 95.5

Hz), 150.78 (triazole C-3), 153.02 (triazole C-5), 167.05

(C=O), 178.57 (C=O). LC-MS m/z (%): 776.31 ([M+K]⁺,

27), 738.31 ([M+1] ⁺, 100). Elemental Anal. Calcd. for

C₃₈H₄₀FN₉O₆(%): C, 61.86; H, 5.46; N, 17.09, Found (%):

C, 61.08; H, 5.11; N, 16.73.

169.79 (triazole C-3), 176.57 (C=O). LC-MS m/z (%):

+

740,27 ([M+1]

, 100). Elemental Anal. Calcd. For

C₃₇H₃₈FN₉O₅S (%): C, 60.07; H, 5.18; N, 17.04, Found

(%):C, 60.08; H, 5.17; N, 17.01.

1-Cyclopropyl-6-fluoro-7-{4-[(3-{[4-(4-nitrophenyl)

piperazin-1-yl]methyl}-4-phenyl-5-oxo-4,5-dihydro-1H-

1,2,4-triazole-1-yl)methyl]piperazin-1-yl}-4-oxo-1,4-

dihydroquinoline-3-carboxylicacid (8k)

mp. 165-166 °C, Yield: 79% (Method 1), 88% (Method

2). FT-IR (υ_max,cm^-1): 3034 (ar-CH), 1728 (C=O), 1668

(C=O), 1489 and 1321 (NO₂), 1250 (C-O). ¹H NMR

(DMSO-d₆, δ ppm): 1.18 (s, 2H, CH₂), 1.33 (s, 2H, CH₂)

2.42 (s, 4H, 2CH₂), 2.51 (s, 4H, 2CH₂), 2.89 (s, 4H, 2CH₂),

3.25 (s, 4H, 2CH₂), 3.70 (s, 2H, CH₂), 3.81 (s, 1H, CH), 4.73

(s, 2H, CH₂), 6.91-7.02 (m, 2H, ar-H), 7.23-7.27 (m, 1H, ar-

H), 7.48 (s, 1H, ar-H), 7.53 (d, 4H, ar-H, J=4.0 Hz), 7.83 (d,

1H, ar-H, J= 12.0 Hz), 8.00 (t, 2H, ar-H, J= 16.0 Hz), 8.62

(s, 1H, quinolone =CH), 15.16 (s, 1H, COOH). ¹³C NMR

(DMSO-d₆, δ ppm): 9.15 (2CH₂), 37.62 (CH), 50.24 (2CH₂),

50.81 (2CH₂), 51.45 (2CH₂), 51.62 (2CH₂), 55.68 (CH₂),

63.95 (CH₂), arC: [109.26 (C), 112.53 (2CH), 113.17 and

114.68 (C), 126.40 (2CH), 128.15 (2CH), 128.54 (2CH),

128.76 (2CH), 136.36 (C), 138.79 (C), 158.58 (C)], 107.55

(CH), 109.41 (C), 113.42 (d, CH, J= 12.5 Hz), 137.16

(C),147.81 (CH), 148.76 and 150.97 (d, C, J= 110.5 Hz),

151.78 (triazole C-5), 153.52 (triazole C-3), 167.46 (C=O),

1-Cyclopropyl-6-fluoro-7-{4-[(3-{[4-(4-nitrophenyl)

piperazin-1-yl]methyl}-4-ethyl-5-thioxo-4,5-dihydro-1H-

1,2,4-triazole-1-yl)methyl]piperazin-1-yl}-4-oxo-1,4-

dihydroquinoline-3-carboxylicacid (8i)

mp. 240-241 °C (dec.), Yield: 86% (Method 1), 92%

(Method 2). FT-IR (υ_max,cm^-1): 3019 (ar-CH), 1719 (C=O),

1

1626 (C=O), 1464 and 1330 (NO₂). H NMR (DMSO-d₆, δ

ppm): 1.15 (d, 2H, CH₂, J=8.0 Hz), 1.30 (s, 5H, CH₃+CH₂),

2.54 (s, 4H, 2CH₂), 2.87 (s, 2H, CH₂), 3.06 (s, 2H, CH₂),

3.31-3.40 (m, 8H, 4CH₂+ H₂O), 3.68 (s, 2H, CH₂), 3.80 (s,

1H, CH₂), 4.09 (s, 1H, CH), 5.09 (s, 2H, CH₂), 6.96-7.01 (m,

2H, ar-H), 7.51-7.56 (m, 1H, ar-H), 7.84-7.89 (m, 2H, ar-H),

8.01 (d, 1H, ar-H, J= 8.0 Hz), 8.64 (s, 1H, quinolone =CH),

15.11 (s, 1H, COOH). ¹³C NMR (DMSO-d₆, δ ppm): 8.04

(2CH₂), 36.24 (CH), 46.57 (2CH₂), 47.97 (2CH₂), 49.99

(2CH₂), 50.26 (2CH₂), 52.13 (2CH₂), 69.22 (CH₂), arC:

[111.62 (C), 113.17 (2CH), 126.01 (2CH), 139.68 (C)], 106.

84 (CH), 107.52 (C), 111.39 (CH), 119.22 (C), 137.77(C),

145.64 and 145.84 (d, C, J= 10.0 Hz), 148.29 (CH), 152.53

and 155.01 (d, C-F, J_C-F= 248.0 Hz) 155.21 (triazole C-5),

166.20 (C=O), 170.47 (triazole C-3), 176.87 (C=O). LC-MS

m/z (%): 692.78 ([M+1] ⁺, 100). Elemental Anal. Calcd. For

C₃₃H₃₈FN₉O₅S (%): C, 57.30; H, 5.54; N, 18.22, Found (%):

C, 57.33; H, 5.58; N, 18.26.

176.77 (C=O). LC-MS m/z (%): 746.30 ([M+Na]⁺, 31),

+

724.29 ([M+1]

, 100). Elemental Anal. Calcd. for

C₃₇H₃₈FN₉O₆(%): C, 61.40; H, 5.29; N, 17.42; Found (%):

C, 61.02; H, 5.08; N, 16.93.

1-Cyclopropyl-6-fluoro-7-{4-[4-(4-fluorophenyl)]-[(3-{[4-

(4-nitrophenyl)piperazin-1-yl]methyl}-5-thioxo-4,5-

dihydro-1H-1,2,4-triazol-1-yl)methyl]piperazin-1-yl}-4-oxo-

1,4-dihydroquinoline-3-carboxylic acid (8l)

mp. 201-202 °C, Yield: 80% (Method 1), 91% (Method

2). FT-IR (υ_max,cm^-1): 3043 (ar-CH), 1744 (C=O), 1665

(C=O), 1491 and 1320 (NO₂), 1254 (C-O). ¹H NMR

(DMSO-d₆, δ ppm): 1.08 (s, 2H, CH₂), 1.33 (s, 2H, CH₂),

2.54 (s, 4H, 2CH₂), 2.72 (d, 8H, 4CH₂, J=16.0 Hz), 2.82 (s,

2H, CH₂), 3.36 (s, 4H, 2CH₂), 4.12 (s, 1H, CH), 5.23 (s, 2H,

CH₂), 6.23 (s, 1H, ar-H), 6.85 (d, 2H, ar-H, J=8.0 Hz), 7.05

(d, 2H, ar-H, J=12.0 Hz), 7.37-7.45 (m, 4H, ar-H), 8.01-8.08

(m, 2H, ar-H), 8.66 (s, 1H, quinolone =CH), 15.21 (s, 1H,

COOH). ¹³C NMR (DMSO-d₆, δ ppm): 7.78 (2CH₂), 36.81

1-Cyclopropyl-6-fluoro-7-{4-[(3-{[4-(4-nitrophenyl)

piperazin-1-yl]methyl}-4-phenyl-5-thioxo-4,5-dihydro-1H-

1,2,4-triazole-1-yl)methyl]piperazin-1-yl}-4-oxo-1,4-

dihydroquinoline-3-carboxylicacid (8j)

mp. 225-226 °C (dec.), Yield: 90% (Method 1), 95%

(Method 2). FT-IR (υ_max,cm^-1): 3355 (OH), 3070 (ar-H),

1721 (C=O), 1624(C=O), 1494 and 1324 (NO₂), 1225 (C-O).

¹H NMR (DMSO-d₆, δ ppm): 1.04 (d, 2H, CH₂, J=8.0 Hz),

54 Letters in Drug Design & Discovery, 2018, Vol. 15, No. 1

Mentese et al.

(CH), 52.05 (4CH₂), 52.71 (2CH₂), 54.82 (2CH₂), 60.71

(CH₂), 65.77 (CH₂), arC: [112.34 (2CH), 115.53 and 116.09

(d, 2CH, J= 28.0 Hz), 126.42 (2CH), 129.88 (2CH), 133.54

(C), 138.75 (C), 158.35 (C), 161.42 and 163.42 (d, C-F, J_C-F

= 100.0 Hz)], 102.73 (CH), 111.41 (C), 114.14 and 114.37

(d, CH, J= 11.5 Hz), 118.21 (C), 138.21 (C), 146.44 (C),

148.75 (CH), 150.16 and 152.32 (d, C-F, J_C-F= 108.0 Hz),

154.65 (triazole C-5), 167.74 (C=O), 173.25 (triazole C-3),

177.19 (C=O). LC-MS m/z (%):758.27 ([M+1] ⁺, 100),

712.26 (37), 680.25 (26). Elemental Anal. Calcd. for

C₃₇H₃₈FN₉O₆(%):C, 58.64; H, 4.92; N, 16.63; Found (%): C,

58.01; H, 4.23; N, 16.02.

TPTZ (2,4,6-tripyridyle-s-triazine) and 20 mM FeCl.6H₂O in

proportions of 10:1:1 (v/v). The mixture was incubated for

30 min at 37ºC and measured at 593 nm. The values were

expressed as µmol of Trolox/g.

2.3.3. CUPRAC (Cupric Ion Reducing Antioxidant Capac-

ity)

CUPRAC was measured following the procedure de-

scribed by Apak et al. [42] with some modification. Briefly,

100 µL of each chemical solution was mixed with 900 µL bi-

distilled water, 1 ml acetate buffer solution (1 mM, pH: 7.0),

1 ml CuCl₂(10 mM) and 1 ml 7.5 mM neocuproine to a final

volume of 4 ml. The reaction mixture was then incubated in

the dark for 30 min at room temperature, and the absorbance

of the reaction mixture was measured at 450 nm against wa-

ter blank. Trolox was used as the standard calibration curves,

and the results were expressed as µmol Trolox equivalent

per g.

2.2. Antimicrobial Activity

The test microorganisms were obtained from the Hifzis-

sihha Institute of Refik Saydam (Ankara, Turkey) and were

as follows: Escherichia coli (E. coli) ATCC35218, Yersinia

pseudotuberculosis (Y. pseudotuberculosis) ATCC911,

Pseudomonas aeruginosa (P. aeruginosa) ATCC43288, En-

terococcus faecalis (E. faecalis) ATCC29212, Staphylococ-

cus aureus (S. aureus) ATCC25923, Bacillus cereus (B.

cereus) 709 Roma, Mycobacterium smegmatis (M. smegma-

tis) ATCC607. All the newly synthesized compounds were

weighed and dissolved in hexane to prepare extract stock

solution of 20.000 microgram/milliliter (μg/mL). The antim-

icrobial effects of the substances were tested quantitatively

in respective broth media by using double microdilution and

the minimal inhibition concentration (MIC) values ( g/mL)

were determined. The antibacterial and antifungal assays

were performed in Mueller-Hinton broth (MH) (Difco, De-

troit, MI) at pH.7.3 and buffered Yeast Nitrogen Base

(Difco, Detroit, MI) at pH 7.0, respectively. The microdilu-

tion test plates were incubated for 18-24 h at 35 °C. Brain

Heart Infusion broth (BHI) (Difco, Detriot, MI) wasused for

M. smegmatis, and incubated for 48-72 h at 35 °C [39].

Ciprofloxacin, Norfloxacin, Ampicillin and Strepromicin

were used as standard antibacterial and antimicobacterial

drugs, respectively. Dimethylsulfoxide with dilution of 1:10

was used as solvent control. The results obtained were sub-

mitted in Table 2.

3. RESULTS AND DISCUSSION

3.1. Chemistry

In this study, we attempted to conventional and MW me-

diated green synthesize of new fluoroquinolone-azole hy-

brids as possible antimicrobial drug candidates. On the basis

1

of H, ¹³C NMR, FT IR and EI- MS data, the structures of

the target products were established. All synthesized com-

pounds were checked for purity and identity using elemental

analysis. The MICs against clinically important pathogens

were determined as well. The synthetic methodologies

adopted to obtain the target compounds were depicted in

Schemes 1 and 2.

The treatment of the starting compound, 1-(4-

nitrophenyl) piperazine (1) with ethyl bromoacetate to give

ethyl 2-[4-(4-nitrophenyl)piperazin-1-yl]acetate (2) was car-

ried out under conventional and also microwave (MW) irra-

diated conditions with a view to maximizing the yield of the

product and minimizing the reaction time. With the assessing

of MW irradiated method, the yield of the reaction was im-

proved to good level (99 %) however, more significantly, the

reaction time for complete consumption of starting materials

was lowered from 3 h with conventional heating to a re-

markable 8 min. Moreover, MW irradiated method with no

solvent supplied more ecofriendly way. Compound 2 was

confirmed by the disappearance of broad singlet for NH and

the presence of triplet at the region 1.24 ppm and a quartet at

4.14 ppm due to the presence of ethyl group proton in the ¹H

NMR spectrum of compound 2. This group appeared at

14.70 ppm (CH₃) and 60.48 ppm (CH₂) in the ¹³C NMR

spectrum. Further, in the FT IR, the appearance of the

stretching band due to C=O group at the region 1741 cm^-1

confirmed the formation of ester (2).

2.3. Antioxidant Activity Studies

2.3.1. DPPH (2,2-diphenyl-1-picrylhydrazyl) Radical Scav-

enging Activity

The scavenging activity of different chemicals was de-

termined using the free radical DPPH (2,2-diphenyl-1-

picrylhydrazyl), as described by Blois [40]. A 100-µL

chemical solution was mixed with 1 ml of freshly prepared

methanolic DPPH solution. The reaction mixture was incu-

bated for 30 min at room temperature in the dark and was

then measured at 520 nm. The activity was expressed as

µmol Trolox equivalent.

The substitution of ester group by hydrazide function

generated [4-(4-nitrophenyl)piperazin-1-yl]acetohydrazide

(3), which were confirmed by the appearance of broad signal

for -NHNH₂group in FT IR. Further, the protons of hydraz-

ide function were resonated at 4.32 (NH₂) and 9.06 (NH) as

D₂O exchangeable singlets confirming the formation of ace-

2.3.2. FRAP (The Ferric Reducing Ability of Plasma)

FRAP was measured using the method described by

Benzie & Strain [41] with some modification. To 100 µl of

each sample was added 2900 µl freshly prepared FRAP rea-

gent containing 300 mM acetate buffer (pH 3.6), 10 mM

Novel Azole-Functionalited Flouroquinolone Hybrids

Letters in Drug Design & Discovery, 2018, Vol. 15, No. 1 55

O

i

ii

N

O N

2

N

NH

O N

2

N

O

O N

2

NHNH

O Et

2

1

3

iii

O

F

OH

N

R

iv

O N

2

N

SH

O

N

4

N

O N

2

N

S

O

5a: R = -C H

2

5

; 5b: R=

Scheme 1. i: BrCH₂COOEt, ii: NH₂NH₂, iii: KOH, CS₂, EtOH-H₂O, iv: HCHO and norfloxacin (for 5a) or ciprofloxacin (for 5b).

O

X

i

N N

ii

3

O N

N

2

O N

2

N

NHNH

NHR

XH

N

R

6a-f

7a-f

v

6a, 7a, 8a, 8g: R= -CH C H , X= S; 6b, 7b, 8b, 8h: R= -CH C H , X= O

2

6

5

2

6

5

O

6c, 7c, 8c, 8i: R= -CH CH , X= S; 6d, 7d, 8d, 8j: R= -C H , X= S

2

3

6

5

F

OH

6e, 7e, 8e, 8k: R= -C H , X= O;

6f, 7f, 8f, 8l: R= -C H F(4-), X= S

6

5

6

4

N

R'

N

O N

2

N

X

N

R

- C H

8a-f: R'=

; 8g-l: R'=

5

2

Scheme 2. i: suitable isocyanate or isothiocyanate, ii: KOH, EtOH-H₂O, v: HCHO and norfloxacin (for 8a-f) or ciprofloxacin (for 8g-l).

tohydrazide (3). In order to optimize microwave (MW) irra-

diation conditions, MW was applied at different power val-

ues of 120 and 150 W without any solvent, while the con-

ventional synthesis of compound 3 required ethanol as reac-

tion solvent. The complete conversion of the compound 2 in

best yield was observed after microwave irradiation at 120

W maximum power for 5 min. Higher MW power or longer

reaction time caused to lower yield.

ited mass fragmental and elemental analysis data confirming

the assigned structures. Two different procedures containing

conventional and microwave prompted techniques were ap-

plied for the syntheses. In the conventional heating, the reac-

tion yielding compounds 6a-f was completed in 12-21 h with

59-79 % yield, while reaction time was 12 min with the yield

73-97 %.

The basic treatment of compounds 6a-f yielded the corre-

sponding 1,2,4-triazoles (7a-f), which can be considered as

important tools for further condensation reactions leading to

the formation of new bioactive molecules. The reaction was

carried out in water as a none toxic ecofriendly solvent under

reflux and also microwave conditions. With the use of MW,

higher yield was assessed, however, the important effect of

MW irradiation was on reaction time. Microwave irradiation

decreased the reaction time from 7-13 h to 14 min and in-

creased the yields from 73-87 % to 81-95%. The optimum

reaction condition was assessed at 150 Watt maximum

Compound 3 produced 5-{[4-(4-nitrophenyl)piperazin-1-

yl]methyl}-1,3,4-oxadiazole-2-thiol (4) on the treatment with

CS₂in basic media. The ¹³C NMR observations reveal the

appearance 1,3,4-oxadiazole C-2 and C-5 carbons at the re-

gion 161.05 ppm and 178.51 ppm confirming the formation

of 1,3,4-oxadiazole. On the other hand, carbo(thio)amides

(6a-f), which were obtained from the reaction of 3 with alky-

liso(thio)cyanates, were confirmed by the presence of addi-

tional signals at the related chemical shift values originated

from alkyliso(thio)cyanate moiety. These compounds exhib-

56 Letters in Drug Design & Discovery, 2018, Vol. 15, No. 1

Mentese et al.

Table 1. Optimization of the model reaction conditions for compound 8a under MW conditions.

Entry

Solvent

MW (Watt)

Time (min)

Yield (%)

1

2

EtOH

100

80

10

12

14

15

12

14

63

65

62

84

87

94

74

78

79

EtOH-H₂O (2:1)

3

H₂O

DMF

-

4

5

6

7

-

75

8

MeCN

THF

DCM

100

9

10

power. The FT IR spectra of compounds 7a-f have -SH or -

NH stretching bands at 2821-2850 cm^-1and C=O stretching

band at 1676-1689 of 1,2,4-triazole nucleus. In the ¹H NMR

spectra, resonances assigned to the -SH or NH protons on

1,2,4-triazole ring were detected at 13.60-13.90 ppm (SH)

and 9.62-11.75 ppm (NH), respectively which are supported

by the literature findings [32-38]. ¹³C NMR spectra of these

compounds have resonances of triazole C-5 and C-3 at

155.05-157.15 ppm and 158.23-181.34 ppm, respectively.

analysis data (carbon, hydrogen and nitrogen) were 0.4% of

the theoretical values.

3.2. Biological Activity

3.2.1. Antimicrobial Activity

All the compounds were tested for their antimicrobial

activities and the results were presented in Table 2. This re-

veals that the newly synthesized compounds, exhibited good

to slight activities against some of the test microorganisms

with the mic values varying between <0.03-250 μg/mL. All

the newly synthesized compounds except 6a-f exhibited ac-

tivity on Mycobacterium smegmatis (Ms), a nonpigmented

rapidly growing mycobacterium leading to mortality with the

mic values varying between 0.03-62.50 µg/mL. In fact, the

activity on Ms of 5a,b and 8a-l was better than standard drug

streptomycin with mic 4 µg/mL It is evident from Table 2

that the aminoalkylation of triazoles 7a-f and oxadiazole, 4

with fluoroquinolones namely norfloxacin and ciprofloxacin

caused to excellent activity towards the test bacteria with the

mic values between <0.03-0.99 μg/mL. It can be concluded

that the good activity of these compounds is due to the pres-

ence of fluoroquinolone core in their structures. In fact, the

mic values of compounds 5a,b and 8a-l are the same or very

close to mic values of norfloxacin and ciprofloxacin.

The one-pot, three-component Mannich type reaction of

compounds 4 and 7a-f with norfloxacin and ciprofloxacin

yielded the corresponding fluoroquinolone-azole hybrids

(5a, b and 8a-l). This reaction proceeds via the formation of

immonium salt which subsequently attacks the N-1 of tria-

zole or oxadiazole N-3 giving rise to the corresponding

Mannich bases. In the preliminary experiment, to optimize

the conditions for this condensation, the synthesis of com-

pound 8a was selected as model reaction and some reaction

parameters including time and MW power were screened on

the model reaction (Table 1). With the aim to provide further

improvement for this synthetic approach, the model reaction

was also performed in the presence of different organic sol-

vents such as acetonitrile, EtOH, EtOH-H₂O, H₂O, THF,

MeCN and DMF, however, the best result was assessed in

solvent free media and the corresponding product was ob-

tained in nearly quantitative yields within 15 min (Table 1,

entry 6) in model reaction under microwave irradiation. In

comparison with the long refluxing time in hazardous sol-

vent, microwave irradiation provided more efficient and

green way for one pot Mannich type condensation with rela-

tively higher product yield. The number of signals and their

chemical shifts are in accordance with the assigned struc-

3.2.2. Antioxidant Activity

To determine antioxidant capacity (AC, µmol TE/g)

value of the newly synthesized compounds, DPPH, FRAP

and CUPRAC assays were assayed. The AC values of the

compounds are given in Table 3 and their statisticall process-

ing (one-way ANOVA) indicated that AC values signifi-

cantly (P<0.05) differed with in and among measured tests.

Compound 8j (134.32µmol TE/g), followed 8d and 8c for

DPPH, which are fluoroquinolone-triazole-piperazine hybrids,

6c (1595.4µmol TE/g), followed 6d (784.61µmol TE/g) and

6e (505.17µmol TE/g), which are carbothioamides, for FRAP

and 8c (940.20µmol TE/g) followed 8j (582.38µmol TE/g)

and 8d (442.36µmol TE/g) for CUPRAC had the highest AC

values, while compounds 7b (2.94 and 201.62µmol TE/g)

1

tures for compounds 8a-l. In the H and ¹³C NMR spectra,

additional signals corresponding tonorfloxacin or ciproflox-

acin were recorded at the related chemical shift values, while

the spectra of these compounds showed the disappearance of

the characteristic bands of triazole (or oxadiazole)-NH or

SH. Moreover, the preparation of Mannich bases (8a-l) was

verified by registration of their mass spectrums which were

in accordance with their molecular masses and the elemental

Novel Azole-Functionalited Flouroquinolone Hybrids

Table 2. Screening for their antimicrobial activity of the newly synthesized 29 compounds.

Microorganizms and Minimal Inhibition Concentrations(μg/mL)

Letters in Drug Design & Discovery, 2018, Vol. 15, No. 1 57

Compound No.

Ec

Pa

Yp

Sa

Ef

Bc

Ms

O

O₂N

N

250

35

OEt

2

O

N

O₂N

NHNH₂

N

250

35

3

N

O₂N

N

62.5

SH

O

4

O

N

O

F

OH

N

0,25

<0,25

0,25

<0,25

1.0

N

O₂N

N

S

O

5a

O

F

OH

N

0.03

N

O₂N

N

S

5b

O

S

O₂N

N

NHNH

N

H

-

125

-

250

-

125

250

-

6a

O

O₂N

N

NHNH

O

N

H

6b

S

O₂N

N

NHNH

N

250

-

125

250

-

125

-

H

6c

O

S

N

NHNH

N

250

H

6d

O

O₂N

N

NHNH

S

N

250

-

250

125

-

H

6e

F

O

O₂N

N

250

125

NHNH

N

H

6f

(Table 2) contd….

58 Letters in Drug Design & Discovery, 2018, Vol. 15, No. 1

Mentese et al.

Microorganizms and Minimal Inhibition Concentrations(μg/mL)

Compound No.

Ec

Pa

Yp

Sa

Ef

Bc

Ms

N N

O₂N

N

SH

O

N

250

62.5

7a

N NH

N

O₂N

N

-

250

-

125

250

125

-

250

-

250

-

62.5

35

7b

N N

N

O₂N

N

SH

7c

N N

N

SH

62.5

7d

N NH

N

O₂N

N

O

125

250

125

250

35

7e

N N

N

SH

N

62.5

7f

F

O

N

O

F

OH

N

0.03

0.48

0.06

0.24

0.488

0.48

0.244

N

O₂N

N

S

N

8a

O

N

O

F

OH

N

0,99

0,50

0,25

0,50

0,25

0,99

N

O₂N

N

O

N

8b

(Table 2) contd….

Novel Azole-Functionalited Flouroquinolone Hybrids

Letters in Drug Design & Discovery, 2018, Vol. 15, No. 1 59

Microorganizms and Minimal Inhibition Concentrations(μg/mL)

Compound No.

Ec

Pa

Yp

Sa

Ef

Bc

Ms

O

N

O

F

OH

N

0,99

0,50

0,25

0,99

0.122

0,25

0.244

N

O₂N

N

S

N

8c

O

N

O

F

OH

N

0.03

0.24

0.06

0.48

0.122

0.24

0.244

N

O₂N

N

S

N

8d

O

N

O

F

OH

N

0.12

0.48

0,25

0.48

0.122

0,25

0.25

N

O₂N

N

O

N

8e

O

F

OH

N

0.12

0.48

0.24

0.48

0.25

0.24

0.244

O₂N

N

S

N

8f

F

O

F

OH

N

<0.03

0.06

<0.03

0.12

0.122

0.12

0.244

N

O₂N

N

S

N

8g

O

N

O

F

OH

N

<0.03

0.24

<0.03

0.24

0.48

0.24

0.244

N

O₂N

N

O

N

8h

(Table 2) contd….

60 Letters in Drug Design & Discovery, 2018, Vol. 15, No. 1

Mentese et al.

Microorganizms and Minimal Inhibition Concentrations(μg/mL)

Compound No.

Ec

Pa

Yp

Sa

Ef

Bc

Ms

O

F

OH

N

0.25

0.122

0.244

N

O₂N

N

S

N

8i

O

N

O

F

OH

N

<0.03

0.03

0.06

0.24

0.25

0.12

0.25

N

O₂N

N

S

8j

O

N

O

F

OH

N

<0.03

0.24

0.03

0.24

0.122

0.03

0.244

N

O₂N

N

O

N

8k

O

N

O

F

OH

N

<0.03

0.24

0.12

0.48

0.122

0.12

0.244

O₂N

N

S

N

8l

F

Cip.

<0.03

<0.041

10

<0.03

<0.041

18

<0.03

<0.041

>128

-

0.122

<0.041

35

0.122

<0.041

10

0.06

<0.041

15

-

Norf.

Amp.

Strep.

-

4

Ec: Escherichia coli ATCC 25922, Pa; Pseudomonas aeruginosa ATCC 43288, Yp; Yersinia pseudotuberculosis ATCC 911, Sa; Staphylococcus aureus ATCC 25923, Ef; Enterococ-

cus faecalis ATCC 29212, Bc; Bacillus cereus 702 Roma, Ms; M. smegmatis ATCC607, Cip.; Ciprofloxacin, Norf.; Norfloxacin Amp.; Ampicillin, Strep.; Streptomycin, (—); no activity.

for DPPH and CUPRAC and 2 (37.95µmol TE/g) for FRAP

had the lowest AC values among the synthesized compounds

(Table 3). In the table, for the compounds 6a, 7a and 7d, no

AC value for FRAP and CUPRAC was determined (Table 3).

positive scoreson PC1 explained 48.75% of the total varia-

tion (79.78%). Respectively, compounds 6c, 6d, 8a, 8e and

8f at the right upper plan and compounds 5a, 5b, 8b, 8c, 8d,

8j and 8g at the right lower plan were low associated and

correlated with FRAP, CUPRAC and DPPH ranging from

0.097 to 0.387 (Fig. (2) at the left upper plan). The remain-

ing compounds 6b, 6e, 6f, 7b, 8h, 8i, 8k and 8l at the left

PCA was carried out by treating data obtained from the

three different antioxidant capacity tests. This separation was

mainly across PC1, with FRAP, CUPRAC and DPPH having

Novel Azole-Functionalited Flouroquinolone Hybrids

Letters in Drug Design & Discovery, 2018, Vol. 15, No. 1 61

Table 3. Antioxidant capacity (AC) values of 29 synthesized novel compounds. Values represent the mean SD of three determi-

nations.

Compd.

No.

DPPH

FRAP

CUPRAC

(μmol TE/g)

2

9.48 0.20^b

7.87 0.29^a

37.95 2.55^a

82.61 3.63^c

91.34 4.52^ab

182.70 11.90^e

258.46 3.15^d

n.d.**

269.50 1.68^c

221.62 2.54^a

215.44 6.51^a

329.15 11.35^g

382.34 12.42^h

n.d.**

3

4

3.94 0.18^a

5a

5b

6a

6b

6c

6d

6e

6f

56.49 2.32^h

64.32 5.08^j

64.33 0.05^g

26.09 0.33^c

63.56 0.00^g

64.18 0.01^g

44.98 0.32^d

35.63 0.28^d

61.60 0.03^fg

2.94 0.29^a

283.65 35.42^ef

1595.4 67.49^ı

784.61 34.46^h

505.17 42.45^g

408.22 36.49^g

n.d.**

254.30 4.47^c

287.32 7.95^d

309.77 8.79^e

261.91 16.99^c

289.74 13.43^c

n.d.**

7a

7b

7c

7d

7e

7f

71.61 4.63^ab

116.70 4.92^bc

n.d**.

201.62 7.54^a

299.20 6.76^de

n.d.**

59.28 0.22^f

54.97 0.05^e

53.46 0.15^e

36.32 0.19^f

42.66 4.33^d

62.29 1.30^h

73.26 3.60^h

120.82 2.32^ı

82.47 2.09^e

69.63 3.04^d

70.45 0.30^h

61.59 2.76^ı

60.28 2.42^h

134.32 5.98^j

53.75 2.21^h

59.66 4.87^d

38.76 2.74^a

125.36 3.88^bc

325.64 19.21^f

118.84 3.78^c

245.23 21.97^de

272.82 21.90^e

137.64 18.53^c

225.19 15.20^e

126.45 4.80^c

172.24 14.98^e

218.46 4.43^c

204.96 4.17^d

235.32 18.86^e

195.90 12.39^f

221.33 6.39^b

278.20 4.65^de

424.08 4.89^f

337.56 12.17^e

940.20 12.42^ı

442.36 12.75^g

347.10 11.18^f

332.54 6.79^ı

315.32 12.40^e

312.47 10.57^g

268.46 11.67^e

582.38 16.33^h

744.75 11.89^ı

284.19 5.67^f

8a

8b

8c

8d

8e

8f

8g

8h

8i

8j

8k

8l

An analysis of variance (SPSS version 11.5. one-way ANOVA) was used for comparisons among the means. Values with the same letter at superscript within a column are not

significantly different at P<0.05. * Not detected.

upper and 6a, 7a, 7c, 7d, 7e, 7f, 4, 3 and 2 at the left lower

plan located on PC2 with negative loadings, accounting

31.04% of the variance, were not associate and correlate with

any measuring tests (Fig. 2).

3.2.2.1. Statistical Analysis

Triplicate measurements (n = 3) were performed during

the measurements of antioxidant capacity (AC) of the com-

pounds. The AC values were presented as mean pooled

62 Letters in Drug Design & Discovery, 2018, Vol. 15, No. 1

Mentese et al.

ꢔꢕꢖꢗꢘꢙꢈꢉꢚꢛꢜ ꢈꢁꢆ!ꢈꢒ"ꢌꢒꢑꢈꢏꢐ

ꢅ

ꢁꢆ

ꢄ

ꢁ

ꢂ

ꢃ

ꢊꢋꢋꢌ ꢍ ꢎꢏꢐꢋꢑ r ꢒꢓꢔꢕꢔꢖ

ꢊꢋꢋꢌꢓꢍ ꢎꢏꢐꢋꢑꢓr ꢒꢓꢔꢕꢗꢇ

ꢃꢄꢅꢁ

ꢁ8

ꢂ8

ꢁꢄ

ꢁꢃ

ꢃ8

ꢁꢅ

ꢃ

ꢇꢂ

ꢅ

ꢀ

ꢄ

ꢆ

ꢂ

ꢁꢂ

ꢇꢉ

ꢆ ꢁꢄꢅꢆ

Rꢃ8

ꢇꢄ

ꢇꢆ

Rꢂ

Rꢂ8

Rꢁ

ꢀꢁꢁꢂ

ꢇꢈ

Rꢄ Rꢁ8

Rꢁ Rꢂ8

Rꢂ Rꢃ8

ꢃ

ꢃ8

ꢂ

ꢂ8

ꢁ

ꢁ8

ꢄ

ꢄ8

ꢃꢋꢈꢉꢎꢑꢌꢒꢓꢈꢏꢐ

Fig. (2). Loading bi-plot of principle component analysis (PCA) of 29 synthesized novel compounds contributing to values obtained from

three antioxidant capacity assays measured by FRAP, CUPRAC and DPPH.

standard deviation (mean SD). For statistical evaluation,

one-way ANOVA and Duncan’s multiple range test for

comparison among the means at significance level of P <

0.05 (IBM SPSS Statistics V22.0) were employed. A statisti-

cal software package (XLSTAT version 2015.6) using

ADDINSOFT (Damremont, Paris, France) was also employed

to perform principal component analysis (PCA).

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or

otherwise.

ACKNOWLEDGEMENTS

The support provided by Scientific and Technological

Research Council of Turkey (TUBITAK, Project no: 113Z181)

and Karadeniz Technical University, BAP, Turkey (Ref. No.

8623) is greatly appreciated.

CONCLUSION

This study reports the conventional and successfully de-

veloped microwave assisted synthesis of some new Norflox-

acin and Ciprofloxacin derivatives incorporating several

other heterocyclic moieties namely 1,3,4-oxadiazole, 1,2,4-

triazole and piperazine. Hence, we combined all these poten-

tial chemotherapeutic units by Mannich reaction, a one pot

three component condensation. The structures of new com-

pounds were confirmed by IR, ¹H-, ¹³C NMR, mass spectro-

scopic and elemental analysis techniques. In addition, the

newly synthesized compounds were screened for their antim-

icrobial and antioxidant activities. The antimicrobial screen-

ing suggests that among the newly synthesized compounds,

the ones containing fluoroquinolone moiety in their struc-

tures exhibited excellent activities against most of the test

microorganisms. Among the synthesized compounds, the

fluoroquinolone derivatives 8j, 8d and 8c displayed antioxi-

dant activity for DPPH, carbo(thio)amides 6c, 6d and 6e for

FRAP and fluoroquinolones 8c, 8j and 8d exhibited antioxi-

dant activity for CUPRAC, while triazole compound 7b for

DPPH and CUPRAC and ester 2 for FRAP had the lowest AC

values. For the synthesis of target compounds, microwave

irradiation was considered more efficient and eco-friendly.

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Article Doi

Novel azole-functionalited flouroquinolone hybrids: Design, conventional and microwave irradiated synthesis, evaluation as antibacterial and antioxidant agents

DOI: 10.2174/1570180814666170823163540

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