DARU Journal of Pharmaceutical Sciences

https://doi.org/10.1007/s40199-018-0226-0

RESEARCH ARTICLE

N-substituted piperazinyl sarafloxacin derivatives: synthesis and in vitro

antibacterial evaluation
Ali Asadipour 1,2 & Mohammad Hassan Moshafi 3 & Leila Khosravani 4 & Setareh Moghimi 4 & Elham Amou 4 &
Loghman Firoozpour 4 & Ghazaleh Ilbeigi 3 & Keivan Beiki 3 & Ehsan Soleimani 3 & Alireza Foroumadi 4,5

Received: 18 July 2018 / Accepted: 23 October 2018

# Springer Nature Switzerland AG 2018

Abstract
Background Fluoroquinolones (FQs) are compounds of major interest with broad antimicrobial activities against community and
hospital-acquired infections such as respiratory tract infections (nosocomial pneumonia, chronic bronchitis and tuberculosis),
skin and soft tissue infections, bone and joint infections, intra-abdominal infections and sexually transmitted diseases. This broad
range of activities along with favorable pharmacokinetic and low toxicity introduced this class of compounds as important
antimicrobial chemotherapy agents. The rapid increase in prevalence of FQs resistant microbes in environment motivated
medicinal chemists to discover new quinolone-based compounds with potent activities against Gram-positive bacteria.
Methods The designed compounds were prepared through the two-component reaction between aromatic α-haloketones or α-
halooximes and sarafloxacin in the presence of NaHCO3 in DMF, affording the corresponding N-[2-(aryl-3-yl) ethyl] piperazinyl
quinolone derivatives in good yields. All synthesized compounds were evaluated for antibacterial activities against Gram-
positive [Staphylococcus aureus ATCC 6538p, Micrococcus luteus, ATCC 1110, Staphylococcus epidermidis ATCC 12228
and Bacillus subtilis ATCC 6633] and Gram-negative [Escherichia coli ATCC 8739, Klebsiella pneumoniae ATCC 10031
Pseudomonas aeruginosa ATCC 9027 and Serratia marcescens PTCC 1111] bacteria.
Results The antibacterial activities of 24 new compounds were reported as MIC values in comparison to sarafloxacin. The most
active compound, 4 g, exhibited similar inhibitory activity against Gram-positive bacteria including S. aureus, S. epidermidis and
B. subtilis compared to positive control. Furthermore, benzyloxime incorporated derivatives (4 s-4x) showed poor activity against
all tested strains, except 4x.
Conclusion The obtained results indicated that the synthesized compounds containing substituted piperazine moiety at the C-7
position displayed same or weak inhibitory activities compared to sarafloxacin.

Keywords Antibacterial activity . Quinolones . Synthesis . Gram-positive bacteria

Introduction
* Alireza Foroumadi
aforoumadi@yahoo.com The fatal infections caused by multiresistant pathogens have
1
become the worldwide concern. In addition, the inappropriate
Department of Medicinal Chemistry, Faculty of Pharmacy, Kerman prescription and misuse of antibiotics which led to the in-
University of Medical Sciences, Kerman, Iran
2
creased rate of hospitalization, illness and death in patients
Environmental Health Engineering Research Center, Kerman have driven infectious disease to global health catastrophic
University of Medical Sciences, Kerman, Iran
3
threat. Therefore, the development of efficient, potent and
Pharmaceutics Research Center, Institute of Neuropharmacology, new compounds would be a highly desirable task [1–4].
Kerman University of Medical Sciences, Kerman, Iran
4
The wide spectrum of activities and compelling chemis-
Drug Design and Development Research Center, The Institute of try of quinolones have made this bicyclic core attractive for
Pharmaceutical Sciences (TIPS), Tehran University of Medical
Sciences, Tehran, Iran researchers. The introduction of fluoroquinolones (FQs) as
5 antibacterial agents in 1960s eradicated the infections
Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran
University of Medical Sciences, Tehran, Iran caused by Gram-negative pathogens. Furthermore, the
 DARU J Pharm Sci

capability of new members to fight against Gram-positive After consumption of sarafloxacin (3), monitored by TLC,
bacteria resulted in successfully introduction of the popular water (20 mL) was added and the precipitate was filtered,
class of antibiotics into the market [5–8]. DNA gyrase, washed with water. For further purification, the products were
topoisomerase IV and bacterial topoisomerase II enzymes recrystallized from CH3OH/CHCl3 to afford target com-
are considered as targets of quinolone derivatives [9–13]. pounds 4a-x.
FQs consist of a 4-quinolone/naphthyridone-3-carboxylic
acid heterocyclic core, a fluorine atom and a secondary 6-Fluoro-1-(4-fluorophenyl)-4-oxo-7-(4-(2-oxo-2-phenylethyl)
amine group attached to the C-6 and -7 positions, respec- piperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid (4a)
tively. The ongoing researches on quinolone and its ana-
logues inaugurated nearly 10,000 analogues with promising Off-white powder, 1H-NMR (500 MHz, DMSO-d6) δ (ppm):
antibacterial activities, opening up new horizons in the field 2.65 (bs, 4H, piperazine), 3.07 (bs, 4H, piperazine), 3.37 (s,
of antibacterial chemotherapy [14, 15]. The C-7 position 2H), 6.39 (d, 4JH-F = 7.5 Hz, 1H, aromatic), 7.30–7.33 (m, 3H,
was subjected to various changes with hopes to find more aromatic), 7.52–7.58 (m, 3H, aromatic), 7.78–7.79 (m, 3H,
potent and effective agents. Based on the previous exten- aromatic), 7.98 (d, 3JH-F = 13 Hz, 1H, aromatic), 8.64 (s, 1H,
sive research in this field, the basic character of this posi- aromatic), 11.35 (s, 1H, COOH).. IR (KBr cm−1), ṽ = 3580–
tion is significantly related to the observed activity against 3300 (OH), 1722, 1672, 1622 (C=O). Anal. Calcd. For
DNA gyrase [16]. The lipophilicity of fluoroquinolones C28H23F2N3O4: C: 66.79; H: 4.60; N: 8.35; Found: C:
plays an important role in the penetration of these com- 66.50; H: 4.82; N: 8.15.
pounds into bacterial cells, indicating that increasing the
lipophilic character at C-7 position may increase their ac- 6-Fluoro-1-(4-fluorophenyl)-7-(4-(2-(4-fluorophenyl)
tivity. In this regard, the presence of a bulky group at the -2-oxoethyl)piperazin-1-yl)
N-4 position of piperazine is permitted. Therefore, different -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (4b)
derivatives containing 2-oxoethyl or 2-oximinoethyl deriva-
tive attached to the piperazine ring at C-7 position were Off-white powder, 1H-NMR (500 MHz, DMSO-d6) δ (ppm):
synthesized [13]. In addition, the attachment of thiophene 2.63–2.67 (m, 4H, piperazine), 3.05–3.10 (m, 4H, piperazine),
[17, 18], furan [19], substituted phenyl [20] and coumarin 3.86 (s, 2H), 6.39 (d, 3JH-F = 7.5 Hz, 1H, aromatic), 7.32 (t,
[21, 22] to piperazine ring was also investigated by our J = 9 Hz, 2H, aromatic), 7.52 (t, J = 8.5 Hz, 2H, aromatic),
research team. In continuation of our expertise in this field 7.76–7.79 (m, 2H, aromatic), 7.97 (d, J = 13 Hz, 1H, aromat-
[23–25], we report some novel analogues of sarafloxacin 3, ic), 8.05–8.08 (m, 2H, aromatic), 8.62 (s, 1H, aromatic), 11.21
possessing α-haloketones- (1a-f), hydroxyimino- (2 g-l), (s, 1H, COOH). IR (KBr cm−1), ṽ = 3580–3300 (OH), 1716,
methoxyimino- (2 m-r) and benzyloxyimino (2 s-x)-func- 1661, 1618 (C=O). 13C-NMR (125 MHz, DMSO-d6) δ
tionalized piperazine as C-7 substituents and evaluate their (ppm): 49.0, 52.0 (CH2 piperazine), 63.4 (CH2), 106.4,
antibacterial activity against Gram-positive and Gram- 107.2, 111.0 (d, 3 J C-F = 23.75 Hz), 115.5 (d, 3 J C-F =
negative bacteria. 21.25 Hz), 117.2 (d, 3JC-F = 22.5 Hz), 119.0, 121.3, 129.8
(d, 1JC-F = 7.5 Hz), 131.2 (d, 1JC-F = 8.75 Hz), 132.4, 136.1,
139.1, 145.2, 148.6, 152.0, 154.0, 165.7 (COOH), 176.6
Methods (C=O), 195.4. Anal. Calcd. For C28H22F3N3O4: C: 64.49; H:
4.25; N: 8.06; C: 64.72; H: 4.47; N: 7.85.
Materials
7-(4-(2-(4-Chlorophenyl)-2-oxoethyl)piperazin-1-yl)
All chemicals and solvents were obtained from Merck and -6-fluoro-1-(4-fluorophenyl)
Aldrich and used without further purification. Melting points -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (4c)
were determined on a Kofler hot stage apparatus and are uncor-
rected. Shimadzu 470 spectrophotometer (potassium bromide Off-white powder, 1H-NMR (500 MHz, DMSO-d6) δ (ppm):
disks) was used to record the IR spectra. 1H- and 13C-NMR 2.63–2.68 (m, 4H, piperazine), 3.06–3.12 (m, 4H, piperazine),
spectra were recorded on Bruker FT-500 (Germany), using 3.86 (s, 2H), 6.39 (d, 4JH-F = 7.5 Hz, 1H, aromatic), 7.52 (t,
TMS as an internal standard. Elemental analyses were mea- J = 8 Hz, 2H, aromatic), 7.57 (d, J = 8.5 Hz, 2H, aromatic),
sured by CHN-O-rapid elemental analyzer (GmbH-Germany). 7.76–7.79 (m, 2H, aromatic), 7.96–8.02 (m, 3H, aromatic),
8.62 (s, 1H, aromatic), 10.20 (s, 1H, COOH). IR (KBr
General procedure for the synthesis of compounds 4a-x A cm−1), ṽ = 3590–3300 (OH), 1725, 1679, 1619 (C=O). 13C-
mixture of compounds (1a-f) or (2 g-x) (0.55 mmol), NMR (125 MHz, DMSO-d6) δ (ppm): 48.9, 51.9 (CH2 piper-
sarafloxacin (3) (0.5 mmol) and NaHCO3 (0.5 mmol) in azine), 63.3 (CH2), 106.3, 107.0, 111.0 (d, 3JC-F = 22.5 Hz),
DMF (5 mL) was stirred at room temperature for 3–7 days. 117.1 (d, 3JC-F = 22.5 Hz), 119.0, 128.5, 129.7, 129.9 (d, 1JC-
DARU J Pharm Sci

3
F = 7.5Hz), 130.0, 134.1, 136.1, 138.0, 139.1, 145.2, 149.3, F = 22.5 Hz), 117.2 (d, JC-F = 22.5 Hz), 119.0, 127.4, 129.8
1
153.7, 165.6 (COOH), 178.1 (C=O), 196.6. Anal. Calcd. For (d, JC-F = 7.5 Hz), 130.7, 131.0, 136.1, 139.1, 139.8, 146.0,
C28H22ClF2N3O4: C: 62.52; H: 4.12; N: 7.81; C: 62.80; H: 148.7, 154.0, 161.2, 162.2, 165.8 (COOH), 177.3 (C=O),
4.39; N: 7.59. 196.6. Anal. Calcd. For C28H21Cl2F2N3O4: C: 58.75; H:
3.70; N: 7.34; C: 59.00; H: 3.47; N: 7.64.
7-(4-(2-(4-Bromophenyl)-2-oxoethyl)piperazin-1-yl)
-6-fluoro-1-(4-fluorophenyl) 6-Fluoro-1-(4-fluorophenyl)-7-(4-(2-(hydroxyimino)
-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (4d) -2-phenylethyl)piperazin-1-yl)
-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (4 g)
Off-white powder, 1H-NMR (500 MHz, DMSO-d6 ) δ
(ppm): 2.30–2.35 (m, 4H, piperazine), 3.01–3.07 (m, 4H, Off-white powder, 1H-NMR (500 MHz, DMSO-d6) δ (ppm):
piperazine), 3.30 (s, 2H), 6.39 (d, 4JH-F = 6 Hz, 1H, aromat- 2.98 (bs, 8H, piperazine), 3.65 (s, 2H), 6.37 (s, 1H, aromatic),
ic), 7.53–7.54 (m, 2H, aromatic), 7.74–7.79 (m, 3H, aromat- 7.34–7.40 (m, 3H, aromatic), 7.51–7.58 (m, 3H, aromatic),
ic), 7.83 (s, 1H, aromatic), 7.88–7.93 (m, 2H, aromatic), 7.75–7.80 (m, 3H, aromatic), 7.95 (d, 3JH-F = 13 Hz, 1H, aro-
8.01–8.03 (m, 1H, aromatic), 8.64 (s, 1H, aromatic), 10.66 matic), 8.62 (s, 1H, aromatic), 10.96 (s, 1H, NOH), 11.44 (s,
(s, 1H, COOH). IR (KBr cm−1), ṽ = 3580–3300 (OH), 1722, 1H, COOH). IR (KBr cm−1), ṽ = 3580–3300 (OH), 1718,
1666, 1621 (C=O). 13C-NMR (125 MHz, DMSO-d6) δ 1618 (C=O). 13C-NMR (125 MHz, DMSO-d6) δ (ppm):
(ppm): 49.1, 52.0 (CH2 piperazine), 63.0 (CH2), 106.5, 49.8, 52.0 (CH2 piperazine), 61.2 (CH2), 106.5, 107.4, 110.9
107.3, 111.0 (d, 1 J C-F = 23.75 Hz), 117.2 (d, 3 J C-F = (d, 3JC-F = 23.75 Hz), 117.2 (d, 3JC-F = 23.75 Hz), 119.0,
22.5 Hz), 119.0, 128.0, 128.6, 129.5, 129.8 (d, 1JC-F = 126.1, 127.7, 128.4 (d, 1JC-F = 7.5 Hz), 129.8, 133.5, 136.1,
7.5 Hz), 133.4, 136.4, 139.4, 146.2, 148.8, 152.5, 154.0, 139.1, 145.1, 148.6, 152.6, 155.0, 161.5 (C=N), 165.7
165.8 (COOH), 176.8 (C=O), 197.3. Anal. Calcd. For (COOH), 176.6 (C=O). Anal. Calcd. For C28H24F2N4O4: C:
C28H22BrF2N3O4: C: 57.74; H: 3.81; N: 7.22; C: 58.00; 64.86; H: 4.67; N: 10.81; C: 65.09; H: 4.40; N: 11.03.
H: 3.54; N: 7.59.
6-Fluoro-1-(4-fluorophenyl)-7-(4-(2-(4-fluorophenyl)
6-Fluoro-1-(4-fluorophenyl)-4-oxo-7-(4-(2-oxo-2-(p-tolyl) -2-(hydroxyimino)ethyl)piperazin-1-yl)
ethyl)piperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (4 h)
(4e)
Off-white powder, 1H-NMR (500 MHz, DMSO-d6) δ (ppm):
Off-white powder, H-NMR (500 MHz, DMSO-d6) δ (ppm):
1
2.97–3.04 (m, 4H, piperazine), 3.17–3.21 (m, 4H, piperazine),
2.39 (s, 3H, CH3), 2.64 (bs, 4H, piperazine), 3.01 (bs, 4H, 3.65 (s, 2H), 6.36 (s, 1H, aromatic), 7.41 (t, 3JH-F = 13 Hz, 1H,
piperazine), 3.84 (s, 2H), 6.39 (d, 4JH-F = 7 Hz, 1H, aromatic), aromatic), 7.51–7.53 (m, 3H, aromatic), 7.64 (d, J = 7.5 Hz,
7.30 (d, J = 8 Hz, 2H, aromatic), 7.50–7.53 (m, 2H, aromatic), 1H, aromatic), 7.76 (s, 3H, aromatic), 7.95 (d, J = 12 Hz, 1H,
7.76 (d, J = 7.5 Hz, 2H, aromatic), 7.87 (t, J = 6.5 Hz, 2H, aromatic), 8.62 (s, 1H, aromatic), 11.14 (s, 1H, NOH), 11.57
aromatic), 7.96 (d, 3JH-F = 12.5 Hz, 1H, aromatic), 8.61 (s, (s, 1H, COOH). IR (KBr cm−1), ṽ = 3585–3300 (OH), 1720,
1H, aromatic), 11.77 (s, 1H, COOH).. IR (KBr cm −1), 1620 (C=O). Anal. Calcd. For C28H23F3N4O4: C: 62.68; H:
ṽ = 3580–3300 (OH), 1716, 1661, 1618 (C=O). Anal. Calcd. 4.32; N: 10.44; C: 62.40; H: 4.05; N: 10.63.
For C29H25F2N3O4: C: 67.30; H: 4.87; N: 8.12; C: 67.55; H:
7.51; N: 8.39. 7-(4-(2-(4-Chlorophenyl)-2-(hydroxyimino)ethyl)
piperazin-1-yl)-6-fluoro-1-(4-fluorophenyl)
7-(4-(2-(2,4-Dichlorophenyl)-2-oxoethyl)piperazin-1-yl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (4i)
-6-fluoro-1-(4-fluorophenyl)
-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (4f) Off-white powder, 1H-NMR (500 MHz, DMSO-d6) δ
(ppm): 2.70–2.79 (m, 4H, piperazine), 3.06–3.11 (m, 4H,
Off-white powder, 1H-NMR (500 MHz, DMSO-d6 ) δ piperazine), 3.87 (s, 2H), 6.42 (d, 4JH-F = 7 Hz, 1H, aro-
(ppm): 2.62 (bs, 4H, piperazine), 3.02 (bs, 4H, piperazine), matic), 7.53 (t, J = 8 Hz, 2H, aromatic), 7.57 (d, J = 8.5 Hz,
3.76 (s, 2H), 6.38 (d, 4JH-F = 7 Hz, 1H, aromatic), 7.54–7.58 1H, aromatic), 7.68 (d, J = 8.5 Hz, 1H, aromatic), 7.73–
(m, 3H, aromatic), 7.72–7.84 (m, 3H, aromatic), 7.96 (d, 7.80 (m, 2H, aromatic), 7.92 (d, 3JH-F = 13 Hz, 1H, aromat-
3
JH-F = 13 Hz, 1H, aromatic), 8.00 (t, J = 7.5 Hz, 1H, aro- ic), 7.97–8.02 (m, 2H, aromatic), 8.63 (s, 1H, aromatic),
matic), 8.63 (s, 1H, aromatic), 12.10 (s, 1H, COOH).. IR 11.14 (s, 1H, NOH), 11.57 (s, 1H, COOH). IR (KBr
(KBr cm−1), ṽ = 3585–3300 (OH), 1720, 1680, 1620 (C=O). cm−1), ṽ = 3600–3300 (OH), 1719, 1620 (C=O). 13C-
13
C-NMR (125 MHz, DMSO-d6) δ (ppm): 48.9, 51.8 (CH2 NMR (125 MHz, DMSO-d6) δ (ppm): 49.7, 51.9 (CH2
piperazine), 65.8 (CH2), 104.3, 106.6, 107.8, 111.0 (d, 3JC- piperazine), 61.0 (CH2), 106.5, 107.3, 111.0 (d, 3JC-F =
 DARU J Pharm Sci

23.75 Hz), 117.2 (d, 3JC-F = 22.5 Hz),127.7, 128.0, 129.8 1H, aromatic), 7.70–7.77 (m, 2H, aromatic), 7.96 (d, 3JH-
(d, 1JC-F = 10 Hz), 130.4, 133.1, 134.7, 136.1, 139.1, 145.1, F = 13 Hz, 1H, aromatic), 8.63 (s, 1H, aromatic), 11.15 (s,
148.6, 151.9, 155.0, 161.6 (C=N), 165.7 (COOH), 176.6 1H, NOH), 11.48 (s, 1H, COOH). IR (KBr cm −1 ),
(C=O). Anal. Calcd. For C28H23ClF2N4O4: C: 60.82; H: ṽ = 3580–3300 (OH), 1716, 1618 (C=O). 13 C-NMR
4.19; N: 10.13; C: 60.63; H: 3.89; N: 10.40. (125 MHz, DMSO-d6) 훅 (ppm): 49.0, 52.1 (CH2 pipera-
zine), 61.0 (CH2), 106.5, 107.3, 111.4 (d, 3JC-F = 22.5 Hz),
7-(4-(2-(4-Bromophenyl)-2-(hydroxyimino)ethyl) 117.3 (d, 3JC-F = 22.5 Hz), 119.0, 127.1, 128.6, 128.2,
piperazin-1-yl)-6-fluoro-1-(4-fluorophenyl) 129.8 (d, 1JC-F = 7.5 Hz), 131.2, 133.4, 136.1, 139.1 (2C),
-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (4j) 146.1, 148.7, 152.0, 154.0, 161.5 (C=N), 165.7 (COOH),
176.6 (C=O). Anal. Calcd. For C28H22Cl2F2N4O4: C:
Off-white powder, 1H-NMR (500 MHz, DMSO-d6) δ (ppm): 57.25; H: 3.78; N: 9.54; C: 57.00; H: 3.98; N: 9.21.
2.98–3.05 (m, 4H, piperazine), 3.17–3.22 (m, 4H, piperazine),
3.69 (s, 2H), 6.36 (d, 4JH-F = 7 Hz, 1H, aromatic), 7.55–7.56
(m, 2H, aromatic), 7.96–7.74 (m, 3H, aromatic), 7.58 (s, 1H, 6-Fluoro-1-(4-fluorophenyl)-7-(4-(2-(methoxyimino)
aromatic), 7.90–7.95 (m, 2H, aromatic), 8.03 (t, J = 7 Hz, 1H, -2-phenylethyl)piperazin-1-yl)
aromatic), 8.63 (s, 1H, aromatic), 11.19 (s, 1H, NOH), 11.60 -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (4 m)
(s, 1H, COOH). IR (KBr cm−1), ṽ = 3590–3300 (OH), 1725,
1619 (C=O). 13C-NMR (125 MHz, DMSO-d6) δ (ppm): 49.0, Off-white powder, 1H-NMR (500 MHz, DMSO-d6) δ
52.2 (CH2 piperazine), 61.0 (CH2), 106.5, 107.3, 111.0, 117.2 (ppm): 2.90–3.00 (m, 8H, piperazine), 3.64 (s, 2H), 3.90
(d, 3JC-F = 22.5 Hz), 119.0, 122.0, 128.2, 129.8 (d, 1JC-F = (s, 3H, NOCH3), 6.35 (d, 4JH-F = 7 Hz, 1H, aromatic),
7.5 Hz), 130.6, 131.0, 136.1, 139.1, 145.1, 148.6, 152.0, 7.36–7.39 (s, 3H, aromatic), 7.50 (t, J = 8.5 Hz, 2H, aro-
155.1, 161.2 (C=N), 165.7 (COOH), 176.6 (C=O). Anal. matic), 7.73–7.75 (m, 4H, aromatic), 7.96 (d, 3JH-F =
Calcd. For C28H23BrF2N4O4: C: 56.29; H: 3.88; N: 9.38; C: 13.5 Hz, 1H, aromatic), 8.62 (s, 1H, aromatic), 15.14 (s,
56.03; H: 3.59; N: 9.54. 1H, COOH). IR (KBr cm−1), ṽ = 3625–3250 (OH), 1724,
1623 (C=O). 13C-NMR (125 MHz, DMSO-d6) δ (ppm):
6-Fluoro-1-(4-fluorophenyl)-7-(4-(2-(hydroxyimino)-2-(p-tolyl) 49.0, 50.4 (CH2 piperazine), 52.2 (CH2), 61.7 (OCH3),
ethyl)piperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic 106.2, 107.1, 111.1 (d, 3JC-F = 23.75 Hz), 117.2 (d, 3JC-
1
acid (4 k) F = 23.75 Hz), 118.0, 126.5, 128.1, 129.0, 129.8 (d, JC-
F = 8.75 Hz), 134.8, 136.1, 139.1, 146.0, 146.8, 152.0,
Off-white powder, 1H-NMR (500 MHz, DMSO-d6) δ (ppm): 153.9, 163.7 (C=N), 165.8 (COOH), 176.8 (C=O). Anal.
2.23 (s, 3H), 2.92–3.09 (m, 8H, piperazine), 3.61 (s, 2H), 6.36 Calcd. For C29H26Cl2F2N4O4: C: 65.41; H: 4.92; N: 10.52;
(d, 4JH-F = 7.5 Hz, 1H, aromatic), 7.32 (d, J = 8 Hz, 2H, aro- C: 65.19; H: 5.11; N: 10.80.
matic), 7.53–7.65 (m, 2H, aromatic), 7.78 (d, J = 7.5 Hz, 2H,
aromatic), 7.89 (t, J = 7.5 Hz, 2H, aromatic), 7.96 (d, 3JH-F =
13 Hz, 1H, aromatic), 8.64 (s, 1H, aromatic), 11.12 (s, 1H, 6-Fluoro-1-(4-fluorophenyl)-7-(4-(2-(4-fluorophenyl)
NOH), 11.40 (s, 1H, COOH). IR (KBr cm−1), ṽ = 3590–3300 -2-(methoxyimino)ethyl)piperazin-1-yl)
(OH), 1719, 1618 (C=O). 13C-NMR (125 MHz, DMSO-d6) δ -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (4n)
(ppm): 20.8 (CH3), 47.0, 49.0 (CH2 piperazine), 52.4 (CH2),
106.5, 107.4, 111.0 (d, 3JC-F = 23.75 Hz), 117.3 (d, 3JC-F = Off-white powder, 1H-NMR (500 MHz, DMSO-d6) δ (ppm):
22.5 Hz), 119.1, 126.1, 128.8, 129.9 (d, 1JC-F = 7.5 Hz), 2.90–2.99 (m, 8H, piperazine), 3.63 (s, 2H), 3.90 (s, 3H,
131.5, 133.5, 136.1, 139.1, 143.1, 148.8, 150.0, 154.5, NOCH3), 6.35 (d, 4JH-F = 6.5 Hz, 1H, aromatic), 7.19–7.21
161.6 (C=N), 165.7 (COOH), 176.7 (C=O). Anal. Calcd. (m, 2H, aromatic), 7.51–7.53 (m, 2H, aromatic), 7.77–7.79
For C29H26F2N4O4: C: 65.41; H: 4.92; N: 10.52; C: 65.18; (m, 4H, aromatic), 7.96 (d, 3JH-F = 12.5 Hz, 1H, aromatic),
H: 5.19; N: 10.82. 8.62 (s, 1H, aromatic), 15.10 (s, 1H, COOH). IR (KBr
cm−1), ṽ = 3600–3250 (OH), 1713, 1619 (C=O). 13C-NMR
7-(4-(2-(2,4-Dichlorophenyl)-2-(hydroxyimino)ethyl) (125 MHz, DMSO-d6) δ (ppm): 49.0, 50.4 (CH2 piperazine),
piperazin-1-yl)-6-fluoro-1-(4-fluorophenyl) 52.1 (CH2), 61.8 (OCH3), 106.7, 107.7, 111.1 (d, 3JC-F =
-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (4 l) 23.75 Hz), 115.0 (d, 3JC-F = 23.75 Hz), 117.2 (d, 3JC-F =
23.75 Hz), 122.1, 128.8 (d, 1JC-F = 8.75 Hz), 129.8 (d, 1JC-
Off-white powder, 1H-NMR (500 MHz, DMSO-d6) δ F = 8.75 Hz), 131.2, 136.2, 139.4 (2C), 146.0, 148.6, 153.0,
(ppm): 2.98–3.19 (m, 8H, piperazine), 3.65 (s, 2H), 6.37 158.2, 161.8 (C=N), 176.4 (COOH), 179.6 (C=O). Anal.
(s, 1H, aromatic), 7.26 (m, 1H, aromatic), 7.43–7.48 (m, Calcd. For C29H25F3N4O4: C: 63.27; H: 4.58; N: 10.18; C:
1H, aromatic), 7.52 (t, J = 5.5 Hz, 2H, aromatic), 7.63 (s, 63.01; H: 4.84; N: 9.94.
DARU J Pharm Sci

7-(4-(2-(4-Chlorophenyl)-2-(methoxyimino)ethyl) aromatic), 15.11 (s, 1H, COOH). IR (KBr cm − 1 ),

piperazin-1-yl)-6-fluoro-1-(4-fluorophenyl) ṽ = 3590–3300 (OH), 1725, 1619 (C=O). 13 C-NMR
-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (4o) (125 MHz, DMSO-d6) δ (ppm): 48.8, 52.4 (CH2 pipera-
zine), 53.4 (CH2), 61.9 (OCH3), 106.4, 107.3, 111.4 (d,
Off-white powder, 1H-NMR (500 MHz, DMSO-d6) δ (ppm): 3
J C-F = 23.75 Hz), 117.3 (d, 3J C-F = 23.75 Hz), 123.0,
2.87–2.95 (m, 8H, piperazine), 3.60 (s, 2H), 3.90 (s, 3H, 126.9, 128.7, 129.8 (d, 1JC-F = 8.75 Hz), 132.2, 133.3 (2C),
NOCH3), 6.22 (d, 4JH-F = 6.5 Hz, 1H, aromatic), 7.36–7.37 133.7, 136.0, 139.0, 146.0, 148.5, 151.0, 155.8, 163.2
(m, 1H, aromatic), 7.41–7.42 (m, 1H, aromatic), 7.46–7.49 (C=N), 166.1 (COOH), 176.43 (C=O). Anal. Calcd. For
(m, 1H, aromatic), 7.62–7.64 (m, 3H, aromatic), 7.73–7.78 C29H24Cl2F2N4O4: C: 57.91; H: 4.02; N: 9.32; C: 57.78;
(m, 3H, aromatic), 8.08 (s, 1H, aromatic), 15.15 (s, 1H, H: 3.88; N: 9.60.
COOH). IR (KBr cm−1), ṽ = 3585–3300 (OH), 1720, 1620
(C=O). Anal. Calcd. For C29H25ClF2N4O4: C: 61.43; H:
4.44; N: 9.88; C: 61.68; H: 4.21; N: 10.09. 7-(4-(2-((Benzyloxy)imino)-2-phenylethyl)piperazin-1-yl)
-6-fluoro-1-(4-fluorophenyl)
7-(4-(2-(4-Bromophenyl)-2-(methoxyimino)ethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (4 s)
piperazin-1-yl)-6-fluoro-1-(4-fluorophenyl)
-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (4p) Off-white powder, 1H-NMR (500 MHz, DMSO-d6) δ (ppm):
2.93–3.05 (m, 8H, piperazine), 3.67 (s, 2H), 5.18 (s, 2H,
Off-white powder, 1H-NMR (500 MHz, DMSO-d6) δ (ppm): NOCH2), 6.34 (d, 4JH-F = 7 Hz, 1H, aromatic), 7.19 (t, J =
2.83–2.90 (m, 8H, piperazine), 3.63 (s, 2H), 3.95 (s, 3H, 8.5 Hz, 2H, aromatic), 7.31 (d, J = 7 Hz, 1H, aromatic), 7.35–
NOCH3), 6.24 (d, 4JH-F = 6.5 Hz, 1H, aromatic), 7.38–7.39 7.40 (m, 5H, aromatic), 7.51 (t, J = 5.5 Hz, 2H, aromatic),
(m, 2H, aromatic), 7.49–7.55 (m, 3H, aromatic), 7.65 (s, 1H, 7.76–7.78 (m, 4H, aromatic), 7.96 (d, 3JH-F = 13 Hz, 1H, aro-
aromatic), 7.71–7.75 (m, 2H, aromatic), 7.83 (t, J = 6.5 Hz, matic), 8.62 (s, 1H, aromatic), 10.11 (s, 1H, COOH). IR (KBr)
1H, aromatic), 8.60 (s, 1H, aromatic), 15.18 (s, 1H, COOH). cm−1; ν: 3590–3300 (OH), 1719, 1618 (C=O). 13C-NMR
IR (KBr cm−1), ṽ = 3580–3300 (OH), 1716, 1618 (C=O). (125 MHz, DMSO-d6) δ (ppm): 48.9, 50.3 (CH2 piperazine),
Anal. Calcd. For C29H25BrF2N4O4: C: 56.97; H: 4.12; N: 52.1 (CH2), 75.8 (OCH2), 106.4, 107.3, 111.0 (d, 3JC-F =
9.16; C: 57.10; H: 3.95; N: 8.99. 23.5 Hz), 117.2 (d, 3JC-F = 23.75 Hz), 118.0, 122.5, 127.8,
128.1, 128.3, 128.6, 129.1, 129.8 (d, 1JC-F = 7.5 Hz), 131.1,
6-Fluoro-1-(4-fluorophenyl)-7-(4-(2-(methoxyimino) 133.9, 136.1, 137.4, 139.1, 146.0, 148.8, 153.6, 163.0 (C=N),
-2-(p-tolyl)ethyl)piperazin-1-yl) 165.6 (COOH), 177.1 (C=O). Anal. Calcd. For
-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (4q) C35H30F2N4O4: C: 69.07; H: 4.97; N: 9.21; C: 69.30; H:
5.11; N: 9.50.
Off-white powder, 1H-NMR (500 MHz, DMSO-d6) δ (ppm):
2.44 (s, 3H, CH3), 2.86–2.94 (m, 8H, piperazine), 3.60 (s,
2H), 3.91 (s, 3H, NOCH3), 6.31 (d, 4JH-F = 6.5 Hz, 1H, aro- 7-(4-(2-((Benzyloxy)imino)-2-(4-fluorophenyl)ethyl)
matic), 7.34 (d, J = 7.5 Hz, 2H, aromatic), 7.52–7.57 (m, 2H, piperazin-1-yl)-6-fluoro-1-(4-fluorophenyl)
aromatic), 7.78 (d, J = 7 Hz, 2H, aromatic), 7.89 (t, J = 6 Hz, -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (4 t)
2H, aromatic), 7.94 (d, 3JH-F = 12.5 Hz, 1H, aromatic), 8.65
(s, 1H, aromatic), 15.25 (1H, COOH). IR (KBr cm −1), Off-white powder, 1H-NMR (500 MHz, DMSO-d6) δ (ppm):
ṽ = 3580–3300 (OH), 1722, 1622 (C=O). Anal. Calcd. For 2.93–2.99 (m, 8H, piperazine), 3.68 (s, 2H), 5.19 (s, 2H), 5.19
C30H28F2N4O4: C: 65.92; H: 5.16; N: 10.25; C: 66.11; H: (s, 2H, NOCH2), 6.33 (d, 4JH-F = 7 Hz, 1H, aromatic), 7.30–
5.01; N: 10.51. 7.39 (m, 5H, aromatic), 7.50 (t, J = 8 Hz, 2H, aromatic), 7.71–
7.75 (m, 4H, aromatic), 7.94 (d, 3JH-F = 13 Hz, 1H, aromatic),
7-(4-(2-(2,4-Dichlorophenyl)-2-(methoxyimino)ethyl) 8.62 (s, 1H, aromatic), 11.22 (s, 1H, COOH) IR (KBr cm−1),
piperazin-1-yl)-6-fluoro-1-(4-fluorophenyl) ṽ = 3580–3300 (OH), 1718, 1619 (C=O). 13 C-NMR
-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (4r) (125 MHz, DMSO-d6) δ (ppm): 48.9, 50.5 (CH2 piperazine),
52.2 (CH2), 75.7 (OCH2), 106.5, 111.5 (d, 3JC-F = 21.25 Hz),
Off-white powder, 1H-NMR (500 MHz, DMSO-d6 ) δ 115.0 (d, 3JC-F = 21.25 Hz), 117.2 (d, 3JC-F = 23.75 Hz),
(ppm): 2.85–2.91 (m, 8H, piperazine), 3.61 (s, 2H), 3.94 118.0, 127.8, 128.1, 128.7 (d, 1JC-F = 7.5 Hz), 131.2 (d, 1JC-
(s, 3H, NOCH3), 6.30 (d, 4JH-F = 6.5 Hz, 1H, aromatic), F = 6.5 Hz), 131.5, 132.3, 135.0, 136.1, 137.5, 139.5, 145.4,
7.42–7.46 (m, 2H, aromatic), 7.52 (t, J = 8 Hz, 2H, aromat- 148.7, 153.5, 154.0, 159.3, 163.9 (C=N), 166.5 (COOH),
ic), 7.63 (s, 1H, aromatic), 7.73–7.75 (m, 2H, aromatic), 177.1 (C=O). Anal. Calcd. For C35H29F3N4O4: C: 67.09; H:
7.94 (d, 3 JH-F = 12.5 Hz, 1H, aromatic), 8.61 (s, 1H, 4.66; N: 8.94; C: 67.25; H: 4.80; N: 9.11.
 DARU J Pharm Sci

7-(4-(2-((Benzyloxy)imino)-2-(4-chlorophenyl)ethyl) 129.8 (d, 1JC-F = 8.75 Hz), 132.2,136.3, 137.8, 138.6, 140.5,
piperazin-1-yl)-6-fluoro-1-(4-fluorophenyl) 145.5, 148.9, 151.2, 154.9, 163.0 (COOH), 169.0 (C=N),
-4-oxo-1,ν4-dihydroquinoline-3-carboxylic acid (4u) 173.0 (C=O). Anal. Calcd. For C36H32F2N4O4: C: 69.44; H:
5.18; N: 9.00; C: 69.62; H: 5.41; N: 9.22.
Off-white powder, 1H-NMR (500 MHz, DMSO-d6) δ (ppm):
2.84–2.90 (m, 4H, piperazine), 2.92–3.00 (m, 4H, piperazine),
7-(4-(2-((Benzyloxy)imino)-2-(2,4-dichlorophenyl)ethyl)
3.68 (s, 2H), 5.23 (s, 2H, NOCH2), 6.33 (d, 4JH-F = 7 Hz, 1H,
piperazin-1-yl)-6-fluoro-1-(4-fluorophenyl)
aromatic), 7.31 (d, J = 8 Hz, 2H, aromatic), 7.36–7.42 (m, 4H,
-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (4x)
aromatic), 7.47–4.53 (m, 2H, aromatic), 7.62 (d, J = 7.5 Hz,
2H, aromatic), 7.73–7.79 (m, 2H, aromatic), 7.96 (d, 3JH-F =
Off-white powder, 1H-NMR (500 MHz, DMSO-d6) δ (ppm):
12.5 Hz, 1H, aromatic), 8.08 (s, 1H, aromatic), 8.62 (s, 1H,
2.62 (bs, 4H, piperazine), 3.02–3.08 (m, 4H, piperazine), 3.58
aromatic), 15.12 (s, 1H, COOH). IR (KBr cm−1), ṽ = 3580–
(s, 2H), 5.16 (s, 2H, NOCH2), 6.44 (d, 4JH-F = 7 Hz, 1H,
3300 (OH), 1718, 161 (C=O). Anal. Calcd. For
aromatic), 7.37 (d, J = 7 Hz, 1H, aromatic), 7.53 (t, 3JH-F =
C35H29ClF2N4O4: C: 65.37; H: 4.55; N: 8.71; C: 65.10; H:
6.5 Hz, 2H, aromatic), 7.63 (d, J = 9 Hz, 1H, aromatic), 7.72–
4.41; N: 8.94.
7.78 (m, 5H, aromatic), 7.96–8.01 (m, 3H, aromatic), 8.01 (s,
1H, aromatic), 8.63 (s, 1H, aromatic), 12.85 (s, 1H, COOH).
7-(4-(2-((Benzyloxy)imino)-2-(4-bromophenyl)ethyl)
IR (KBr cm−1), ṽ = 3580–3300 (OH), 1715, 1619 (C=O). 13C-
piperazin-1-yl)-6-fluoro-1-(4-fluorophenyl)
NMR (125 MHz, DMSO-d6) δ (ppm): 45.0, 49.0 (CH2 piper-
-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (4v)
azine), 51.7 (CH2), 76.0 (OCH2), 106.8, 111.1 (d, 3JC-F =
22.5 Hz), 117.9 (d, 3JC-F = 22.5 Hz), 119.0, 128.3, 130.6,
Off-white powder, 1H-NMR (500 MHz, DMSO-d6) δ (ppm):
129.8 (d, 1JC-F = 8.75 Hz), 132.2, 132.2, 136.3, 137.8,
2.92–3.09 (m, 8H, piperazine), 3.67 (bs, 2H), 5.19 (s, 1H,
138.6, 146.0, 148.9, 151.2, 154.9, 166.1 (COOH), 172.0
NOCH2), 6.33 (s, 1H, aromatic), 7.36–7.42 (m, 4H, aromatic),
(C=N), 176.43 (C=O). Anal. Calcd. For C35H28Cl2F2N4O4:
7.51–7.55 (m, 4H, aromatic), 7.67 (d, J = 8 Hz, 2H, aromatic),
C: 62.05; H: 4.17; N: 8.27; C: 62.32; H: 4.36; N: 8.55.
7.76–7.79 (m, 2H, aromatic), 7.94 (d, 3JH-F = 12 Hz, 1H, aro-
matic), 8.09–8.11 (m, 2H, aromatic), 8.62 (s, 1H, aromatic),
15.10 (s, 1H, COOH). IR (KBr cm−1), ṽ = 3580–3300 (OH),
1712, 1620 (C=O). 13C-NMR (125 MHz, DMSO-d6) δ Pharmacology
(ppm): 48.9, 50.3 (CH 2 piperazine), 52.1 (CH 2 ), 75.8
(OCH2), 106.4, 107.3, 111.0 (d, 3JC-F = 23.5 Hz), 117.2 (d, Conventional agar-dilution method was used to determine the
3
JC-F = 23.75 Hz), 118.0, 122.5, 127.8, 128.1, 128.3, 128.6, minimum inhibitory concentrations (MIC) of the synthesized
129.1, 129.8 (d, 1JC-F = 7.5 Hz), 131.1, 133.9, 136.1, 137.4, compounds (4a-x), according to previously reported method
139.1, 146.0, 148.8, 153.6, 163.0 (C=N), 165.6 (COOH), [26]. The results of antibacterial testing of N-[2-(aryl-3-yl)
177.1 (C=O). Anal. Calcd. For C35H29BrF2N4O4: C: 61.14; ethyl] piperazinyl quinolones 4 and their oxime derivatives
H: 4.25; N: 8.15; C: 61.33; H: 4.01; N: 8.32. (4 g-x) against a panel of selected Gram-positive
[Staphylococcus aureus ATCC 6538p, Micrococcus luteus,
7-(4-(2-((Benzyloxy)imino)-2-(p-tolyl)ethyl)piperazin-1-yl) ATCC 1110, Staphylococcus epidermidis ATCC 12228,
-6-fluoro-1-(4-fluorophenyl) Bacillus subtilis ATCC 6633], and Gram-negative
-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (4w) [Escherichia coli ATCC 8739, Klebsiella pneumoniae
ATCC 10031 and Pseudomonas aeruginosa ATCC 9027,
Off-white powder, 1H-NMR (500 MHz, DMSO-d6) δ (ppm): Serratia marcescens PTCC 1111] bacteria are reported in
2.23 (s, 3H, CH3), 2.99–3.11 (m, 4H, piperazine), 2.84–2.89 Table 2, compared to the reference drug sarafloxacin.
(m, 4H, piperazine), 3.64 (s, 2H), 5.35 (s, 2H, NOCH2), 6.20 Two-fold dilution of compounds 4a-x and positive control
(d, 4JH-F = 7 Hz, 1H, aromatic), 7.08 (d, J = 8 Hz, 1H, aromat- were done by dissolving 6.4 mg in dimethylsulfoxide
ic), 7.15 (d, J = 7 Hz, 1H, aromatic), 7.28–7.35 (m, 4H, aro- (DMSO; 1 mL), which were diluted with water (9 mL) and
matic), 7.38 (t, 3JH-F = 7 Hz, 2H, aromatic), 7.47–7.50 (m, 3H, added to molten Mueller-Hinton (MH) agar to give a final
aromatic), 7.59–7.63 (m, 2H, aromatic), 7.77 (d, 3JH-F = concentration of 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.13, 0.06,
13 Hz, 1H, aromatic), 8.04 (s, 1H, aromatic), 11.02 (s, 1H, 0.03, 0.015, 0.0075 and 0.00375 μg/mL−1. Petri dishes were
COOH). IR (KBr) cm−1; ν 3580–3300 (COOH), 1726, 1620 incubated with 1–5 × 104 colony forming units (cfu) at 35–
(C=O). 13C-NMR (125 MHz, DMSO-d6) δ (ppm): 20.7 37 °C and examined after 18 h. The lowest concentration of
(CH 3 ), 49.0, 50.4 (CH 2 piperazine), 52.3 (CH 2 ), 75.7 the agent, which completely led to the visible growth inhibi-
(OCH2), 106.3, 108.8, 111.8 (d, 3JC-F = 23.75 Hz), 117.9 (d, tion on the Petri dish of the microorganisms was determined
3
JC-F = 23.75 Hz), 121.5, 126.4, 127.8, 128.1, 128.2, 128.7, as the minimum inhibitory concentration (MIC).
DARU J Pharm Sci

Table 1 Synthetic pathway and physical data of target compounds 4a-x

1 2
Compd. R R Y mp (oC) Yield (%)a Reaction
time (days)
4a H H O 190-192 31 4
4b F H O 197-199 48 3
4c Cl H O 199-200 36 3
4d Br H O 193-194 46 3
4e CH3 H O 200-201 35 3
4f Cl Cl O 195-197 41 3
4g H H NOH 205-208 52 4
4h F H NOH 217-220 60 3
4i Cl H NOH 211-213 58 3
4j Br H NOH 210-212 58 3
4k CH3 H NOH 233-235 50 3
4l Cl Cl NOH 224-226 53 3
4m H H NOCH3 207-209 63 5
4n F H NOCH3 198-200 67 4
4o Cl H NOCH3 206-208 70 4
4p Br H NOCH3 202-204 66 4
4q CH3 H NOCH3 235-237 62 5
4r Cl Cl NOCH3 219-221 68 5
4s H H NOBn 162-164 67 7
4t F H NOBn 165-166 75 5
4u Cl H NOBn 172-175 76 5
4v Br H NOBn 169-170 72 5
4w CH3 H NOBn 185-187 61 7
4x Cl Cl NOBn 179-181 70 6
a
Isolated yields

Results and discussion Then, the reaction of 3 with compounds (1a-f) and (2 g-r) in
DMF in the presence of NaHCO3 at 25 °C afforded correspond-
Chemistry ing N-[2-(aryl-3-yl) ethyl] piperazinyl quinolones (4a-x) which
was purified by recrystallization from methanol-chloroform.
The synthetic pathways for the synthesis of intermediates
(2 g-r), the target compounds (4a-x) and their physical data Antibacterial activity
are shown in Table 1. Compounds (2 g-r) were prepared by
stirring the ketone analogues with excess amounts of hydroxyl- The activity of synthesized compounds (4a-x) were eval-
amine, O-methylhydroxylamine and O-benzylhydroxylamine uated against Gram-positive [Staphylococcus aureus ATCC
hydrochloride salts in methanol at room temperature [20–22]. 6538p, Micrococcus luteus, ATCC 1110, Staphylococcus
 DARU J Pharm Sci

Table 2 In vitro antibacterial activities of compounds 4a-x in Comparison to sarafloxacin (MICs in μg/mL)

Compd. E. coli Klebsiella Serratia Pseudomona S. S. M. B.

aureus epidermidis luteus subtilis
4a 0.5 4 2 0.5 0.5 0.5 8 0.5
4b 8 8 8 1 16 1 16 1
4c 0.5 1 1 1 0.5 1 0.5 0.5
4d 1 8 8 8 2 1 16 2
4e 4 4 16 1 0.5 1 16 0.5
4f 0.5 1 1 0.5 2 16 16 2
4g 0.5 4 4 4 <0.125 <0.125 2 <0.125
4h 2 8 8 4 0.25 0.25 1 0.25
4i 8 16 8 8 32 16 32 16
4j 8 8 16 4 0.5 1 16 0.5
4k 0.2 2 16 1 1 1 16 1
4l 4 32 32 8 1 2 0.5 0.5
4m >64 >64 >64 >64 >64 >64 >64 >64
4n 1 4 2 1 1 1 8 1
4o >64 >64 >64 32 16 64 >64 16
4p 64 64 >64 16 16 64 64 64
4q >64 >64 >64 >64 >64 >64 >64 >64
4r 8 8 4 4 4 4 8 4
4s >64 >64 >64 >64 32 32 >64 8
4t >64 >64 >64 >64 >64 >64 >64 >64
4u 32 >64 >64 64 32 >64 >64 32
4v >64 >64 >64 >64 >64 >64 >64 >64
4w >64 >64 >64 >64 >64 >64 >64 >64
4x 0.25 4 8 2 1 0.5 8 0.5
Sarafloxacin <0.125 <0.125 <0.125 <0.125 <0.125 <0.125 <0.125 <0.125

epidermidis ATCC 12228 and Bacillus subtilis ATCC 6633] and results, among ketones, O-methyloximes and O-
Gram-negative [Escherichia coli ATCC 8739, Klebsiella benzyloximes derivatives of target compounds, lower suscep-
pneumoniae ATCC 10031 and Pseudomonas aeruginosa tibilities (higher MICs) were observed in O-methyloxime and
ATCC 9027 and Serratia marcescens PTCC 1111] using con- O-benzyloxime-incorporated derivatives. Thus, O-
ventional agar-dilution method. methyloxime and O-benzyloxime moiety diminished the ac-
The MIC (minimum inhibitory concentration) values were tivity against both Gram-positive and Gram-negative bacteria.
determined against the eight strains and summarized in The most potent compound against Gram-positive (compound
Table 2. As indicated in this table, it was concluded that com- 4 g) belongs to the oxime series.
pound 4 g exhibited comparable results with sarafloxacin
against S. aureus, S. epidermidis and B. subtilis, while other
synthesized compounds showed moderate to poor activity Conclusions
against these bacteria. The obtained data suggested that the
good activities were obtained in case of Gram-positive micro- In conclusion, a series of FQ derivatives are synthesized and
organism, Bacillus subtilis. In accordance with antibacterial evaluated for their biological activity. Compound 4 g showed
DARU J Pharm Sci

good activity against S. aureus, S. epidermidis and B. subtilis. 14. Odagiri T, Inagaki H, Nagamochi M, Kitamura T, Komoriya S,
Takahashi A. Design, synthesis, and biological evaluation of novel
It was concluded that the introduction of bulky moieties on
7-[(3aS,7aS)-3a-Aminohexahydropyrano[3,4-c]pyrrol-2(3H)-yl]-
piperazine ring at C-7 position of fluoroquinolones reduced 8-methoxyquinolines with potent antibacterial activity against re-
the antibacterial activities against both Gram-negative and spiratory pathogens. J Med Chem. 2018;61:7234–44.
Gram-positive bacteria. In addition, the antibacterial activity 15. Koga H, Itoh A, Murayama S, Suzue S, Irikura T. Structure-activity
of target compounds could not be improved by O-methylation relationship of anti-bacterial 6,7- and 7,8-disubstituted 1-alkyl-1,4-
dihydro-4-oxoquinolone-3-carboxylic acids. J Med Chem.
or O-benzylation of oxime derivatives. 1980;23:1358–63.
16. Cooper CS, Klock PL, Chu DT, Hardy DJ, Swanson RN, Plattner
Acknowledgments The authors declare no conflict of interests. This JJ. Preparation and in-vitro and in-vivo evaluation of quinolones
work was supported by a grant from the Iranian National Science with selective activity against gram-positive organism. J Med
Foundation (INSF); Grant no. 93023097. Chem. 1992;35:1392–8.
17. Shafiee A, Haddad Zahmatkesh M, Mohammadhosseini N,
Khalafy J, Emami S, Moshafi MH, et al. Synthesis and in-vitro
antibacterial activity of N-piperazinyl quinolone derivatives with
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