SYNTHESIS AND BIOLOGICAL EFFICACY OF NOVEL PIPERAZINE ANALOGUES BEARING QUINOLINE AND PYRIDINE MOIETIES
© 2015 M. Al-Ghorbani*, N. D. Rekha**, V. Lakshmi Ranganatha*, V. Prashanth*, T. Veerabasappagowda**, and S. A. Khanum*, ##
*Department of Chemistry, Yuvaraja's College, University of Mysore, Mysore, Karnataka, India **Department of Studies in Biotechnology, JSS College of Arts, Commerce and Science, Mysore, Karnataka, India
Received 24.08.2014; in final form 12.01.2015
A series of novel piperazine analogues bearing quinolin-8-yloxy-butan-1-ones/pyridin-2-yloxy-ethanones were synthesized by a simple and convenient approach based on various substituted piperazine incorporating quinoline and pyridine moieties. The analogues were evaluated for in vitro antioxidant activity against 2,2-diphenyl-1-picryl-hydrazyl (DPPH) and ferrous ion radical scavenging activities and anti-inflammatory activity by inhibition of Vipera russelli venom (PLA2) and gastric K+/H+-ATPase activities. Most of the title compounds exhibited promising activity. Best antioxidant and PLA2-inhibiting activities were found for piperazine analogues with phenyl and nitro phenyl groups, whereas methoxy group on phenyl piperazine indicated selectivity for the H+/K+-ATPase.
Keywords:piperazine analogues, antioxidant, PLA2, H+ /K+-ATPase.
DOI: 10.7868/S0132342315040028
INTRODUCTION
Antioxidant therapies are gaining importance due to their ability to retard disease progression by reducing the damage caused by free radical oxidative stress in a patient [1]. Physiological levels of reactive oxygen species (ROS) play a vital role as signaling molecules to mediate numerous biological functions causing alterations in cell growth, gene expression, and host defense [2]. Under inflammatory conditions, the presence of excess ROS (O^-, 'OH, H2O2, NO *, ONOO) can initiate damage to nucleic acids, proteins, carbohydrates, and lipids in many types of cells, including macrophages [3].
The association of antioxidants with inflammation stems from the recognition that free radicals are produced during the inflammatory process by macrophages. It has been reported that ROS are involved in the cyclooxygenase- and lipoxygenase-mediated conversion of arachidonic acid into proinflammatory intermediates and possess the ability to activate PLA2 enzyme, which further augments the inflammatory process and worsens the disease during chronic inflammatory conditions [4]. Therefore, suppression of these pro-inflammatory lipid mediators in conjunction with free radicals has long been considered in the therapeutic process of various inflammatory disorders.
On the other hand, the inhibition of gastric acid secretion, especially by antagonism of the H2 receptor,
# Corresponding author (phone: +9901888755; fax: +821 2419239; e-mail: shaukathara@yahoo.co.in).
has been proven a powerful tool in the treatment of gastric and duodenal ulcer diseases [5]. Recently, agents that completely suppress acid secretion by inhibition of the gastric proton pump H+/K+-ATPase have been identified.
Piperazine and their derivatives have been found to exhibit a variety of biological activities and are well known for their medicinal importance and recognized for their use as antidepressive [6], antihistamine [7], anticancer [8-10], and antioxidant [11] activities.
The incorporation of synthetic piperazine is an important strategy in drug discovery due to its easy mod-ifiability, proper alkality, water solubility, and the capacity for the formation of hydrogen bonds and adjustment of molecular physicochemical properties [12]. The piperazine nucleus incorporated the quinoline and pyridine moiety into a rigid framework. It has been reported that quinoline and pyridine derivatives possess appreciable anti-inflammatory activity [13]. Moreover, piperazine and related derivatives have shown special ability to scavenge ROS in processes involving free radical injury [14] and are effective as reversible inhibitors of gastric H+/K+-ATPase [15].
Based on the above information and continuing our research program aimed at developing simple and efficient synthesis of pharmacologically useful heterocyclic analogues, we envisage that incorporating quinoline and pyridine cores in substituted piperazine frame could lead to the potent antioxidant activity, as well as PLA2 and H+/K+-ATPase inhibition activities.
RESULTS AND DISCUSSION
In this study, novel derivatives of piperazine analogues were synthesized in an attempt to find new compounds having antioxidant activity and anti-inflammatory related activities, such as inhibition of PLA2 and gastric H+/K+-ATPase activity. The synthetic routes for the newly synthesized piperazine analogues (Va—l) are illustrated and outlined in the scheme. The structure elucidations of the newly synthesized compounds were confirmed by XH and 13C NMR, mass spectrometry, and elemental analysis. In the 1H NMR spectra of (Va—l), two sets of multiplet signals at 5 3.1—4.0 ppm each belonging to the four protons of two
CH2 groups in piperazine ring were observed. The XH NMR spectrum of compound (Va ) showed the multiplet signals in the region of 6 6.8—7.3 ppm, which appeared due to phenyl protons. 13C NMR spectra also confirmed the piperazine structure of (V&—l) due to peaks appearance in the range 6 44.08—67.89. The mass spectra of compounds (V&—l) were in agreement with their assigned structures. The mass spectrum of (Va) showed molecular ion peak at 376 (M + 1), which corresponds to the molecular formula C23H25N3O2. Similarly, the spectral values for all the compounds and C, H, N analyses are given in the experimental part.
Compd Ar
Ar—OH + X (Ia-c) o
(IIa-b)
a, X = Br, n = 3
b, X = Cl; n = 1
,OH / '
+ HN
O N-'
(IVa-c)
K2CO3, reflux Anhyd. acetone
ArO
O
(IIIa—c)
ArO
¿v <
NaOH
Ethanol, reflux
R
\ TBTU, Et3N
N_R Anhd. acetonitrile, ArO ^lf
N.
Compd Ar
inert atmosphere, RT
R
N
,R
O
(Va-l)
Compd Ar
R
(Va)
n = 3
(Vb)
n = 3
(Vc)
n = 3
(Vd)
n = 3
N
W^NO2 n =1
(Ve)
n = 1
(Vf)
n = 1
(Vg)
n = 3
(Vh)
IN
N CH3
\ /
NO
(Vi)
2n = 1
\ /
NO
(Vj)
2n = 3
(Vk)
\ / n = 1
H3CO
N CH3
(Vl)
\ / n = 1
H3CO
Scheme. Synthesis of piperazine analogues (Va-1).
N
w
H3CO
CH3
CH3
N CH3
CH3
N
In vitro antioxidant activities were measured against DPPH and ferrous ion chelating radicals. DPPH radical scavenging activity evaluation is a rapid and convenient technique for screening the antioxi-dant activities. It can be seen from Table 1 that, in DPPH assay, compounds (Vc), (Vf), and (Vk) with IC50 values of 4.1, 3.5, and 3.8 ^g/mL, respectively,
showed better radical scavenging activities than the synthetic commercial antioxidant BHT with the highest scavenging of92—97%. Compounds (Vfe), (Vi), (Vj), and (Vl) with IC50 values of 4.4, 4.5, 4.4, and 4.6 ^g/mL displayed good DPPH radical scavenging activity. Compounds (Vb), (Vd), (Vg), and (Vh) showed moderate radical scavenging abilities, while compound (Va) showed
Table 1. DPPH radical scavenging activity of the compounds (Va—l)*
Test samples
Concentration, p.g/mL
2 4 6 8 10 IC50, Mg/mL
(Va ) 23.74 34.23 45.47 57.45 77.53 6.7
(Vb) 29.72 45.64 59.62 73.71 99.4 4.6
(Vc ) 36.63 48.48 67.1 79.65 92.65 4.1
(Vd ) 22.73 45.51 52.25 74.18 87.3 5.2
(Ve) 26.4 47.27 65.61 78.29 90.17 4.4
(Vf) 38.31 53.46 71.12 82.35 92.52 3.5
(Vg ) 30.14 42.57 58.3 75.03 95.24 5.1
(Vh) 21.52 41.59 64.61 84.72 98.55 4.7
(Vi) 24.59 43.74 67.66 86.51 98.58 4.5
(Vj) 33.39 46.58 66.78 77.58 84.22 4.4
(Vk) 39.71 51.71 65.64 83.22 97.52 3.8
(Vl) 29.56 41.31 63.62 79.14 93.86 4.6
BHT 34.86 48.46 65.48 78.6 90.46 4.4
* Results presented here are the mean values from three independent experiments.
Table 2. Ferrous ion radical scavenging activity of the compounds (\&—l)*
Test samples
Concentration, p.g/mL
4 8 12 16 20 IC50, Mg/mL
(Va) 28.5 48.82 69.59 83.58 94.7 9.5
(Vb) 33.28 57.45 67.89 79.44 88.13 7.6
(Vc) 23.6 46.56 64.5 78.51 94.43 9.1
(Vd) 19.64 37.64 55.47 72.48 89.14 10.9
(Ve) 31.46 43.44 66.44 78.12 90.34 9.7
(Vf) 24.57 48.48 65.45 78.35 91.5 8.6
(Vg ) 30.54 42.24 57.47 70.42 83.59 10.6
(Vi) 32.65 41.92 54.83 76.12 94.51 11.2
(Vj) 34.49 56.17 74.88 82.84 94.86 6.2
(Vl) 21.24 41.29 63.62 81.73 92.54 9.3
BHT 22.65 43.5 64.57 86.62 93.58 9.6
* Results presented here are the mean values from three independent experiments.
poor radical scavenging ability in comparison with the standard.
Metal chelating capacity is important since it reduces the concentration of the catalyzing transition metal in lipid peroxidation (thus delaying metal-catalyzed oxidation) [16]. Since ferrous ions constitute the most effective pro-oxidants in food and biological systems, the good chelating effect and removal of free iron from circulation would be beneficial and correct approach to prevent oxidative stress-induced disorder. From the results of ferrous ion chelating assay (Table 2), the compounds (Vb), (Vc), (Vf), (Vj), and (Vl) with IC50 values of7.65, 9.12, 8.60, 6.23, and 9.33 ^g/mL, respec-
tively, showed higher radical scavenging activities than that of the standard BHT Other compounds exhibited good to moderate radical scavenging activity; compounds (Vh) and (Vk) failed to scavenge ferrous ion radical. Compounds (Vb), (Vc ), (Vf), (Vj), and (Vl) demonstrated a marked capacity for iron binding, suggesting their role as hydroxyl radical protector. The results reveal that phenyl and nitrophenyl groups in the piperazine ring of (Vb), (Vc ), and (Vf), as well as compounds (Vj), (Vk), and (Vl) with the methyl group in the pip-erazine, possess potent DPPH and ferrous ion radical scavenging activities. However, with few exceptions, it has been noted that phenyl, nitrophenyl and ^-methyl
Table 3. PLA2 inhibition activity of compounds (Va-l)
Concentration, pg/mL
10 20 30 40 50 60 IC50, pg/mL
(\a) 12.38 37.9 54.37 66.74 78.33 95.63 27.5
(Vb) 24.26 40.04 56.59 68.53 79.03 93.61 26
(Vc ) 26.74 37.24 46.94 58.13
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