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Letters in Drug Design & Discovery, 2013, 10, 75-85 75

Design, Synthesis and Evaluation of Novel 2-piperidinyl Quinoline Chalcones/ Amines as Potential Antidepressant Agents
Obaid Afzala, Sandhya Bawaa*, Suresh Kumara,b, Rajiv Kumara and Md Quamrul Hassanc
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jamia Hamdard, New Delhi-110062, India; bJubiliant Lifesciences, Sector-16A, Noida, Uttar Pradesh-201301, India; cDepartment of Pharmacology, Faculty of Pharmacy, Jamia Hamdard, New Delhi-110062, India.
Abstract: A novel series of 2-piperidinyl quinoline chalcones/amines (3-21) as structural analogues of quipazine were designed in order to find a promising candidate having antidepressant potential. They were synthesized, characterized and screened in vivo for their antidepressant potential by two behavioural models viz. forced swim test (FST) and learned helplessness test (LST). FST showed that compound 5, 8 and 17 reduced significantly the duration of immobility at 20 mg/kg, when compared with the control (p<0.001), and demonstrated comparable activity to clomipramine (p<0.001). LST further supported the antidepressant potential of these compounds. Furthermore, in 5-HTP-induced head-twitch test and yohimbine-induced mortality test, most active compound 5 increased the rate of head-twitching and the prevalence of mortality. Thus, the mechanism of action of the antidepressant effects of compound 1-(2,4-Dichlorophenyl)-3-[2(piperidin-1-yl) quinolin-3-yl] prop-2-en-1-one (5) may be attributed to increased 5HT and NE level in the synapse.
a

Keywords: Antidepressant behavioral test; Chalcone; 5-HTP induced mouse head-twitch test; Molinspiration; 2-Piperidinyl quinoline; Quipazine; Reductive amination; Schiffs base; Yohimbine toxicity potentiation test. INTRODUCTION Depression is the most prevalent mental disorder that is characterized by anhedonia (Loss of the capacity to experience pleasure), feelings of guilt or low self-worth, impaired sleep or appetite, poor mental concentration and low energy [1]. According to WHO's prediction, more than 350 million people of all ages suffer from depression worldwide [2]. A metabolic disorder of catecholamines in the CNS is believed to be the main biochemical etiology behind depression [3]. Despite the availability of monoamine oxidase inhibitors (MAOIs) and drugs that inhibit the reuptake of catecholamines, the prevalence of remission is one-third and subjects suffer from several side-effects such as gastrointestinal distress, anxiety, insomnia, weight gain and sexual dysfunction [4-6]. Therefore, the discovery of new antidepressant drugs with faster onset of action, fewer side-effects, better efficacy and tolerability is necessary. Quipazine Fig. (1), chemically 2-(1-piperzinyl)quinoline is a weak inhibitor of monoamine oxidase as well as moderately selective serotonin receptor agonist [7]. The antidepressant potential of quipazine has prompted us to design, synthesize and evaluate new structural analogues in which substituents could be arranged in a new molecular framework to display possible higher order of antidepressant activity. For designing new analogues, we chose natural products, as an impressive number of modern drugs have been developed from natural sources, especially from plants used as traditional folk medicine. Chalconoids (open chain flavonoids), with the common skeleton of 1,3-diaryl-2*Address correspondence to this author at the Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jamia Hamdard, New Delhi-110062, India; Tel: 011-26059688; Ext: 5644; +91-9810 2000 22; Fax: 00-91-11-608 8874; E-mail: sbawa@jamiahamdard.ac.in; sandhyabawa761@yahoo.com 17-;/13 $58.00+.00

propen-1-ones, are the biogenetic precursors and essential intermediate compounds in flavonoid biosynthesis in plants [8]. They present a broad spectrum of biological activities such as anticancer, anti-inflammatory, antimalarial, antilipidemic, and antiviral etc [9-15]. With more attention being paid to the antidepressant activity of plant products containing chalconoids, it was observed that compounds viz. isoliquiritigenin, licochalcone A, curcumin, rosamarinic acid, quercetin, kaempferol, luteolin, myricetin, isorhamnetin, apigenin and nobiletin having antidepressant potential has increased in recent years [16-21]. The structures of these natural products are presented in Fig. (1). Moreover, Chimenti et al. has recently reported chalcones as a valid scaffold for monoamine oxidase inhibitors [22]. On the other hand, the amine function (secondary and tertiary) is also an important structural requirement for designing the antidepressant drugs [23-24]. Keeping these facts in mind, nineteen new structural analogues of quipazine were designed by varying the substituents at 3 position of quinoline moiety Fig. (2). The piperazine ring in quipazine was replaced by piperidine as NH is isosteric with CH2 group. Among them seven are chalcone derivatives and twelve are different amine derivatives. Thus, we report herein the synthesis and evaluation of a new series of 2-piperidinyl quinoline chalcone/amine derivatives (3-21) as potential antidepressant agents. MATERIAL AND METHOD Chemistry All the reagents and solvents used were purchased from E Merck (India) Ltd., S. D. Fine (India) and Qualigens (India). Melting points were determined by the open
2013 Bentham Science Publishers

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Afzal et al.

N NH HO OCH3

Quipazine

Curcumin (Isolated from Curcuma longa)

OCH3

OH

OH CH3 HO OH H2C CH3 O

HO O

OCH3

OH

Isoliquiritigenin (Isolated from Glycyrrhiza glabra)

OH O O OH

Licochalcone A (Isolated from Glycyrrhiza glabra)

R6 OH R7 R1 R2 O R8

HO OH

Rosamarinic acid (Isolated from Ocimum sanctum and Perilla fruitescence)

R3 R4 O

R5

Quercetn (Isolated from Hypericum perforatum and Zizyphus zylopyrous): R1 = H; R2 = OH; R3 = H; R4 = OH; R5 = OH; R6 = OH; R7 = OH; R8 = H. Kaempferol (Isolated from Hypericum perforatum and Zizyphus zylopyrous): R1 = H; R2 = OH; R3 = H; R4 = OH; R5 = OH; R6 = H; R7 = OH; R8 = H. Luteolin (Isolated from Hypericum perforatum, Siphocamphylus vercillatus and Eremostachys laciniata): R1 = H; R2 = OH; R3 = H; R4 = OH; R5 = H; R6 = OH; R7 = OH; R8 = H. Myricetin (Isolated from Hypericum perforatum): R1 = H; R2 = OH; R3 = H; R4 = OH; R5 = OH; R6 = OH; R7 = OH; R8 = OH. Isorhamnetin (Isolated from Hypericum perforatum): R1 = H; R2 = OH; R3 = H; R4 = OH; R5 = OH; R6 = OCH3; R7 = OH; R8 = H. Apigenin (Isolated from Eremostachys laciniata): R1 = H; R2 = OH; R3 = H; R4 = OH; R5 = H; R6 = H; R7 = OH; R8 = H. Nobiletin (Isolated from the peels of Citrus fruits): R1 = OCH3; R2 = OCH3; R3 = OCH3; R4 = OCH3; R5 = H; R6 = OCH3; R7 = OCH3; R8 = H.

Fig. (1). Structure of quipazine and some naturally occurring chalcones having antidepressant potential.

capillary method using the electrical melting point apparatus and are uncorrected. The elemental analyses (C, H, N) of all compounds were performed on the CHNS Elimentar (Analysen systime, GmbH) Germany Vario EL III. IR (KBr) spectra were recorded on a Bio Rad, FT-IR spectrometer (vmax in cm-1). 1H NMR spectra were recorded in CDCl3 on a Bruker 300 MHz spectrometer using tetramethylsilane (TMS) as internal reference (Chemical shift in  ppm). Mass spectra (DART-MS) were recorded on a JEOL-AccuTOF JMS-T100LS Mass spectrometer having a DART (Direct Analysis in Real Time) source. The purity of the compounds was checked by thin layer chromatography (TLC) on silica gel G (Merck) coated plates by using toluene: ethylacetate: formic acid (5:4:1) and hexane: ethylacetate (6:1) as solvent system. Iodine chamber and UV lamp were used for the visualization of TLC spots. 2-Chloro quinoline-3-carbaldehyde (1) Compound 1 was synthesized by Vilsmeier-Haack cyclization reaction according to the reported method [25]. 2-(Piperidin-1-yl) quinoline-3-carbaldehyde (2) A mixture of piperidine (5 ml) and 2-chloroquinoline-3carbaldehyde (1gm) was refluxed on oil bath maintained at

95-100 0C for 10 hrs. The contents of the flask were cooled and poured over crushed ice. Excess piperidine was removed by washing thoroughly 2-3 times with water. The solid product so obtained was dried and recrystallized from ethanol to give the yellow solid product. The progress of reaction and purity of compound was checked by TLC using TEF (5:4:1) as mobile phase. Yield: 92%; mp: 79-81 C; FTIR (KBr) cm
1: 1621 (C=N), 1561 (C=C), 1052 (C-N), 1687 (C=O); 1H NMR (CDCl3, 300 MHz)
(ppm): 1.68-1.78 (m, 6H, CH23), 3.42-3.46 (t, 4H, N (CH2)2), 7.31-7.36 (m, 1H, H-6), 7.64-7.69 (m, 1H, H-7), 7.75-7.82 (m, 2H, H-5 & H-8), 8.46 (s, 1H, H-4), 10.15 (s, 1H, CHO); FAB-MS: m/z 240 (M+); Anal. Calcd for C15H16N2O: C, 74.97; H, 6.71; N, 11.66; Found : C, 75.18; H, 6.73; N, 11.69 %. General Method for the Synthesis of Chalcones (3-9) Substituted aromatic acetophenone (0.01 mol) was added to the mixture of 2-(piperidin-1-yl) quinoline-3-carbaldehyde (0.01 mol) (2), and aq. sodium hydroxide solution (30%, 1 ml), in 30 ml of ethanol. The reaction mixture was stirred overnight at room temperature. Subsequently, this reaction mixture was poured over crushed ice and neutralized to pH 7 with dilute HCl. The solid thus obtained was filtered, washed

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R' A
N N NH

R B

Quipazine

Chalcone scaffold selected from the plant products having MAO inhibitory activity

B
N N

2-Piperidinyl quinoline chalcones

Replacement of enone function by azomethine function

Replacement of enone function by methylene amine function

R
N N

N H

2-Piperidinyl quinoline amines

Fig. (2). Designing of 2-piperidinyl quinoline chalcone/amine derivatives.

with water and dried. The crude product was crystallized with ethanol to afford pure chalcones. 1-Phenyl-3-[2-(piperidin-1-yl) quinolin-3-yl] prop-2-en-1one (3) FT-IR (KBr) cm
1: 1625 (C=N), 1604 (C=C), 1721 (C=O); 1H NMR (CDCl3, 300 MHz)
(ppm): 1.67-1.77 (m, 6H, CH23), 3.35 (bs, 4H, N (CH2)2), 7.32-7.37 (t, 1H, H6, J = 7.3 Hz), 7.43-7.64 (m, 5H, Ar-H & CH=CH), 7.707.73 (d, 2H, Ar-H, J = 9 Hz), 7.82- 7.84 (d, 1H, Ar-H, J = 8.1 Hz), 8.03- 8.08 (m, 2H, Ar-H), 8.24 (s, 1H, H-4); FABMS: m/z 342 (M+); Anal. Calcd for C23H22N2O: C, 80.67; H, 6.48; N, 8.18; Found : C, 80.37; H, 6.50; N, 8.20 %. 1-(4-Chlorophenyl)-3-[2-(piperidin-1-yl) prop-2-en-1-one (4) quinolin-3-yl]

1.63 (bs, 6H, CH2 3), 3.28 (bs, 4H, N (CH2)2), 7.16-7.25 (m, 1H, Ar-H), 7.32-7.44 (m, 3H, Ar-H & CH=CH), 7.507.53 (d, 1H, Ar-H, J = 9.3 Hz), 7.59-7.71 (m, 2H, Ar-H & CH=CH), 7.69- 7.71 (d, 1H, Ar-H, J = 8.1 Hz), 7.79- 7.82 (d, 1H, Ar-H, J = 8.4 Hz), 8.19 (s, 1H, H-4); Anal. Calcd for C23H20Cl2N2O: C, 67.16; H, 4.90; N, 6.81; Found : C, 67.40; H, 4.89; N, 6.79 %. 1-(4-Hydroxyphenyl)-3-[2-(piperidin-1-yl) quinolin-3-yl] prop-2-en-1-one (6) FT-IR (KBr) cm
1 : 1697 (C=O), 1625 (C=N), 1579 (C=C); 1H NMR (CDCl3, 300 MHz)
(ppm): 1.69-1.81 (m, 6H, CH23), 2.16 (s, 1H, OH), 3.37 (bs, 4H, N (CH2)2), 7.23-7.38 (m, 5H, Ar-H & CH=CH), 7.59-7.64 (t, 1H, H-7, J = 7.5 Hz), 7.70-7.73 (d, 1H, H-5, J = 8.1Hz), 7.83- 7.85 (d, H-8, J = 8.4 Hz), 7.95- 8.00 (d, 1H, CH=CH, J = 15.9), 8.22 (s, 1H, H-4); Anal. Calcd for C23H22N2O2: C, 77.07; H, 6.19; N, 7.82; Found : C, 77.27; H, 6.17; N, 7.85 %. 1-(2-Hydroxyphenyl)-3-[2-(piperidin-1-yl) quinolin-3-yl] prop-2-en-1-one (7) FT-IR (KBr) cm
1: 1627 (C=N), 1585 (C=C), 1703 (C=O); 1H NMR (CDCl3, 300 MHz)
(ppm): 1.69-1.80 (m, 6H, CH23), 2.63 (s, 1H, OH), 3.36 (bs, 4H, N (CH2)2), 6.88-7.06 (m, 2H, Ar-H), 7.33- 7.38 (t, 1H, Ar-H, J = 7.2 Hz), 7.49-7.55 (t, 1H, Ar-H, J = 7.7 Hz), 7.60-7.65 (t, 1H, Ar-H, J = 7.3 Hz), 7.71-7.74 (d, 1H, Ar-H, J = 7.8 Hz), 7.807.85 (m, 2H, Ar-H & CH=CH), 7.97-8.00 (d, 1H, Ar-H, J = 8.1 Hz), 8.10-8.15 (d, 1H, CH=CH, J = 15.3 Hz), 8.24 (s,

FT-IR (KBr) cm
1: 1623 (C=N), 1594 (C=C), 1698 (C=O); 1H NMR (CDCl3, 300 MHz)
(ppm):  1.68-1.77 (m, 6H, CH23), 3.35 (bs, 4H, N (CH2)2), 7.32-7.37 (t, 1H, Ar-H, J = 7.5 Hz), 7.49-7.51 (d, 2H, Ar-H, J = 7.8 Hz), 7.597.66 (m, 2H, Ar-H), 7.70-7.73 (d, 1H, Ar-H, J = 7.8 Hz), 7.82-7.84 (d, 1H, Ar-H, J = 8.4 Hz), 7.99-8.02 (m, 3H, ArH), 8.23 (s, 1H, H-4); Anal. Calcd for C23H21ClN2O: C, 73.30; H, 5.62; N, 7.43; Found : C, 73.04; H, 5.64; N, 7.41 %. 1-(2, 4-Dichlorophenyl)-3-[2-(piperidin-1-yl) quinolin-3yl] prop-2-en-1-one (5) FT-IR (KBr) cm
1 : 1698 (C=O), 1627 (C=N), 1579 (C=C), 747 (C-Cl); 1H NMR (CDCl3, 300 MHz)
(ppm):

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1H, H-4); Anal. Calcd for C23H22N2O2: C, 77.07; H, 6.19; N, 7.82; Found : C, 77.29; H, 6.17; N, 7.86 %. 1-(4-Methylphenyl)-3-[2-(piperidin-1-yl) prop-2-en-1-one (8) quinolin-3-yl]

8.59 (s, 1H, H-4), 8.69 (s, 1H, CH=N); Anal. Calcd for C21H19Cl2N3: C, 65.63; H, 4.98; N, 10.93; Found : C, 65.87; H, 4.97; N, 10.97 %. 3-Chloro, 4-fluoro-N-{[2-(piperidin-1-yl) quinolin-3-yl] methylidene} aniline (12) FT-IR (KBr) cm
1: 1633 (C=N), 1591 (C=C), 770 (C-Cl); H NMR (CDCl3, 300 MHz)
(ppm): 1.59-1.78 (m, 6H, CH23), 3.38 (bs, 4H, N (CH2)2), 7.13-7.22 (m, 2H, Ar-H2 & 6), 7.31-7.39 (m, 2H, Ar-H-5 & H-6), 7.61-7.66 (t, 1H, H-7, J = 7.5 Hz), 7.77-7.80 (d, 1H, H-5, J = 7.8 Hz), 7.84-7.87 (d, 1H, H-8, J = 8.4 Hz), 8.59 (s, 1H, H-4), 8.68 (s, 1H, CH=N); FAB-MS: m/z 367 (M+), 369 [(M+2)+]; Anal. Calcd for C21H19ClFN3: C, 68.57; H, 5.21; N, 11.42; Found : C, 68.37; H, 5.19; N, 11.46 %.
1

FT-IR (KBr) cm
1 : 1700 (C=O), 1627 (C=N), 1584 (C=C); 1H NMR (CDCl3, 300 MHz)
(ppm): 1.66-1.78 (m, 6H, CH23), 2.45 (s, 3H, CH3), 3.35 (s, 4H, N (CH2)2), 7.32-7.37 (m, 3H, Ar-H), 7.58-7.73 (m, 4H, Ar-H & CH=CH), 7.81-7.84 (d, 1H, Ar-H), 7.97-8.02 (m, 3H, Ar-H), 8.23 (s, 1H, H-4); Anal. Calcd for C24H24N2O: C, 80.87; H, 6.79; N, 7.86; Found : C, 81.17; H, 6.77; N, 7.82 %. 1-(4-Nitrophenyl)-3-[2-(piperidin-1-yl) prop-2-en-1-one (9) quinolin-3-yl]

FT-IR (KBr) cm
1 : 1712 (C=O), 1630 (C=N), 1575 (C=C); 1H NMR (CDCl3, 300 MHz)
(ppm): 1.68-1.77 (m, 6H, CH23), 3.35 (bs, 4H, N (CH2)2), 7.34-7.39 (t, 1H, H6, J = 7.5 Hz), 7.62-7.67 (m, 2H, H-7 & CH=CH), 7.72-7.75 (d, 1H, H-5, J = 8.1 Hz), 7.83-7.85 (d, 1H, H-8, J = 8.1 Hz), 8.02-8.08 (d, 1H, CH=CH, J = 15.6 Hz), 8.17-8.20 (d, 2H, Ar-3 & 5, J = 8.4 Hz), 8.27 (s, 1H, H-4), 8.37-8.39 (d, 2H, Ar-H-2 & 6, J = 5.7 Hz); Anal. Calcd for C23H21N3O3: C, 71.30; H, 5.46; N, 10.85; Found : C, 71.55; H, 5.43; N, 10.88 %. General Method for the Synthesis of Schiff's Bases (10-15) To a solution of 2-(piperidin-1-yl) quinoline-3carbaldehyde (1 mmol, 0.240 g) (2) and substituted aniline (1 mmol) in 10 mL of absolute ethanol, 2-3 drops of glacial acetic acid was added and the mixture was refluxed for 8 hrs. The content of the flask were reduced to half of the volume and cooled. The product obtained was filtered, washed with water, dried and recrystallized from ethanol to give the crystalline product. The progress of reaction & purity of compound was checked by TLC using TEF (5:4:1) as mobile phase. 4-Chloro-N-{[2-(piperidin-1-yl) idene}aniline (10) quinolin-3-yl] methyl-

4-Fluoro-N-{[2-(piperidin-1-yl) idene} aniline (13)

quinolin-3-yl]

methyl-

FT-IR (KBr) cm
1 : 1621 (C=N), 1598 (C=C); 1H NMR (CDCl3, 300 MHz)
(ppm): 1.67-1.77 (m, 6H, CH23), 3.37 (bs, 4H, N (CH2)2), 7.09-7.14 (m, 2H, Ar-H-2 & 6), 7.257.28 (m, 2H, Ar-H-3 & 5), 7.33-7.38 (t, 1H, H-6, J = 7.5 Hz), 7.60-7.65 (t, 1H, H-7, J = 7.8 Hz), 7.77-7.80 (d, 1H, H5, J = 8.1 Hz), 7.84-7.87 (d, 1H, H-8, J = 8.4 Hz), 8.62 (s, 1H, H-4), 8.70 (s, 1H, CH=N); Anal. Calcd for C21H20FN3: C, 75.65; H, 6.05; N, 12.60; Found : C, 75.44; H, 6.07; N, 12.65 %. 4-Methyl-N-{[2-(piperidin-1-yl) idene} aniline (14) quinolin-3-yl] methyl-

FT-IR (KBr) cm
1 : 1624 (C=N), 1600 (C=C); 1H NMR (CDCl3, 300 MHz)
(ppm): 1.66-1.77 (m, 6H, CH23), 2.39 (s, 3H, CH3), 3.39 (bs, 4H, N (CH2)2), 7.19-7.25 (m, 4H, Ar-H), 7.32-7.37 (t, 1H, H-6, J = 7.3), 7.59-7.64 (t, 1H, H-7, J = 7.3 Hz), 7.77-7.80 (d, 1H, H-5, J = 8.1 Hz), 7.83-7.86 (d, 1H, H-8, J = 8.1), 8.66 (s, 1H, H-4), 8.71 (s, 1H, CH=N); Anal. Calcd for C22H23N3: C, 80.21; H, 7.04; N, 12.76; Found : C, 80.00; H, 7.07; N, 12.80 %. 4-Methoxy-N-{[2-(piperidin-1-yl) quinolin-3-yl] methylidene} aniline (15) FT-IR (KBr) cm
1 : 1623 (C=N), 1590 (C=C); 1H NMR (CDCl3, 300 MHz)
(ppm): 1.68-1.77 (m, 6H, CH23), 3.38 (bs, 4H, N (CH2)2), 3.84 (s, 3H, OCH3), 6.95-6.98 (d, 2H, Ar-H-2 & 6, J = 8.7 Hz), 7.28-7.36 (m, 3H, Ar-H-3 & 5 and H-6), 7.58-7.63 (t, 1H, H-7, J = 7.3 Hz), 7.76-7.79 (d, 1H, H-5, J = 7.8 Hz), 7.83-7.86 (d, 1H, H-8, J = 8.1), 8.66 (s, 1H, H-4), 8.69 (s, 1H, CH=N); Anal. Calcd for C22H23N3O: C, 76.49; H, 6.71; N, 12.16; Found : C, 76.79; H, 6.69; N, 12.19 %. General Method for the Synthesis of Amine Derivatives (16-21) To a solution of 2-(piperidin-1-yl) quinoline-3carbaldehyde (1 mmol, 0.240 g) (2) in 10 ml of methanol, substituted aniline (1 mmol) was added and then 50 mg iodine was added portion wise with stirring at room temperature. To the stirred solution 55 mg of sodium

FT-IR (KBr) cm
1: 1623 (C=N), 1590 (C=C), 770 (C-Cl); 1 H NMR (CDCl3, 300 MHz)
(ppm): 1.67-1.76 (m, 6H, CH23), 3.38 (bs, 4H, N (CH2)2), 7.18-7.21 (d, 2H, Ar-H2 & 6, J = 8.4 Hz), 7.36-7.39 (m, 3H, Ar-H-3 & 5 and H6), 7.61-7.65 (t, 1H, H-7, J = 7.6 Hz), 7.77-7.79 (d, 1H, H-5, J = 7.6 Hz), 7.88 (s, 1H, H-8), 8.60 (s, 1H, H-4), 8.70 (s, 1H, CH=N); Anal. Calcd for C21H20ClN3: C, 72.09; H, 5.76; N, 12.01; Found : C, 71.85; H, 5.79; N, 12.05 %. 3-4-Dichloro-N-{[2-(piperidin-1-yl) quinolin-3-yl] methylidene} aniline (11) FT-IR (KBr) cm : 1631 (C=N), 1590 (C=C), 766 (C-Cl); H NMR (CDCl3, 300 MHz)
(ppm): 1.69-1.78 (m, 6H, CH23), 3.38 (bs, 4H, N (CH2)2), 7.09-7.12 (m, 1H, Ar-H6), 7.35-7.39 (m, 2H, Ar-H-2 & 5), 7.47-7.50 (d, 1H, H-6, J = 8.7 Hz), 7.62-7.67 (t, 1H, H-7, J = 7.6 Hz), 7.77-7.80 (d, 1H, H-5, J = 8.1 Hz), 7.84-7.87 (d, 1H, H-8, J = 8.4 Hz),
1
1

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borohydride was added slowly, stirring further for 3 hrs. The precipitate was formed which was filtered, washed with water, dried and recrystallized from ethanol to give solid product. The progress of reaction and purity of the compound was checked by TLC, using Hexane: Ethyl acetate (6:1) as mobile phase. 4-Chloro-N-{[2-(piperidin-1-yl) aniline (16) quinolin-3-yl] methyl}

4-Methyl-N-{[2-(piperidin-1-yl) aniline (20)

quinolin-3-yl]

methyl}

FT-IR (KBr) cm
1: 1596 (C=C), 1036 (C-N), 3389 (NH), 729 (C-Cl); 1H NMR (CDCl3, 300 MHz)
(ppm): 1.661.76 (m, 6H, CH23), 3.26 (bs, 4H, N (CH2)2), 4.40 (bs, 2H, CH2), 4.60 (bs, 1H, NH), 6.52-6.54 (d, 2H, Ar-H-2 & 6, J = 8.4 Hz), 7.08-7.10 (d, 2H, Ar-H-3 & 5, J = 8.8 Hz), 7.31-7.35 (t, 1H, H-6, J = 7.2 Hz), 7.55-7.59 (t, 1H, H-7, J = 7.4 Hz), 7.61-7.63 (d, 1H, H-5, J = 7.6 Hz), 7.89-7.90 (d, 1H, H-8, J = 6.8 Hz), 8.00 (s, 1H, H-4); Anal. Calcd for C21H22ClN3: C, 71.68; H, 6.30; N, 11.94; Found : C, 71.90; H, 6.28; N, 11.97 %. 3-4-Dichloro-N-{[2-(piperidin-1-yl) quinolin-3-yl] methyl} aniline (17) FT-IR (KBr) cm
1: 1603 (C=C), 1021 (C-N), 3390 (NH), 721 (C-Cl); 1H NMR (CDCl3, 300 MHz)
(ppm): 1.671.77 (m, 6H, CH23), 3.24 (bs, 4H, N (CH2)2), 4.36-4.38 (d, 2H, CH2, J = 5.1 Hz), 4.57 (bs, 1H, NH), 6.41-6.45 (m, 1H, Ar-H-6), 6.63-6.66 (m, 1H, Ar-H-2), 6.88-6.94 (t, 1H, H-6, J = 8.8 Hz), 7.32-7.37 (t, 1H, H-7, J = 7.4 Hz), 7.557.65 (m, 2H, H-5 & Ar-H-5), 7.86-7.89 (d, 1H, H-8, J = 8.4 Hz), 7.99 (s, 1H, H-4); Anal. Calcd for C21H21Cl2N3: C, 65.29; H, 5.48; N, 10.88; Found : C, 65.02; H, 5.50; N, 10.93 %. 3-Chloro, 4-fluoro-N-{[2-(piperidin-1-yl) quinolin-3-yl] methyl} aniline (18) FT-IR (KBr) cm
1: 1596 (C=C), 1036 (C-N), 3287 (NH), 729 (C-Cl); 1H NMR (CDCl3, 300 MHz)
(ppm): 1.671.77 (m, 6H, CH23), 3.24 (bs, 4H, N (CH2)2), 4.36-4.38 (d, 2H, CH2, J = 5.1 Hz), 4.57 (bs, 1H, NH), 6.41-6.45 (m, 1H, Ar-H-6), 6.63-6.66 (m, 1H, Ar-H-2), 6.88-6.94 (t, 1H, H-6, J = 8.8 Hz), 7.32-7.37 (t, 1H, H-7, J = 7.4 Hz), 7.557.65 (m, 2H, H-5 & Ar-H-5), 7.86-7.89 (d, 1H, H-8, J = 8.4 Hz), 7.99 (s, 1H, H-4); FAB-MS: m/z 369 (M+), 371 [(M+2)+]; Anal. Calcd for C21H21ClFN3: C, 68.19; H, 5.72; N, 11.36; Found : C, 68.43; H, 5.75; N, 11.32 %. 4-Fluoro-N-{[2-(piperidin-1-yl) aniline (19) quinolin-3-yl] methyl}

FT-IR (KBr) cm
1: 1613 (C=C), 1024 (C-N), 3360 (NH); 1H NMR (CDCl3, 300 MHz)
(ppm): 1.65-1.76 (m, 6H, CH23), 2.23 (s, 3H, CH3), 3.25-3.28 (t, 4H, N (CH2)2, J = 4.6 Hz), 4.41 (bs, 3H, CH2NH), 6.55-6.58 (d, 2H, Ar-H-2 & 6, J = 8.1 Hz), 6.97-6.99 (d, 2H, Ar-H-3 & 5, J = 7.8 Hz), 7.30-7.35 (t, 1H, H-6, J = 7.3 Hz), 7.53-7.58 (t, 1H, H-7, J = 7.6 Hz), 7.62-7.65 (d, 1H, H-5, J = 8.1 Hz), 7.85-7.87 (d, 1H, H-8, J = 8.4 Hz), 8.06 (s, 1H, H-4); Anal. Calcd for C22H25N3: C, 79.72; H, 7.60; N, 12.68; Found : C, 79.50; H, 7.63; N, 12.73 %. 4-Methoxy-N-{[2-(piperidin-1-yl) quinolin-3-yl] methyl} aniline (21) FT-IR (KBr) cm
1: 1616 (C=C), 1033 (C-N), 3378 (NH); 1H NMR (CDCl3, 300 MHz)
(ppm): 1.16-1.76 (m, 6H, CH23), 3.26 (bs, 4H, N (CH2)2), 3.72 (s, 3H, OCH3), 4.28 (bs, 1H, NH), 4.39 (s, 2H, CH2), 6.59-6.61 (d, 2H, Ar-H-2 & 6, J = 8.7 Hz), 6.75-6.78 (d, 2H, Ar-H-3 & 5, J = 8.7 Hz), 7.30-7.35 (t, 1H, H-6, J = 7.8 Hz), 7.53-7.58 (t, 1H, H7, J = 8.1 Hz), 7.62-7.65 (d, 1H, H-5, J = 7.8 Hz), 7.85-7.88 (d, 1H, H-8, J = 8.4 Hz), 8.05 (s, 1H, H-4); Anal. Calcd for C22H25N3O: C, 76.05; H, 7.25; N, 12.09; Found : C, 76.33; H, 7.23; N, 12.05 %. Pharmacological Evaluation The investigations were carried out on wistar albino rats (180-200 g) and swiss albino mice (25-30 g). The rats and mice were kept under standard conditions at ambient temperature of 252 0C and on a 12/12 hours light-dark cycle with free access to food and water. They were acclimatized prior to the experiment. All the experimental protocols were carried out with the permission from Institutional Animal Ethics committee (IAEC), Form no. 611. Animals were obtained from Central Animal House Facility, Hamdard University, New Delhi-62. Registration no. and date of registration is 173/CPCSEA, 28 Jan., 2000. Forced Swimming Test (FST) The forced swimming test (FST) or Despair swim test was proposed as a model to test for antidepressant activity by Porsolt et al [26]. On the first day of the experiment (pretest session), rats were individually placed in a cylindrical recipient (Plexiglas cylinder) of dimensions (diameter 20 cm, height 40 cm) containing 30 cm of water maintained at 251 C. The animals were left to swim for 15 minutes before being removed, dried and returned to their cages. The procedure was repeated 24 hours later, for 5 minutes swim session (test session). Rats received the test compounds (20mg/kg) and standard drug (20 mg/kg) intraperitoneally (i.p.) 1 hr, 19 hrs and 23 hrs after the first exposure to swimming. During 5 minutes test session, the duration of immobility was recorded. Learned Helplessness Test (LST) The learned helplessness test as a model of behavioural despair was carried out according to the method reported by

FT-IR (KBr) cm
1: 1596 (C=C), 1034 (C-N), 3284 (NH); 1H NMR (CDCl3, 300 MHz)
(ppm): 1.65-1.76 (m, 6H, CH23), 3.24-3.38 (m, 4H, N (CH2)2), 4.40-4.44 (bs, 3H, CH2NH), 6.53-6.58 (m, 2H, Ar-H-2 & 6), 6.84-6.90 (t, 2H, Ar-H-3 & 5, J = 8.5 Hz), 7.30-7.35 (t, 1H, H-6, J = 7.3 Hz), 7.54-7.59 (t, 1H, H-7, J = 7.3 Hz), 7.62-7.64 (d, 1H, H5, J = 7.8 Hz), 7.85-7.88 (d, 1H, H-8, J = 8.4 Hz), 8.02 (s, 1H, H-4); Anal. Calcd for C21H22FN3: C, 75.20; H, 6.61; N, 12.53; Found : C, 75.50; H, 6.59; N, 12.58 %.

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O
c

R = H; 4-Cl; 2,4-(Cl)2; 4-OH; 2-OH; 4-CH3; 4-NO2

O N H

CHO
a b

CHO
d

N N N

CH3

Cl

R = Cl; 3,4-(Cl)2; 3-Cl,4-F; 4-F; 4-CH3; 4-OCH3

N H N N

R = Cl; 3,4-(Cl)2; 3-Cl,4-F; 4-F; 4-CH3; 4-OCH3

Fig. (3). (Scheme 1 ): Synthetic pathway to compound 3-21. (a) DMF/POCl3 (b) Piperidine (c) Substituted aromatic acetophenones, NaOH (d) Substituted anilines, glacial acetic acid (e) Substituted anilines, I2/NaBH4.

Vollmayr et al [27]. The test was performed in a two compartment box (56
21
25 cm) separated by a door, consisting of an electrified chamber (chamber with a grid floor connected to a scrambled shock generator) and an unelectrified chamber with the escape door. On day 1, each rat was then exposed to inescapable electric foot shocks (1.1 mA, 10 s) every 30 s during 30 min. Control vehicle treated animals were kept in the chamber but received no shock. On day 2, after this inescapable shock treatment, the rats were subjected to avoidance training, using the same apparatus but keeping the escape route to the unelectrified chamber open. Shocks delivered through the grid floor were terminated as soon as the animal entered into the other compartment. The assay consisted of 30 stimulus shock trials of 8 s with a 30-s resting period between each trial. During this training, the rat was placed in the electrified chamber and allowed to acclimatise for 5 minutes before being subjected to 30 avoidance trials. During the first 5 sec of the trial a buzzer stimulus (conditional stimulus) was presented. If the animal did not cross within this period to the other compartment, an electric shock (0.8 mA, 3-s maximal duration) was delivered. Avoidance sessions were performed during 3 consecutive days and the numbers of escape failures and of inter-trial crossings were recorded. Animals received either saline or treatment throughout the 4-day period. On day 1, the drug was given 6 h after exposure to the inescapable shocks and on days 2-4 the drug was administered twice a day, 30 min before shuttle-box exposure and 6 h after. 5-Hydroxytryptophan (5-HTP) Induced Mouse Headtwitch Test To investigate whether the serotonergic system was involved in the antidepressant-like effect of compound 5, we performed a 5-HTP induced mouse head-twitch test [28,29]. Male swiss albino mice (20-25g) were randomly chosen and

divided into 3 groups viz. normal control group, test group for compound 5, and positive control group (Fluoxetine). Mice were administered an i.p. injection of compound 5 (10mg/kg), Fluoxetine (30mg/kg) or 2% aqueous solution of Tween 80 (p.o), 60 min before 5-HTP (100mg/kg, i.p.) administration. Immediately after the second injection, mice were placed into plastic cages. Ten minutes later, the cumulative number of head twitches (rapid movements of the head with little or no involvement of the trunk) was recorded for 6 min. Yohimbine Toxicity Potentiation Test To unravel whether the noradrenergic system is involved in the antidepressant-like effect of the compound 5, the yohimbine toxicity potentiation test was performed [28]. Male swiss albino mice (20-25g) were randomly chosen and divided into 3 groups: normal control group, group for compound 5, and positive control group (clomipramine). Mice were administered a i.p. injection of compound 5 (10mg/kg), clomipramine (30mg/kg) or 2% aqueous solution of Tween 80 (p.o), 1hr prior to yohimbine administration (20 mg/kg, s.c.). The number of dead mice was calculated during a 20 hrs period after the injection of yohimbine. Prediction of Pharmacokinetic (ADME) Parameters A computational study of titled compounds (3-21) was performed for the prediction of ADME properties. Polar surface area (TPSA) [30], miLog P, number of rotatable bonds, molecular volume, number of hydrogen donor and acceptor atoms and violations of Lipinskis rule of five [31] were calculated using Molinspiration online property calculation toolkit [32]. Absorption (%ABS) was calculated by: % ABS = 109-(0.345
TPSA) [33]. The pharmacokinetic

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Table 1.

Physico-chemical parameters of synthesized compounds 3-21.

R H 4-CH3 2,4-Cl 4-OH 2-OH 4-Cl 4-NO2 4-Cl 3,4-Cl 3-Cl,4-F 4-F 4-CH3 4-OCH3 4-Cl 3,4-Cl 3-Cl,4-F 4-F 4-CH3 4-OCH3 Molecular formula C23H 22N2 O C24H 24N2 O C23H 20Cl2N2O C23H 22N2 O2 C23H 22N2 O2 C23H 21ClN2O C23H 21N3 O3 C21H 20ClN3 C21H 19Cl2N3 C21H 19ClFN3 C21H 20FN3 C22H 23N3 C22H 23N3 O C21H 22ClN3 C21H 21Cl2N3 C21H 21ClFN3 C21H 22FN3 C22H 25N3 C22H 25N3 O Molecular Weight 342.43 356.46 411.32 358.43 358.43 376.87 387.43 349.85 384.30 367.84 333.40 329.43 345.43 351.87 386.31 369.86 335.41 331.45 347.45 Yielda (%) 70 86 68 78 70 78 86 89 92 67 70 67 65 56 58 58 56 51 55 Mp ( C) 113-114 115-117 109-111 127-130 131-132 140-142 205-207 123 112 120 116 113 104 117 127 130 115 119 98 Rf valueb 0.48b1 0.33b1 0.66b1 0.30b1 0.51b1 0.55b1 0.62b1 0.54b1 0.50b1 0.53b1 0.56b1 0.59b1 0.47b1 0.38b2 0.30b2 0.28b2 0.38b2 0.48b2 0.26b2

Compound 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

a- Solvent used for crystallization ethanol:water (9:1). b1- Solvent system toluene:ethyl acetate:formic acid (5:4:1). b2- Solvent system hexane:ethyl acetate (6:1).

parameters of the titled compounds (3-21) are presented in Table 6. Statistical Analyses Results are expressed as mean S.E.M.; n represents the number of animals. All the statistical analyses were carried out using the software SigmaStat 4.0 using ANOVA followed by dunnett's multiple comparison tests and the results are expressed in Mean SEM. RESULTS AND DISCUSSION Chemistry The synthesis of various quipazine analogues (3-21) was carried out as per the Scheme 1 outlined in Fig. (3). 2-Chloroquinoline-3-carbaldehyde (1) was synthesized according to the method reported in literature, by the action of Vilsmeier-Haack reagent (DMF/POCl3) on acetanilide. The 2-chloroquinoline-3-carbaldehyde was further reacted with piperidine, which yielded penultimate intermediate 2(piperidin-1-yl) quinoline-3-carbaldehyde (2). The clasienschmidt condensation of compound (2) with various substituted aromatic acetophenone in ethanol afforded

chalcones (3-9), while reaction of compound (2) with substituted aromatic amines yielded schiffs bases (10-15). Compounds (16-21) were synthesized by direct reductive amination using I2 and NaBH4 in absolute methanol. The structures of all the compounds were established by combined use of IR, 1H-NMR and mass spectral data of some selected compounds. The elemental analysis of the final compounds was found to be within 0.4 % limit. The physico-chemical data of all the final compounds (3-21) have been reported in Table 1 . The 1H NMR spectrum of compound 2 showed a multiplet resonating between  1.68 and 1.78 ppm, which was assigned to the six protons of piperidine ring. A triplet integrating for four protons of N(CH2)2< of piperidine ring appeared downfield at  3.4 ( J = 5.1 Hz). Furthermore the mass spectrum of compound 2 showed the molecular ion peak i.e. m/z (M+) at 240, which confirmed its synthesis. The functional group transformation of CHO in compound 2 into COCH=CH in compounds 3-9, CH=N in compounds 10-15 and in CH2NH in compounds 16-21 was established on the basis of IR, 1H NMR and mass spectral data. In the 1H NMR spectra of chalcones (3-9), the protons of
,-unsaturated system absorbed as two doublets around  7.4 ppm for H-
and  7.9 for H- with coupling constant J = 15-16 Hz. In the 1H NMR spectrum of

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Table 2.

In vivo antidepressant activity of the synthesized compounds (3-21) using forced swim test (FST) on wistar albino rats.
Duration of immobility (sec) (MeanS.E.M.) % change relative to control

Compound

3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Control Clomipramine

96.615.1** 92.515.6* 61.68.5*** 92.612.2* 93.513.4** 68.69.2*** 89.811.8* 102.513.3* 97.010.2** 97.212.9*** 109.513.5* 109.812.4*** 112.314.2* 85.315.2*** 74.012.4*** 81.610.1* 85.810.8** 87.814.9*** 89.013.5* 199.510.9 57.69.3***

-51.58 -53.63 -69.12 -53.58 -53.13 -65.61 -54.99 -48.62 -51.38 -51.28 -45.11 -44.96 -43.70 -57.24 -62.90 -59.10 -56.99 -55.99 -55.39 --71.13

Data was analysed by ANOVA with Dunnetts multiple comparisons test. n = 8; Dose = 20mg/kg; ***p<0.001, **p<0.01& *p<0.05 (compared to control). The percentage change from control [(test/control)
100) - 100] is calculated for each group.

compounds 10-15, a singlet resonated between  8.6-8.7 indicating the proton of CH=N. However in the 1H NMR spectrum of compounds 16-21, the methylene group of CH2NH appeared as a singlet, broad singlet (bs) and in some compounds as a doublet (J = 5.1 Hz) resonating between  4.3-4.4 ppm due to coupling with the NH proton whereas the NH signal was observed as a broad singlet resonating around  4.6 ppm. The above spectral analysis suggested the successful synthesis of titled compounds 3-21. This fact was further supported by FAB-MS spectra of some selected compounds. Pharmacological Evaluation The preliminary antidepressant activities for the compounds (3-21) were performed by forced swim test (FST) in rat at dose of 20 mg/kg in comparison with the standard drug clomipramine (20 mg/kg). All the test compounds and reference drug were administered

intraperitoneally (i.p.) as suspension in aqueous Tween 80 (2 % w/v, 0.9 % w/v NaCl), 1 hr, 19 hrs and 23 hrs after the pre-test session of 15 minutes. Antidepressant activity was assessed as mean immobility time in seconds and data has been presented as Mean S.E.M in Table 2. Results of FST revealed that compounds 5, 8, and 17 exhibited significant (P<0.001) reduction in the immobility time compared to the control, while compounds 16, 18 and 19 showed moderate antidepressant activity. The preliminary SAR of 2-piperidinyl quinoline chalcones/amines suggested that chalcones showed good antidepressant activity followed by amines having freely rotatable methylene amine function, while schiffs bases showed least activity among all the derivatives. Among all the compounds, chalcone derivatives having chloro substitution on the phenyl ring showed excellent antidepressant activity, followed by amine compounds having halogen substitution. It appeared that an increase in the numbers of the -Cl or -F substitution on the

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Table 3.

In vivo antidepressant activity of the synthesized compounds (5, 8 and 17) using learned helplessness test (LST) on wistar albino rats.
Number of escape failures (MeanSEM) Treatment (mg/kg/day; i.p) SB1 Escapable shocks- vehicle vehicle 5 (30) 6.30.8 22.11.1** 12.60.5b 13.01.0b 15.72.1b 11.80.7b SB2 6.00.7 20.51.1** 7.10.8b 8.10.7b 9.00.8b 5.60.8b SB3 5.60.8 19.80.9** 4.50.7b 4.80.8b 5.61.4b 3.21.0b

Inescapable shocks

8 (30) 17 (30) Clomipramine (30)

Data are the meansSEM of escape failures in each of the three consecutive shuttle-box sessions (SB1-3) and was analysed by ANOVA with Dunnetts multiple comparisons test. n = 8; p value: **<0.01 in comparison to escapable shock vehicle treated group, while b<0.01 in comparison to inescapable shock vehicle treated group.

phenyl ring could influence activity. The hypothesis was that the introduction of halogens would increase the lipophilic property of the compounds. This would increase their permeability across the bloodbrain barrier, which would probably enhance their antidepressant activity. Compounds 5, 8 and 17 showing excellent antidepressant activity in FST were further investigated by the learned helplessness test (LHT) in rats at a lower dose of 15 mg/kg as compared to standard drug clomipramine (15 mg/kg). All the test compounds and reference drug were administered intraperitoneally (i.p.) as suspension in aqueous Tween 80 (2 % w/v, 0.9 % w/v NaCl), on 4 consecutive days, 6 h after inescapable shocks on day 1 and then twice a day (30 min before shuttle-box sessions and 6 h later). Data has been presented as Mean S.E.M in Table 3 . The data further confirmed the antidepressant potential of these compounds. In the present study, two behavioural models were also used to study possible monoaminergic participation in antidepressant activity. The most active compound 5 was chosen for these tests. Compound 5 significantly increased the cumulative number of head twitches (p<0.05 vs control) in the 5-hydroxy-l-tryptophan (5-HTP)-induced head-twitch test Table 4, and enhanced the mouse mortality (p<0.05 vs control) induced by yohimbine Table 5. The 5-HTP-induced head-twitch test is an effective method to evaluate the serotonergic effects of drugs in vivo [34].
Table 4. Effect of compound 5 and fluoxetine on 5-HTPinduced head twitches in mice.
Dose (mg/kg) 30 30 -5-HTP (mg/kg) 100 100 100 Number of head twitches 38.212.4* 44.111.3** 16.45.3

elicits
2-adrenergic release by its antagonistic action on presynaptic
2-adrenoceptors. The yohimbine toxicity potentiation test is usually employed for evaluation of the noradrenergic effects of antidepressants [35]. Results suggested that the mechanism of action of the antidepressant effects of compound 5 may be related to the reinforcement of central monoamine neurotransmitters (especially to 5hydroxytryptamine (5HT) and norepinephrine (NE).
Table 5. Effect of compound 5 and clomipramine on yohimbine-induced toxicity (mortality) in mice.
Dose (mg/kg) 30 30 -Yohimbine (mg/kg) 20 20 20 % Mortality 70* 80* 20

Compounds 5 Clomipramine Control

Data was analysed by Fischers exact test; n = 10; *p<0.05 (compared to control).

Prediction of ADME Properties A computational study for prediction of ADME properties of titled compounds (3-21) was performed. Topological polar surface area (TPSA), i.e., surface belonging to polar atoms, is a descriptor that was shown to correlate well with passive molecular transport through membranes and, therefore, allows prediction of transport properties of drugs in the intestines and blood-brain barrier (BBB) crossing [30]. The percentage of absorption (%ABS) was calculated using TPSA [33]. From all these parameters, it was observed that all titled compounds exhibited an excellent %ABS ranging from 90.57 to 99.28 % Table 6 . The lipophilicity data also suggested that the derivatives were fairly lipophilic and hence able to cross BBB. Furthermore, among the series compounds 4, 5, 8, 10-12, 14 and 16-18 violated only one Lipinskis parameter. The excellent pharmacokinetic parameters of these compounds makes them potentially promising agent for antidepressant therapy.

Compounds 5 Fluoxetine Control

Data was analysed by ANOVA with Dunnetts test; n = 8; **p<0.01& *p<0.05 (compared to control).

In general, it is accepted that the number of head twitches represents the level of 5-HT in the synapses. Yohimbine

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Table 6. Pharmacokinetic parameters important for good oral bioavailability of compounds 3-21.
TPSA (A2) --

Compound Lipinski Rule 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

%ABS --

n-ROTB --

MW <500

MV --

n-OHNH donors <5

n-ON acceptors <10

milogP <5

Lipinskis violations
1

97.54 97.54 97.54 90.57 90.57 97.54 81.74 99.17 99.17 99.17 99.17 99.17 95.98 99.28 99.28 99.28 99.28 99.28 96.10

33.20 33.20 33.20 53.43 53.43 33.20 79.02 28.49 28.49 28.49 28.49 28.49 37.73 28.16 28.16 28.16 28.16 28.16 37.39

4 4 4 4 4 4 5 3 3 3 3 3 4 4 4 4 4 4 5

342.44 356.47 411.33 358.44 358.44 376.88 387.44 349.86 384.31 367.85 333.41 329.45 345.45 351.88 386.33 369.87 335.43 331.46 347.46

327.64 344.20 354.71 335.66 335.66 341.17 350.97 318.03 331.57 322.97 309.43 321.06 330.04 323.98 337.51 328.91 315.37 327.00 335.99

0 0 0 1 1 0 0 0 0 0 0 0 0 1 1 1 1 1 1

3 4 3 4 4 3 6 3 3 3 3 3 4 3 3 3 3 3 4

4.91 5.36 6.20 4.43 4.85 5.59 4.87 5.43 6.03 5.52 4.91 5.20 4.81 5.15 5.76 5.24 4.64 4.92 4.53

0 1 1 0 0 1 0 1 1 1 0 1 0 1 1 1 0 0 0

%ABS, percentage of absorption; TPSA, topological polar surface area; n-ROTB, number of rotatable bonds; MW, molecular weight; MV, molecular volume; n-OHNH, number of hydrogen bond donors; n-ON, number of hydrogen bond acceptors; milogP, logarithm of compound partition coefcient between octanol and water calculated as per molinspiration online property toolkit; %ABS = 109 (0.345
TPSA)

CONCLUSION A novel series of 2-piperidinyl quinoline chalcones/amines as structural analogue of quipazine was designed, synthesized and screened for their antidepressant potential by Forced swim test (FST) and Learned helplessness test (LST). The chalcone derivative bearing 2,4dichloro substituted phenyl ring (5) showed promising result and reduced significantly the duration of immobility (p<0.001) as compared to control; it reduced the immobility time by 69.12 % as compared to standard drug clomipramine, 71.13 %. Similarly promising result was obtained in LST for this compound. Furthermore, in 5-HTPinduced head-twitch test and yohimbine-induced mortality test, most active compound 5 increased the rate of headtwitching and the prevalence of mortality. Thus, the mechanism of action of the antidepressant effects of this compound 5 may be attributed to increased 5HT and NE level in the synapse. These findings indicated that compound 5 (1-(2,4-Dichlorophenyl)-3-[2-(piperidin-1-yl) quinolin-3-

yl] prop-2-en-1-one), would be a potential antidepressant agent and needs further research in terms of its mechanism of action. CONFLICT OF INTEREST None of the authors have any conflict of interest in the context of this work. ACKNOWLEDGEMENT The author (Obaid Afzal) is grateful to the Council of Scientific and Industrial Research (CSIR), New Delhi, India, for the award of senior research fellowship (SRF). Authors are also thankful to Department of Pharmaceutical Chemistry and Pharmacology, Jamia Hamdard for providing necessary facilities. The spectral data provided by Central Instrumentation Facility, JNU, New Delhi and CDRI, Lucknow is also acknowledged.

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Received: August 01, 2012

Revised: October 08, 2012

Accepted: October 17, 2012