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22

Chapter 2

Synthesis and antibacterial activity

of piperazine derivatives

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2.1. Introduction

Piperazine consists of a six-member ring containing the two opposing nitrogen

atoms was originally named because of its chemical similarities with piperidine, a

constituent of piperine in the black pepper plant (Piper nigrum). It is a weak base with

pka of 4.19 and freely soluble in water and ethylene glycol but insoluble in diethyl

ether.

Piperazine is an interesting heterocyclic structure present in many biologically

active molecules. The polar nitrogen atoms into the piperazine ring confer bioactivity

of molecules and enhance favorable interaction with macromolecules.1,2 Piperazine

and substituted piperazines are important pharmacophores that can be found in many

marketed drugs such as the Merck HIV protease inhibitor Crixivan.3-10 Piperazinyl-

linked ciprofloxacin dimers reported as potent antibacterial agents against resistant

strains,11 antimalarial agents

12 and potential antipsychotic agents.

13 Recently,

piperazine derivatives containing tetrazole nucleus have been reported as an

antifungal agent.14

S,S-1-adamantan-1-yl-3-[2-(5-benzyl-piperazine-2-yl)-ethyl]urea a

piperazine containing dialkyl urea exhibited good potency against human SEH

(soluble epoxide hydrolase) with an IC50 value of 1.37 µM and developed as a drug

for anti-hypertension and anti-inflammation.15 Substituted benzamide piperazine

derivatives have shown strong agonistic activity while the substituted acetamide

piperazine derivative have better dopamine D4 receptor agonist activity than

substituted benzamide piperazine derivatives.16,17

Diphenyl piperazine derivative

possesses broad pharmacological action on central nervous system (CNS), especially

on dopaminergic neurotransmission.18 Sulfonamides are among the most widely used

antibacterial agents because of their low toxicity and excellent activity against

common bacterial diseases. N-sulfonamide derivatives of 1-[bis(4-fluorophenyl)-

methyl]piperazine exhibited potent antibacterial activity against Escherichia coli,

Proteus vulgaris and Salmonella typhi.19 Most of the quinoline drugs, such as

norfloxacin and ciprofloxacin having piperazine nucleus showed broad spectrum

activity of respiratory, urinary, gastrointestinal tracts, skin and soft tissue infection

caused by either Gram-negative or Gram-positive bacteria.20 Various cyano

derivatives of piperazine are known for their uses in the synthesis of pharmaceutical

intermediates, peptide analogues and antibacterial drugs.21-23

Cyano derivatives of

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N-alkyl and N-aryl substituted piperazine derivatives exhibited potent activity against

Pseudomonas aeruginosa.24 Dihydro-1,2-oxazine and 2-pyrazoline oxazolidinones

related to linezolid and eperezolid showed potent antibacterial activity.25 A novel

series of N-aryl piperazine-1-carboxamide derivatives were found to exhibit potent

antiandrogenic activity.26 The new piperazine linked chalcone derivatives showed

potent antibacterial activity against Staphylococcus aureus, Escherichia coli, Proteus

vulgari and antifungal activity against Aspergillus fumigatus and Candida albicans.27

Many other piperazine derivatives are notably successful drugs.

In the present study, we have aimed to synthesize new piperazinyl-linked

antibacterials by nucleophilic substitution reaction of N-alkyl and N-aryl piperazine

derivatives with different p-substituted phenacyl halides.

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2.2. Experimental

2.2.1. Reaction scheme for the synthesis of piperazine derivatives (Pz 1 to

Pz 9)

N NHH3C

R

O

BrN NH3C

O

R

+

N-methyl piperazine p-substituted

phenacyl bromide

Pz 1 - Pz 3

N NH

R

O

BrN N

O

R

+

N-phenyl piperazine p-substituted

phenacyl bromide

Pz 4 - Pz 6

R

O

Br+

N-benzyl piperazine p-substituted

phenacyl bromidePz 7 - Pz 9

N

NHN

NO

R

where R= -Br, -CH3, -OCH3

Scheme 2.1. Reagent and conditions: (i) K2CO3, acetonitrile, 0 oC- rt, 8-10 h.

i

i

i

2.2.2. General experimental procedure for synthesis of piperazine

derivatives

To a solution of substituted piperazine derivatives (1.0 mequiv) in acetonitrile

(20 ml), were added powdered potassium carbonate (5.0 mequiv) at 0 oC, and stirred

the resulting solution for 15 min at 0 oC then p-substituted phenacyl bromide

derivatives (1.0 mequiv) were added at 0 oC. The reaction mixture was stirred at room

temperature for about 8-10 h, progress of reaction was monitored by TLC using 5%

methanol in DCM. After completion of reaction the reaction mixture was diluted with

distilled water (50 ml) and extracted with DCM (3×50 ml), combined organic layer

was washed with aqueous solution of sodium bicarbonate (3×50 ml), distilled water

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(3×50 ml), brine solution (3×50 ml) and dried over anhydrous sodium sulphate and

concentrate it under reduced pressure, obtained crude products. which was purified by

column chromatography using silica gel (60-120 mesh) as adsorbent with DCM:

MeOH (99:1 to 95:5) as an eluent to obtain the pure compounds in 62–71% yields.

All the synthesized compounds were characterized with the help of their IR, MS, and

NMR (1H &

13C NMR) spectral data.

2.3. Synthesis of derivatives

2.3.1. Synthesis of 1-(4-bromophenyl)-2-(4-methylpiperazin-1-yl)ethanone

(Pz 1)

The general synthetic procedure described earlier, afforded compound Pz 1

from N-methyl piperazine (1.0 g, 9.9 mmol, 1.0 mequiv) with p-bromophenacyl

bromide (2.7 g, 9.9 mmol, 1.0 mequiv) and powdered potassium carbonate (6.8 g,

49.9 mmol, 5.0 mequiv) in dry acetonitrile (20 ml) as a reaction solvent.

NNH3C

Br

O

1-(4-bromophenyl)-2-(4-methylpiperazin-1-yl)ethanone

Molecular Formula: C13H17BrN2O (M.W. 296.19); Physical state: solid; Colour:

yellow; Yield: 64%; Purity: 95%; mp: 81-83 oC; MS: [M

+1] & [M

+1+2], m/z 297.07

& m/z 299.09; IR υmax: 2938, 2799, 2696, 2475, 1693, 1513, 1376, 1172, 810 cm-1; 1H

NMR (500 MHz, CDCl3): δ 7.87 (d, 2H, J = 8.5 Hz, Ar-H), 7.60 (d, 2H, J = 8.5 Hz,

Ar-H), 3.77 (s, 2H, N-CH2), 3.07 (brs, 2H, piperazine- H), 2.64 (brd, 3H, piperazine-

H), 2.56 (brs, 3H, piperazine-H), 2.32 (s, 3H, N-CH3); 13

C NMR (125 MHz, CDCl3):

δ 195.3 (C=O), 134.4 (CAr), 131.6 (2 × CHAr), 129.5 (2 × CHAr), 128.3 (CAr), 64.3 (N-

CH2), 54.5 (2 × piperazine-CH2), 53.0 (2 × piperazine-CH2), 45.5 (N-CH3).

2.3.2. Synthesis of 2-(4-methylpiperazin-1-yl)-1-p-tolylethanone (Pz 2)

The general synthetic procedure described earlier, afforded compound Pz 2

from N-methyl piperazine (1.0 g, 9.9 mmol, 1.0 mequiv) with p-methylphenacyl

bromide (2.1 g, 9.9 mmol, 1.0 mequiv) and powderd potassium carbonate (6.8 g, 49.9

mmol, 5.0 mequiv) in dry acetonitrile (20 ml) as a reaction solvent.

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NNH3C

CH3

O

2-(4-methylpiperazin-1-yl)-1-p-tolylethanone

Molecular Formula: C14H20N2O (M.W. 232.32); Physical state: solid; Colour:

yellow; Yield: 68%; Purity: 91%; mp: 108-110 oC; MS: [M

+1], m/z 233.23; IR υmax:

2947, 2785, 2680, 2477, 1695, 1606, 1455, 1376, 1284 cm-1;

1H NMR (500 MHz,

CDCl3): δ 7.84 (d, 1H, J = 8.0 Hz, Ar-H), 7.06 (d, 3H, J = 11.0 Hz, Ar-H), 3.88 (brs,

2H, piperazine-H), 3.48 (s, 2H, N-CH2), 3.13 (brs, 2H, piperazine-H), 2.98 (brs, 2H,

piperazine-H), 2.42 (brs, 2H, piperazine-H), 2.20 (s, 3H, N-CH3), 2.18 (s, 3H, CH3);

13C NMR (125 MHz, CDCl3,): δ 195.6 (C=0), 144.5 (CAr), 132.6 (CAr), 129.3 (2 ×

CHAr), 127.8 (2 × CHAr), 63.9 (N-CH2), 54.3 (2 × piperazine-CH2), 52.8 (2 ×

piperazine-CH2), 45.5 (N-CH3), 21.6 (CH3).

2.3.3. Synthesis of 1-(4-methoxyphenyl)-2-(4-methylpiperazin-1-yl)

ethanone (Pz 3)

The general synthetic procedure described earlier, afforded compound Pz 3

from N-methyl piperazine (1.0 g, 9.9 mmol, 1.0 mequiv) with p-methoxyphenacyl

bromide (2.2 g, 9.9 mmol, 1.0 mequiv) and powderd potassium carbonate (6.8 g, 49.9

mmol, 5.0 mequiv) in dry acetonitrile (20 ml) as a reaction solvent.

NNH3C

OCH3

O

1-(4-methoxyphenyl)-2-(4-methylpiperazin-1-yl)ethanone

Molecular Formula: C14H20N2O2 (M.W. 248.32 ); Physical state: solid; Colour:

yellow; Yield: 70%; Purity: 96%; mp: 88-92 0C MS: [M

+1], m/z 249.36; IR υmax:

2947, 2875, 2799, 2686, 2471, 1690, 1460, 1284, 1147 cm-1;

1H NMR (500 MHz,

CDCl3): δ 7.96 (d, 2H, J = 7.0 Hz, Ar-H), 6.92 (d, 2H, J = 7.0 Hz, Ar-H), 3.85 (s, 3H,

OCH3), 3.77 (s, 2H, N-CH2), 2.64 (brd, 8H, piperazine-H), 2.34 (s, 3H, N-CH3); 13

C

NMR (125 MHz, CDCl3): δ 194.5 (C=O), 163.3 (CAr), 130.1 (2 × CHAr), 128.8 (CAr),

113.4 (2 × CHAr), 63.8 (N-CH2), 55.2 (OCH3), 54.3 (2 × piperazine-CH2), 52.8 (2 ×

piperazine-CH2), 45.3 (N-CH3).

2.3.4. Synthesis of 1-(4-bromophenyl)-2-(4-phenylpiperazin-1-yl)ethanone

(Pz 4)

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The general synthetic procedure described earlier, afforded compound Pz 4

from N-phenyl piperazine (1.0 g, 6.1 mmol, 1.0 mequiv) with p-bromophenacyl

bromide (1.7 g, 6.1 mmol, 1.0 mequiv) and powderd potassium carbonate (4.2 g, 30.8

mmol, 5.0 mequiv) in dry acetonitrile (20 ml) as a reaction solvent.

NN

Br

O

1-(4-bromophenyl)-2-(4-phenylpiperazin-1-yl)ethanone

Molecular Formula: C18H19BrN2O (M.W. 358.07); Physical state: solid; Colour:

off white; Yield: 62%; Purity: 97%; mp: 132-134 oC; MS: [M

+1] & [M

+1+2], m/z

359.18 & m/z 361.11; IR υmax: 3085, 3027, 2937, 2813, 2770, 1697, 1585, 1397,

1216, 987, 817 cm-1;

1H NMR (500 MHz, CDCl3): δ 7.92 (d, 2H, J = 8.5 Hz, Ar-H),

7.62 (d, 2H, J = 8.5 Hz, Ar-H), 7.25- 7.29 (m, 2H, Ar-H), 6.94 (d, 2H, J = 8.0 Hz, Ar-

H), 6.87 (t, 1H, J = 7.5 Hz, Ar-H), 3.83 (s, 2H, N-CH2), 3.27 (t, 4H, J = 5.0 Hz,

piperazine-H), 2.77 (t, 4H, J = 5.0 Hz, piperazine-H); 13

C NMR (125 MHz, CDCl3):

δ 195.4 (C=O), 151.2 (N-CAr), 134.6 (CAr), 131.9 (2 × CHAr), 129.8 (2 × CHAr), 129.1

(2 × CHAr), 128.5 (CAr), 119.8 (CHAr), 116.1 (2 × CHAr), 64.6 (N-CH2), 53.5 (2 ×

piperazine-CH2), 49.0 (2 × piperazine-CH2).

2.3.5. Synthesis of 2-(4-phenylpiperazin-1-yl)-1-p-tolylethanone (Pz 5)

The general synthetic procedure described earlier, afforded compound Pz 5

from N-phenyl piperazine (1.0 g, 6.1 mmol, 1.0 mequiv) with p-methylphenacyl

bromide (1.3 g, 6.1 mmol, 1.0 mequiv) and powderd potassium carbonate (4.2 g, 30.8

mmol, 5.0 mequiv) in dry acetonitrile (20 ml) as a reaction solvent.

NN

CH3

O

2-(4-phenylpiperazin-1-yl)-1-p-tolylethanone

Molecular Formula: C19H22N2O (M.W. 294.39); Physical state: solid; Colour: off

white; Yield: 67%; Purity: 97%; mp: 125-128 oC; MS: [M

+1], m/z 295.63; IR υmax:

3062, 3027, 2912, 2880, 2770, 1682, 1568, 1455, 1170, 978, 752 cm-1;

1H NMR (500

MHz, CDCl3): δ 7.94 (d, 2H, J = 8.5 Hz, Ar-H), 7.27- 7.30 (m, 4H, Ar-H), 6.96 (d,

2H, J = 8.0 Hz, Ar-H), 6.88 (t, 1H, J = 7.5 Hz, Ar-H), 3.88 (s, 2H, N-CH2), 3.30 (t,

4H, J = 5.0 Hz, piperazine-H), 2.80 (t, 4H, J = 5.0 Hz, piperazine-H), 2.44 (s, 3H,

CH3); 13

C NMR (125 MHz, CDCl3): δ 195.7 (C=O), 151.2 (N-CAr), 143.5 (CAr),

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133.5 (CAr), 129.2 (2 × CHAr), 129.1 (2 × CHAr), 128.2 (2 × CHAr), 119.8 (CHAr),

116.2 (2 × CHAr), 64.2 (N-CH2), 53.5 (2 × piperazine-CH2), 49.0 (2 × piperazine-

CH2), 21.7 (CH3).

2.3.6. Synthesis of 1-(4-methoxyphenyl)-2-(4-phenylpiperazin-1-yl)

ethanone (Pz 6)

The general synthetic procedure described earlier, afforded compound Pz 6

from N-phenyl piperazine (1.0 g, 6.1 mmol, 1.0 mequiv) with p-methoxyphenacyl

bromide (1.4 g, 6.1 mmol, 1.0 mequiv) and powderd potassium carbonate (4.2 g, 30.8

mmol, 5.0 mequiv) in dry acetonitrile (20 ml) as a reaction solvent.

NN

OCH3

O

1-(4-methoxyphenyl)-2-(4-phenylpiperazin-1-yl)ethanone

Molecular Formula: C19H22N2O2 (M.W. 310.39); Physical state: solid; Colour: off

white; Yield: 66%; Purity: 95%; mp: 156-158 oC; MS: [M

+1], m/z 311.29; IR υmax:

3085, 2936, 2812, 2701, 1693, 1607, 1455, 1295, 1011, 810 cm-1;

1H NMR (500

MHz, CDCl3): δ 8.02 (d, 2H, J = 7.0 Hz, Ar-H), 7.26 (m, 2H, Ar-H), 6.93 (d, 4H, J =

9.0 Hz, Ar-H), 6.85 (t, 1H, J = 7.5 Hz, Ar-H), 3.82 (s, 2H, N-CH2), 3.27 (t, 4H, J =

5.0 Hz, piperazine-H), 2.87 (s, 3H, OCH3), 2.76 (t, 4H, J = 5.0 Hz, piperazine-H);

13C NMR (125 MHz, CDCl3): δ 194.6 (C=O), 163.4 (CAr), 151.1 (N-CAr), 130.3 (2 ×

CHAr), 128.9 (3 × CHAr), 119.5 (CHAr), 115.9 (2 × CHAr), 113.5 (2 × CHAr), 64.1 (N-

CH2), 55.3 (OCH3), 53.4 (2 × piperazine-CH2), 48.8 (2 × piperazine-CH2).

2.3.7. Synthesis of 2-(4-benzylpiperazin-1-yl)-1-(4-bromophenyl)ethanone

(Pz 7)

The general synthetic procedure described earlier, afforded compound Pz 7

from N-benzylpiperazine (1.0 g, 5.6 mmol, 1.0 mequiv) with p-bromophenacyl

bromide (1.5 g, 5.6 mmol, 1.0 mequiv) and powderd potassium carbonate (3.9 g, 28.3

mmol, 5.0 mequiv) in dry acetonitrile (20 ml) as a reaction solvent.

N

N

O

Br

2-(4-benzylpiperazin-1-yl)-1-(4-bromophenyl)ethanone

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Molecular Formula: C19H21BrN2O (M.W. 372.29); Physical state: solid; Colour:

yellow; Yield: 71%; Purity: 98%; mp: 142-144 oC; MS: [M

+1] & [M

+1+2], m/z

373.22 & m/z 375.11; IR υmax: 3062, 2937, 2813, 2700, 1697, 1585, 1397, 1216, 978,

817 cm-1;

1H NMR (500 MHz, CDCl3): δ 7.89 (d, 2H, J = 8.5 Hz, Ar-H), 7.59 (d,

2H, J = 8.5 Hz, Ar-H), 7.25- 7.32 (m, 5H, Ar-H), 3.75 (s, 3H, N-CH2-Ph), 3.53 (s, 2H,

N-CH2-C=O), 2.59 (brd, 8H, piperazine-H); 13

C NMR (125 MHz, CDCl3): δ 195.4

(C=O), 137.6 (CAr), 134.5 (CAr), 131.6 (2 × CHAr), 129.6 (2 × CHAr), 129.0 (2 ×

CHAr), 128.2 (CAr), 128.0 (2 × CHAr), 126.9 (CHAr), 64.1 (N-CH2-C=O), 62.7 (N-

CH2-Ph), 53.2 (2 × piperazine-CH2), 52.6 (2 × piperazine-CH2).

2.3.8. Synthesis of 2-(4-benzylpiperazin-1-yl)-1-p-tolylethanone (Pz 8)

The general synthetic procedure described earlier, afforded compound Pz 8

from N-benzylpiperazine (1.0 g, 5.6 mmol, 1.0 mequiv) with p-methylphenacyl

bromide (1.2 g, 5.6 mmol, 1.0 mequiv) and powerd potassium carbonate (3.9 g, 28.3

mmol, 5.0 mequiv) in dry acetonitrile (20 ml) as a reaction solvent.

N

N

O

CH3

2-(4-benzylpiperazin-1-yl)-1-p-tolylethanone

Molecular Formula: C20H24N2O (M.W. 308.42); Physical state: solid; Colour:

yellow; Yield: 68%; Purity: 94%; mp: 131-135 0C: MS: [M

+1], m/z 309.31; IR υmax:

3085, 3028, 2936, 2812, 2769, 1693, 1607, 1455, 1170, 975, 746 cm-1;

1H NMR (500

MHz, CDCl3): δ 7.86 (d, 2H, J = 8.0 Hz, Ar-H), 7.28- 7.33 (m, 4H, Ar-H), 7.21-7.26

(m, 3H, Ar-H), 3.80 (s, 2H, N-CH2-Ph), 3.59 (s, 2H, N-CH2-C=O), 2.64 (brd, 8H,

piperazine-H), 2.38 (s, 3H, CH3); 13

C NMR (125 MHz, CDCl3): δ 196.3 (C=O),

144.7 (CAr), 137.5 (CAr), 134.1 (CAr), 130.1 (2 × CHAr), 129.8 (2 × CHAr), 128.9 (2 ×

CHAr), 128.7 (2 × CHAr), 127.9 (CHAr), 64.6 (N-CH2-C=O), 63.2 (N-CH2-Ph), 53.6 (2

× piperazine-CH2), 53.1 (2 × piperazine-CH2), 22.2 (CH3).

2.3.9. Synthesis of 2-(4-benzylpiperazin-1-yl)-1-(4-methoxyphenyl)

ethanone (Pz 9)

The general synthetic procedure described earlier, afforded compound Pz 9

from N-benzylpiperazine (1.0 g, 5.6 mmol, 1.0 mequiv) with p-methoxyphenacyl

bromide (1.2 g, 5.6 mmol, 1.0 mequiv) and powderd potassium carbonate (3.9 g, 28.3

mmol, 5.0 mequiv) in dry acetonitrile (20 ml) as a reaction solvent.

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N

N

O

OCH3

2-(4-benzylpiperazin-1-yl)-1-(4-methoxyphenyl) ethanone

Molecular Formula: C20H24N2O2 (M.W. 324.42); Physical state: solid; Colour:

yellow; Yield: 64%; Purity: 96%; mp: 124-128 0C; MS: [M

+1]: m/z 325.29; IR υmax:

3085, 3027, 2937, 2813, 1684, 1585, 1455, 1295, 1170, 978, 752 cm-1;

1H NMR (500

MHz, CDCl3): δ 7.97 (d, 2H, J = 8.0 Hz, Ar-H), 7.29-7.32 (m, 5H, Ar-H), 6.92 (d,

2H, J = 7.0 Hz, Ar-H), 3.84 (s, 3H, OCH3), 3.77 (s, 2H, N-CH2-Ph), 3.59 (s, 2H, N-

CH2-C=O), 2.64 (brd, 8H, piperazine-H); 13

C NMR (125 MHz, CDCl3): δ 194.6

(C=O), 163.4 (CAr), 136.8 (CAr), 130.2 (2 × CHAr), 129.3 (2 × CHAr), 128.9 (CAr),

128.1 (2 × CHAr), 127.1 (CHAr), 113.5 (2 × CHAr), 63.9 (N-CH2-C=O), 62.5 (N-CH2-

Ph), 55.3 (OCH3), 53.0 (2 × piperazine-CH2), 52.4 (2 × piperazine-CH2).

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Figure 2.1. 1H NMR spectrum of Pz 1

Figure 2.2. 13

C NMR spectrum of Pz 1

NNH3C

Br

O

NNH3C

Br

O

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Figure 2.3. 1H NMR spectrum of Pz 2

Figure 2.4. 13

C NMR spectrum of Pz 2

NNH3C

CH3

O

NNH3C

CH3

O

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Figure 2.5. 1H NMR spectrum of Pz 3

Figure 2.6. 13

C NMR spectrum of Pz 3

NNH3C

OCH3

O

NNH3C

OCH3

O

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Figure 2.7. 1H NMR spectrum of Pz 4

Figure 2.8. 13

C NMR spectrum of Pz 4

NN

Br

O

NN

Br

O

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Figure 2.9. 1H NMR spectrum of Pz 5

Figure 2.10. 13

C NMR spectrum of Pz 5

NN

CH3

O

NN

CH3

O

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Figure 2.11. 1H NMR spectrum of Pz 6

Figure 2.12. 13

C NMR spectrum of Pz 6

NN

OCH3

O

NN

OCH3

O

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Figure 2.13. 1H NMR spectrum of Pz 7

Figure 2.14. 13

C NMR spectrum of Pz 7

N

N

O

Br

N

N

O

Br

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Figure 2.15. 1H NMR spectrum of Pz 8

Figure 2.16. 13

C NMR spectrum of Pz 8

N

N

O

CH3

N

N

O

CH3

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Figure 2.17. 1H NMR spectrum of Pz 9

Figure 2.18. 13

C NMR spectrum of Pz 9

N

N

O

OCH3

N

N

O

OCH3

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2.4. Results and discussion

The nucleophilic substitution reactions of N-alkyl and N-aryl substituted

piperazine with different phenacyl bromide derivatives were carried out in presence of

mild base potassium carbonate in different solvents (N,N-dimethylformamide,

ethanol, acetone and acetonitrile) to improve the yields.28-32

Among the different

solvents used acetonitrile showed a better nucleophilic substitution reaction for the

series of compounds Pz 1 to Pz 9 [Table 2.1].

Table 2.1. Effect of solvent on the yield (%) of reaction

% Yields in different solvents used Compounds

N,N-

Dimethylformamide

Acetone Ethenol Acetonitrile

Pz 1 9% < 5% < 5% 64%

Pz 2 13% < 5% < 5% 68%

Pz 3 10% < 5% < 5% 70%

Pz 4 15% < 5% < 5% 62%

Pz 5 20% < 5% < 5% 67%

Pz 6 16% < 5% < 5% 62%

Pz 7 20% < 5% < 5% 71%

Pz 8 15% < 5% < 5% 68%

Pz 9 15% < 5% < 5% 64%

The nucleophilic substitution reaction of 1.0 mequiv of N-methyl piperazine,

N-phenyl piperazine and N-benzyl piperazine with 1.1 mequiv of 2-bromo-1-(4-

bromophenyl)ethanone, 2-bromo-1-p-tolyl ethanone, 2-bromo-1-(4-methoxyphenyl)-

ethanone and 5.0 equiv of potassium carbonate in acetonitrile at 0 oC to 25

oC for 8-10

h gave 1-(4-bromophenyl)-2-(4-methylpiperazin-1-yl)ethanone (Pz 1), 2-(4-methyl-

piperazin-1-yl)-1-p-tolylethanone (Pz 2), 1-(4-methoxyphenyl)-2-(4-methylpiperazin-

1-yl)ethanone (Pz 3), 1-(4-bromophenyl)-2-(4-phenylpiperazin-1-yl)ethanone (Pz 4),

2-(4-phenylpiperazin-1-yl)-1-p-tolylethanone (Pz 5), 1-(4-methoxyphenyl)-2-(4-

phenylpiperazin-1-yl)ethanone (Pz 6), 2-(4-benzylpiperazin-1-yl)-1-(4-bromo-

phenyl)ethanone (Pz 7), 2-(4-benzylpiperazin-1-yl)-1-p-tolylethanone (Pz 8), 2-(4-

benzylpiperazin-1-yl)-1-(4-methoxyphenyl)ethanone (Pz 9) respectively with 62-71%

yields. Purity of all the synthesized compounds were checked by TLC and HPLC. The

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reaction conditions and physicochemical properties of the compounds are summerized

in Table 2.2.

Table 2.2. Physicochemical properties of piperazine derivatives

Comp Structures Reaction

conditions

Yield

(%)

Melting

point

Physical

state

Purity

(%)

Pz 1

K2CO3,

CH3CN, rt, 8 h

64%

81-83 oC

yellow solid

95 %

Pz 2

K2CO3,

CH3CN, rt, 10h

68%

108-110 oC

yellow solid

97 %

Pz 3

K2CO3,

CH3CN, rt, 10h

70%

88-92 oC

yellow solid

96 %

Pz 4

K2CO3,

CH3CN, rt, 10h

62%

132-134 oC

off white

solid

97 %

Pz 5

K2CO3,

CH3CN, rt, 9 h

67%

125-128 oC

off white

solid

97 %

Pz 6

K2CO3,

CH3CN, rt, 10h

62%

156-158 oC

off white

solid

95 %

Pz 7

K2CO3,

CH3CN, rt, 9h

71%

142-144 oC

yellow solid

98 %

Pz 8

K2CO3,

CH3CN, rt, 10h

68%

131-135 oC

yellow solid

94 %

Pz 9

K2CO3,

CH3CN, rt, 10h

64%

124-128 oC

yellow solid

96 %

Formation of the products was confirmed by the absence of –NH stretching

absorption at 3300-3400 cm-1 and presence of stretching absorption at 1680-1700 cm

-1

for >C=O group in IR spectrum, which was further confirmed by the MS and NMR

spectrum (1H &

13C NMR) of respective compounds. The compound Pz 1 was

N NH3C

O

Br

N NH3C

O

CH3

N NH3C

O

OCH3

N N

O

Br

N N

O

OCH3

N N

O

CH3

N

N

O

Br

N

N

O

CH3

N

N

O

OCH3

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obtained as yellow amorphous solid. The mass of the compound displayed a

molecular ion peak at m/z 297.07 [M+1] & 299.09 [M

+1+2] corresponding to the

molecular formula C13H17BrN2O. A stretching absorption at 1693 cm-1 in IR spectrum

of compound revealed the presence of >C=O group which is confirmed by the

presence of 13C resonance at δ 195.3 in

13C NMR. Broad singlet at δ 2.56 for 3H, at δ

2.64 for 3H and at δ 3.07 for 2H showed the presence of piperazine nucleus, which is

also, supported by the 13C resonance at δ 53.0 and 54.5 in

13C NMR. A sharp singlet

at δ 2.32 in 1H NMR spectrum of compound revealed the presence of N-CH3 group.

Presence of methylene group was confirmed by the presence of singlet for two

protons at δ 3.77 in 1H NMR and

13C resonance at δ 64.3 in

13C NMR spectrum.

Doublet at δ 7.60 (d, 2H, J = 8.5 Hz) and at δ 7.87 (d, 2H, J = 8.5 Hz) confirmed the

presence of para substituted phenyl aromatic ring, which was also, supported by the

13C resonance at δ 128.3 & 134.4 for quaternary aromatic carbon, at δ 131.6 & 129.5

for four CH aromatic carbon. Similarly, all the other analogues where characterized

by their spectroscopic studies.

2.5. Antibacterial activity of piperazine derivatives

2.5.1. Bacterial culture

Standard pure cultures of bacteira were procured from the Institute of

Microbial Technology (IMTECH), Chandigarh, India as microbial type culture

collection (MTCC) and maintained in the laboratory by regular sub-culturing on the

nutrient agar. Antimicrobial assays were performed with four Gram positive

(Streptococcus mutans MTCC- 890, Staphylococcus aureus MTCC- 96, Bacillus

subtilis MTCC- 121, Staphylococcus epidermidis MTCC- 435) and one Gram

negative (Escherichia coli MTCC- 723) bacterial strains.

2.5.2. Zone of inhibition

A standarized filter paper disc-agar diffusion procedure known as Kirby-

Bauer method was used to determine the drug susceptibility of microorganism33. The

antibiotic impregnated disc absorbes moisture from agar and diffuses into the agar

medium. The rate of extraction of antibiotic from disc is greater than the rate of

diffusion. Visible growth of the bacteria occurs on the surface of agar where antibiotic

concentration has fallen below its inhibitory level for the test strain. The point at

which the sritical cell mass is reached appears as a circle of bacterial growth, with the

middle of the antibiotic disc forming centre of the circle.

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The zones of inhibition of the synthesized compounds were determined by the

paper disc diffusion method, performed in sterilized (autoclaved at 120 oC for 1 h)

petri dish. Bacterial inoculums were prepared from over night (16 hrs) grown culture

in nutrient broth (Himedia, India) and the turbidity was adjusted equivalent to 0.5

McFarland standard (approximetly 3 × 106 cfu ml

-1 bacteria). An aliquot (100 µl) of

cultures were spread over the surface of agar plate with sterile glass spreaded.

Compound with 100 µg/ disc concentration were impregnated on the paper disces

(diameter 5 mm, Whatman filter paper No. 3), which were placed on the surface of

agar plates already inoculated with pathogenic bacteria. The plates were incubated at

37 oC and examined after 24 h for zone of inhibition. Ampicillin/ streptomycin were

used as a standard. An additional control disc with an equivalent amount of solvent

(DMSO) was also used in the assay. The results showed that some of the compounds

exhibited significant zones.

2.5.3. Minimum inhibitory concentration

Minimum inhibitory concentrations (MICs) are considered as the ‘gold

standard’ for determining the susceptibility of organisms to antimicrobial and are

therefore used to judge the performance of all other methods of susceptibility testing.

The minimum inhibitory concentration was detrmined by the well established

microbroth dilution technique.34 The range of antibiotic concentrations used for

determining MICs is universally accepted to be in doubling dilution step up and down

for 1 mg/ L is required. Various concentrations of compounds were prepared in the

well by two-fold dilution method. The last well of micro titer plate was considered as

control, contained no test compounds. The inoculum was prepared using a 16 h broth

culture of each bacterial strains adjusted to a turbidity equivalent to a 0.5 Mc Farland

standard. The micro titer plates were incubated for 24 h at 37 oC. The MIC was

defined as the lowest concentration of compound giving complete inhibition of visible

growth.

2.5.4. Results and discussion

Antibacterial activity of all the synthesized derivatives were evaluated against

four Gram positive (S. mutans MTCC- 890, S. aureus MTCC- 96, B. subtilis MTCC-

121, S. epidermidis MTCC- 435) and one Gram negative (E. coli MTCC- 723)

bacterial strains using disc diffusion33 and microbroth dilution methods.

34 Ampicillin

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was used as a standard drug. The inhibition zone (IZ) and MIC of the compounds

against above bacterial strain are summerized in Table 2.3.

Results showed that most of the compounds possess potent to moderate

activity as compared to the reference drug ampicillin. Benzyl piperazine analougues

(Pz 7 to Pz 9) showed potent activity against Gram positive and significant activity

against Gram negative bacterial strains. Compound Pz 9 having benzyl group in

piperazine and methoxy group in phenacyl nucleus exhibited potent activity against

B. subtilis (IZ = 31 mm and MIC = 5.8 µg/ml), S. epidermidis (IZ = 30 mm and MIC

= 5.8 µg/ml) and S. aureus (IZ = 28 mm and MIC = 11.7 µg/ml) while significant

activity against S. mutans (IZ = 29 mm and MIC = 11.7 µg/ml) and E. coli (IZ = 25

mm and MIC = 23.4 µg/ml). When methoxy group was replaced by methyl group

(Pz 8) the activity was slightly enhanced for S. mutans (IZ = 30 mm and MIC = 5.8

µg/ml) while it was diminished for S. aureus (IZ = 26 mm and MIC = 11.7 µg/ml)

S. epidermidis (IZ = 27 mm and MIC = 11.7µg/ ml) and B. subtilis (IZ = 25 mm and

MIC = 23.4 µg/ml). Compound Pz 7 showed significant activity against only

S. epidermidis with IZ 28 mm and MIC value 7.8 µg/ ml while moderate activity

were noticed against other strains. Methyl piperazine analogues Pz 3 having methoxy

group in phenacyl nucleus was found to be active against S. aureus, B. subtilis,

S. epidermidis and E. coli bacterial strains with MIC value 23.4 to 46.8 µg/ml. All the

phenyl substituted analogues Pz 4 to Pz 6 showed poor activity against both Gram

positive and Gram negative bacterial strains. Compounds Pz 3, Pz 7, Pz 8 and Pz 9

revealed better activity in comparison to other compounds used in study, indicating

that methyl and benzyl substitution at 4-position of piperazine nucleus showed better

activity as compared to phenyl substitution. Enhanced activity of compound Pz 9 and

Pz 3 might be due to the presence of methoxy group at para position of phenacyl

nucleus.

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Tab

le 2

.3. A

nti

bacte

rial acti

vit

y o

f p

ipera

zin

e d

eriv

ati

ves

Pz

1 t

o P

z 9

Zone of inhibition (mm) and Minimum inhibitory concentrations (µg ml-1)

Streptococcus mutans

Staphylococcus aureus

Bacillus subtilis

Staphylococcus epidermidis

Escherichia coli

*Compounds

zone of

inhibition

MIC

zone of

inhibition

MIC

zone of

inhibition

MIC

zone of

inhibition

MIC

zone of

inhibition

MIC

Pz 1

12± 0.53

250

18 ± 0.72

62.5

18 ± 0.72 62.5

17 ± 0.81

62.5

15 ± 0.66 125

Pz 2

NA

ND

10 ± 0.44

500

8 ± 0.34

500

NA

ND

NA

ND

Pz 3

22 ± 1.03

46.8

26 ± 1.18

23.4

25 ± 1.12 23.4

24 ± 0.98

23.4

23 ± 0.87 46.8

Pz 4

7 ± 0.29

500

7 ± 0.28

500

14 ± 0.64 125

13 ± 0.58

250

11 ± 0.52 250

Pz 5

9 ± 0.37

500

12 ± 0.53

250

12 ± 0.49 250

11 ± 0.61

250

10 ± 0.44 500

Pz 6

12 ± 0.46

250

16 ± 0.76

125

13 ± 0.58 125

17 ± 0.81

62.5

NA

ND

Pz 7

18 ± 0.86

62.5

20 ± 0.89

31.2

26 ± 1.22 15.6

28 ± 1.26

7.8

22 ± 0.98 31.2

Pz 8

30 ± 1.29

5.8

26 ± 1.18

11.7

25 ± 1.12 23.4

27 ± 1.22

11.7

19 ± 0.91 93.7

Pz 9

29 ± 1.26

11.7

28 ± 1.26

11.7

31 ± 1.36

5.8

30 ± 1.32

5.8

25 ± 1.07

23.4

Ampicillin**

27± 1.21

4

22 ± 0.94

8

25 ± 1.12

4

25 ± 1.07

2

12 ± 0.49

12

values are mean of three determinations, the ranges of which are less than 5% of the mean in all cases.

*compounds (100µg/disc) were used for experiments; NA = not active; ND = not determined.

**used as positive reference (20µg/disc).

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2.6. Structures of potent compounds

N

N

O

Br

N

N

O

CH3

N

N

O

OCH3

N NH3C

O

OCH3

Pz 03 Pz 07

Pz 08 Pz 09

2.7. Conclusion

In conclusion, the synthesis of nine new N-substituted piperazine analogues

was carried out and their antibacterial activity has been determined. Among the

synthetic piperizine derivatives under investigation, Pz 3, Pz 7, Pz 8 and Pz 9 showed

significant activity. The benzyl piperazine derivatives Pz 8 & Pz 9 viz. 2-(4-

benzylpiperazin-1-yl)-1-p-tolylethanone Pz 8 and 2-(4-benzylpiperazin-1-yl)-1-(4-

methoxyphenyl)ethanone Pz 9, in particular, showed remarkable antibacterial activity

even at low concentration against S. epidermidis, S. mutans and B. subtilis which were

closer to ampicillin. Furthermore, benzyl substitution increased the antibacterial

activity as compared to the methyl and phenyl substituents under identical conditions

and might be of interest for developing new antibacterial molecules.

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