Synthesis and Antimicrobial Evaluation of Some 2- (Piperazinomethylamino) Imidazole Derivatives

 

SP Wate, AN Ingale and PS Tarte*

Sharad Pawar College of Pharmacy, Wandongari, Hingana Road, Nagpur-441110 (M. S.)

*Corresponding Author E-mail: pawantarte@rediffmail.com

ABSTRACT:

Benzoin was reacted with aminomethamine in ethanol to yield 2-amino-4,5-diphenylimidazole, which on further reaction with dichloromethane in presence of ethanolic potassium hydroxide yielded 2-(chloromethylamino)-4,5-diphenylimidazole. The 2-(chlormethylamino)-4,5-diphenylimdazole was reacted with piperazine and its derivatives, which yielded 2-(piperazinomethylamino)-4,5-diphenylimiazole and its respective derivatives. All the compounds were characterized on the basis of IR and ¹HNMR spectral data were screened for antimicrobial activity.

 

 

INTRODUCTION:

The piperazine derivatives reportedly have antimicrobial activities¹ and imidazole derivatives are also reported to possess antimicrobial ^{2, 3} and some other activities. In the present work, an attempt was made to synthesize some substituted piperazinomethylimidazole derivatives and to study their pharmacological activities. It was planned to club the imidazole and piperazine molecules and their derivatives through a methylene bridge to form a single moiety with the rationale and hope that it may yield a compound with enhanced pharmacological activities. The purity and homogeneity of the products was ascertained by thin layer chromatography.

 

The infrared spectra of some of the products show common features such as strong bands at 3400 cm^-1  (Ar N-H stretching), 3060-3040 cm^-1  (Ar C-H stretching), 2960-2840 cm^-1       (C-H stretching in CH₂), 1680-1620 cm^-1  (Stretching vibration of C═C and C=N), 1250 cm^-1  (Ar N-H stretching), 1200 cm^-1  (C-N bending).

 

The ¹H-NMR spectral data of some of the synthesized compounds show expected peaks in the region of 7.25 δ ppm triple of Ar- C-H, singlet of CH₂ AT 5.85 δ ppm, singlet by protons of piperazine N-H at 7.45 δ ppm, singlet  by protons of imidazole ring 7.85 δ ppm, singlet by proton of piperazine ring at 4.40 δ ppm.

 

The results of activity indicated that the tested compounds possessed pronounced antimicrobial activity.

 

EXPERIMENTAL:

Synthesis procedure:-

2- Amino-4,5-diphenylimidazole (III):

Benzoin (I) (21 g, 0.01 mol) and aminomethamine (II) (6.5 g, 0.01 mol) were taken in ethanol (50 ml) and refluxed for three hours. Further, the contents was cooled and triturated with crushed ice. The product was allowed to separate. Then, it was filtered and washed thoroughly with small portions of cold water and recrystallised.⁴

 

2-(Chloromethylamino)-4,5-diphenylimidazole (V):

4,5-Diphenyl-2-aminoimidazole (III) (25g, 0.01 mol) and dichloromethane (IV) (8g, 0.01mol) were suspended in 5% ethanolic potassium hydroxide solution (50 ml). This mixture was stirred well and refluxed on water-bath for three hours. Ethanol was removed by evaporation as much as possible. Residue was cooled with crushed ice. The product obtained was filtered, washed with small portions of cold water and recrystallised.

 

2-(Piperazinomethyl amino)-4,5-diphenylimidazole and derivatives (VIIa-j):

Using piperazine and substituted piperazines, various derivatives of 2-(piperazinomethylamino)-4,5-diphenylimidazole (VIIa-j) were prepared. For each of these 2-(Chloromethylamino)-4,5-diphenylimidazole (V) (0.01 mol) and substituted piperazines (Via-j) (0.01mol) were suspended in 5% ethanolic potassium hydroxide solution (50ml).

 

The mixtures were stirred well and refluxed on water–bath for three hours. Ethanol was removed by evaporation as much as possible. Residues were cooled with crushed ice. The products obtained were filtered and washed with small portion of cold water and recrystallised from ethanol.

 

 

Table -1: - Physical data of the synthesized compound

Compounds	R	M. P*. (C)	Rf value**	% yield	λmax (nm)
VIIa	H	120-125	0.73	84.74	315
VIIb	CH3	138-140	0.13	81.52	289
VIIc	C2H5	130-132	0.33	69.80	272
VIId	COCH3	118-123	0.44	76.27	286
VIIe	COC6H5	105-107	0.26	64.76	266
VIIf	CH2C6H5	145-149	0.53	70.51	329
VIIg	COC6H5Cl	175-180	0.60	65.75	341
VIIh	COC6H5NH2	168-170	0.55	80.60	360
VIIi	3-COC6H5NO2	88-90	0.39	70.55	287
VIIj	3-COC6H5NH2	98-100	0.89	70.86	290

* - Solvent for recrystallisation: ethanol, ** -Solvent system used was benzene: methanol (7:3)

 

Synthesis Scheme:

 

 

Table -2: Antimicrobial activity of 2-(piperazinomethylamino)imidazole (VII)

Compound No.	R	Zone of inhibition (mm)
		S. aureus	E. coli	C. albicans
VIIa	-H	28	14	29
VIIb	-CH3	30	22	25
VIIc	-C2H5	29	25	23
VIId	-COCH3	23	23	20
VIIe	COC6H5	25	15	24
VIIf	-CH2-C6H5	24	18	22
VIIg	-COC6H5Cl	21	13	28
VIIh	-COC6H5NH2	29	18	25
VIIi	3- COC6H4NO2	30	11	28
VIIj	3 –COC6 H4NH2	20	12	26
Std	--	35	25	30

Activity of the compounds are as 3i>3a>3c>3j against S.aureus but found less active against E. Coli. The antifungal activity of synthesized compounds 3a>3g>3i>3j against C. albicans was significant.

Characterization of synthesized compounds:-

Melting points were determined in open capillaries and are uncorrected. All the products were subjected to thin layer chromatography for confirmation of completion of reaction and identification using Silica gel-G plates activated at 110º C for 30 minutes. The infrared spectra of compounds were recorded using KBr pellets on Shimadzu-DR-8031 at Department of Pharmaceutical Sciences, Nagpur. ¹H-NMR spectra (CDCl₃) were recorded on Varian EM-390 Spectrophotometer (chemical shift in δ ppm), at Department of Chemistry, Pune University, Pune.

 

Spectral investigations:-

Compounds VIIa to VIIc were subjected to IR and NMR investigations. The results are as under.

 

IR details:

VIIa.: 3400 (Ar N-H stretching), 3060-3040 (Ar C-H stretching), 2960-2840 (C-H stretching in CH₂), 1960-1920 (stretching of substituted benzene).

VIIb. : 2960-2840 cm^-1: stretching vibration indicates the merging of methyl group.

VIIc. : 2960-2840 cm^-1: Stretching vibration indicates the merging of ethyl group.

 

NMR details:

VIIa. : 7.25 δ ppm triplet of Ar-C-H, singlet of CH₂ at 5.85 δ ppm, singlet by protons of piperazine N-H at 7.45 δ ppm, singlet by protons of imidazole ring 7.85 δ ppm, singlet by proton of piperazine ring at 4.40 δ ppm.

VIIb. : Shows singlet at 4.6 δ ppm shows total protons of methyl group.

VIIc. : Shows singlet at 4.6 δ ppm assigned the total protons of ethyl group.

 

Antimicrobial activity: -

The preliminary antimicrobial activities of compounds have been studied against Gram-negative bacteria E. coli; Gram-positive bacteria S. aureus and fungus C. albicans species using dimethylformamide (DMF) as solvent at concentration 100 µg/ml by cup-plate  method. ^5-7 After 24 hr of incubation at 37º C, the zone of inhibition was measured in mm and the results are given in Table-2. Cefalotoxin and Ketoconazole were used as standard for antibacterial and antifungal activity, respectively.

 

All the tested compounds showed higher activity against Gram-positive S. aureus than fungus C. albican and Gram- negative E. coli.

 

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Received on 16.08.2009          Modified on 13.10.2009

Accepted on 12.11.2009         © RJPT All right reserved