Short communication
Synthesis of New Series of Pyrazole and Imidazole Derivatives and their Antimicrobial Activity
A. Idhayadhulla, R. Surendra Kumar and A. Jamal Abdul Nasser*
P. G. & Research Department of Chemistry, Jamal Mohamed College, Tiruchirappalli-620020,
Tamil Nadu, India
* Corresponding author: E-mail: amal_abdulchem@ymail.com
Received: 27-01-2012
Abstract
New series of pyrazole derivatives 3-(furan-2-yl)-4-(5-hydroxy-4_ff-pyrazol-3-yl)-N-phenylbutanamide 1-5 and imidazole derivatives 3-(furan-2-yl)-3-(1_ff-imidazol-1-yl)-N-phenylpropanamide 6-10 were synthesized by the Mannich base method. Synthesized compounds 1-10 were confirmed by IR, 1H NMR, 13C NMR, Mass and elemental analysis and further screened for antimicrobial activity.
Keywords: Pyrazole derivative, Imidazole derivatives, Mannich condensation, Antibacterial activity, Antifungal activity.
1. Introduction
In recent years serious attention has been directed toward the discovery and development of new antimicrobial drugs. Pyrazoles show important biological activity such as antimicrobial,1-3 anticoagulant activities,4-6 anti-inflammatory,7-9 antirheumatic1314 and anti-inflammatory15 activities. Also imidazole and their derivatives represent an important class of heterocyclic compounds and many naturally occurring imidazoles are known to possess biological activity.16 A number of antifungal imidazole agents has been studied and now they are used in clinical practice such as miconazole and bifonazole.17 The imidazole nucleus is also a major component of a variety of drugs such as angiotensin II receptor antagonists, oral anti-inf amma-tory agents, protein kinase inhibitors and fungicides.18 Imidazole derivatives have many pharmacological properties and play important roles in biochemical processes.19 Many of the substituted imidazoles are inhibitors, used as fungicides and herbicides, plant growth regulators and therapeutic agents.20 Imidazotes are frequently found as part of a large number of medicinally significant substances.21,22 Imidazole derivatives possess a broad spectrum of pharmacological activities such as anticonvulsant,23 antiparkin-son24 and monoamineoxidase (MAO) inhibitory25 activity. Indeed, Mannich reaction is of considerable importance
for the synthesis and modification of biologically active compounds.26,27 Mannich bases have several biological activities such as antimicrobial,28-32 cytotoxic,33,34 and anticancer.35,36 In the present study, a new series of pyrazote and imidazole derivatives have been synthesized and screened for the antimicrobial activity.
2. Results and Discussion
2. 1. Chemistry
The compounds 1-10 were synthesized by the Mannich base method (Schemes 1 and 2). Physicochemical data of compounds 1-10 are given in Tabte 1. Compounds were confirmed by recording the IR, 1H NMR, 13C NMR and elemental analyses. The IR spectrum of compound 1 shows absorption bands at 669 and 1649 cm-1 corresponding to an aromatic C-Hstr and NHCO groups respectively. The 1H NMR spectrum of compound 1 shows singlets at 8 10.21, 3.21 and 2.60 corresponding to CONH, -CH-and CH2-CO-NH protons, respectively. 13C NMR spectrum of compound 1 shows peaks at 8 172.9, 31.9 and 33.0 corresponding to CONH, -N-CH- and CH2-CO-NH carbons, respectively. Mass spectrum (Figure 1) of compound 1 shows a motecutar ion peak at m/z 311.42 (M+, 12%), which confirmed the molecular mass of compound 1, mass spectral fragmentation pattern of 1 is shown in Scheme 3.
Table 1. Physicochemical characterization of compounds 1-10
Compd.	R	Molecular	m.w.	Yield
No.		formula		(%)
1	-	C17HnN3O3	311.33	82
2	-H	C19H19N3O2	321.37	80
3	-Cl	Cj^ClNA	355.81	76
4	-OH	C19H19N3O3	337.37	77
5	-no2	C19H18N4O4	366.37	79
6	-	C16H15NA	281.30	87
7	-H	C18H17N3O	291.34	89
8	-Cl	C^H^ClNjO	325.79	79
9	-OH	C18H17N3O2	307.34	84
10	-no2	C18H16N4O3	336.34	82
The IR spectrum of compound 6 shows absorption bands at 641 and 1640 cm-1 corresponding to aromatic CHstr and NHCO groups, respectively. The 1H NMR spectrum of compound 6 shows singlets at 8 10.35, 5.41 and 3.42 corresponding to CONH, -CH- and -CH-CO-NH protons, respectively. 13C NMR spectrum of compound 6 shows peaks at 8 173.2, 53.8 and 38.6 corresponding to CONH, N-CH- and CH2-CH- carbons, respectively. Mass spectrum (Figure 2) of compound 6 shows a molecular ion peak at m/z 281.76 (M+, 27%), which confirmed the molecular mass of compound 6, mass spectral fragmentation pattern of compound 6 shown is shown in Scheme 4.
Figure 1. Mass spectrum of compound 1
>4	/=Y "	
	Y	
-NH-Ph	W J	-co
		
	CT	

•CHa
m/z 190.19
mft 162 IS
w
-Furyl
w
JCH»
m/z 143.16
m. ;: di io	Scheme 3. Mass spectral fragmentation of compound 1
Figure 2. Mass spectrum of compound 6
2. 2. Biological Screening 2. 2.1. Antibacterial Activity
The bacterial zones of inhibition (in mm) for Escherichia coli and Staphylococcus aureus for compounds 1-10 are summarized in Table 2. Compound 6 was found to be highly active against S. aureus as compared with ciprofloxacin.
Table 2. Antibacterial activity of compounds 1-10
Compounds No	E. coli	S. aureus
1	10	13
2	8	16
3	12	20
4	10	14
5	8	19
6	0	26
7	12	16
8	15	8
9	10	12
10	15	20
Standard	20	24
The compounds were used at concentration 100 |g/mL, ciprofloxacin used as the standard. Zone of inhibition measured in mm
2. 2. 2. Antifungal Activity
The zones of inhibition (in mm) for Aspergillus niger and Candida albicans for compounds 1-10 are summarized in Table 3. Compound 1 has equipotent activity against C. albicans as compared with standard clotrimazole.
Table 3. Antifungal activity of compounds 1-10
Com pounds No.	A. niger	C. albicans
1	15	22
2	8	16
3	12	10
4	6	12
5	13	21
6	24	10
7	12	8
8	15	12
9	16	19
10	8	18
Standard	23	25
The compounds were used at concentration 100 |g/mL, clotrimazole used as the standard. Zone of inhibition measured in mm.
2. 2. 3. Structural Activity Relationship
The OH and NHCO groups in compounds 6-10 have significance for antibacterial activity but for the majority of the compounds, though the compound 6 having furyl and imidazole rings along with OH and NHCO groups exhibits the highest activity against S. aureus compared with standard ciprofloxacin. Also antifungal screening for the compound 6 showed its high activity against A. niger compared with standard clotrimazole, whereas the compound 1 has equipotent activity against C. albicans compared with the standard clotrimazole. A rough comparison of the structure with the activity shows the imidazole derivatives to possess a higher potential biological activity compared with the pyrazole derivatives.
Compound 1
Compound 6
3. Experimental 3. 1. Chemistry
Melting points were recorded in open capillary tubes and are uncorrected. The IR spectra was recorded in KBr on a FT-IR Shimadzu 8201pc (4000-400 cm-1) and NMR and 13C NMR on Bruker DRX-300 MHz. Elemental analysis (C, H, and N) were undertaken using an Elemental analyzer model vario EL III. The purity of the compounds was checked by thin layer chromatography (TLC) with silica gel plates.
3. 1. 1. General procedure for the synthesis of compounds 1-10
3-(Furan-2-yl)-4-(5-hydroxy-4_ff-pyrazol-3-yl)-N-phen ylbutanamide (1)
To prepare the solution of 5-methyl-4H-pyrazol-3-ol (9.8 g, 0.1 mol), acetanilide (13.5 g, 0.1 mol) and fural-dehyde (9.6 g, 0.1 mol) in ethanol, the reaction mixture was refluxed for 3 h. The reaction mixture were cooled and poured into ice-cold water. The precipitated material was obtained in a few minutes. The precipitate was collected by filtration, dried and recrystallised from absolute ethanol. Using above procedure was followed by all the remaining compounds 2-5.
m.p. 167 °C; IR (cm-1): u 3423 (C-OH), 1649 (CONH), 669 (CH); 1H NMR (DMSO-d6): 8 2.21 (s,1H, OH), 1.60 (s, 2H, CH in pyrazole), 1.82 (d, 2H, CH2), 3.21 (tt, 1H, CH), 2.60 (d, 2H, CH2-CO), 10.21 (s, 1H, CONH), 7.19-7.61 (m, 5H, Ph), 7.58 (d,1H, pyrazote), 6.42 (dd, 1H, furyl), 6.12 (d,1H, furyl); 13C NMR (DMSO-d6): 172.9 (CONH), 164.8 (C-OH), 31.8 (CH2 in pyrazole), 164.2 (C-CH2-C-), 39.8 (-CH2-CH-), 31.9 (-CH-), 33.0 (-CH-CH2-CO-NH), 138.5, 128.9, 121.8, 128.1 (Ph), 156.0, 141.5, 110.0, 121.1 (furyl ring). MS (m/z): 311.42 (M+, 20%), 245.27, 169.22 (100%), 154.16, 126.15, 112.12, 98.10, 84.07, 68.07. Elemental analysis: Calcutated for C, 65.58; H, 5.50; N, 13.50%; Found: C, 65.50; H, 5.54; N, 13.58%.
4-(5-Hydroxy-4_ff-pyrazol-3-yl)-N,3-diphenylbutanam i de (2)
m.p. 154 °C; IR (cm-1): u 3420 (C-OH), 1647 (CONH), 642 (CH); 1H NMR (DMSO-d6): 8 2.31 (s, 1H, OH), 1.54 (s, 2H, CH2 in pyrazote), 1.80 (d, 2H, CH2), 3.49 (tt, 1H, CH), 2.66 (d, 2H, CH2-CO), 10.11 (s, 1H, CONH), 7.45-7.61 (dd, 4H, NH-Ph2), 7.20-7.34 (m, 5H, Ph); 13C NMR(DMSO-d6): 173.6 (CONH), 163.2 (C-OH), 31.8 (CH2 in pyrazole), 163.6 (C-CH2-C-), 39.2 (CH2-CH-), 32.5 (C-CH-), 33.6 (-CH-CH2-), 138.5, 128.9, 121.8, 128.1 (Ph), 125.5, 126.1, 123.7, 142.8 (Ph ring). MS (m/z): 321.72 (M+, 34%), 245.27, 169.21 (100%), 154.19, 110.98, 98.01, 85.21, 68.18. Elemental analysis: Calcutated for C, 71.01; H, 5.96; N, 13.12%; Found: C, 71.11; H, 5.90; N, 13.12%.
3-(4-Chlorophenyl)-4-(5-hydroxy-4fl-pyrazol-3-yl)-N-phenylbutanamide (3)
m.p. 173 °C; IR (cm1): u 3423 (C-OH), 1649 (CONH), 669 (CH), 836 (C-Cl); 1H NMR (DMSO-d6): 8 2.24 (s,1H, OH), 1.61 (s, 2H, CH in pyrazole), 1.82 (d, 2H, CH2), 3.43 (tt, 1H, CH), 2.60 (d, 2H, CH2-CO), 10.21 (s, 1H, CONH), 7.41-7.24 (m, 4H, Ph); 13C NMR (DMSO-d6): 131.9 (C-Cl), 31.2 (CH2 in pyrazole ring), 164.2 (C-CH2-C-), 39.8 (CH2-CH-), 31.9 (C-CH-), 33.0 (-CH-CH2-), 72.9 (CONH), 138.5, 128.9, 121.8, 128.1 (Ph), 156.0, 141.5, 110.0, 121.1 (furyl ring). MS (m/z): 355.21 (M+, 42%), 244.91, 169.65 (100%), 154.54, 110.74, 98.22, 85.36, 68.41. Elemental analysis: Calcutated for C, 64.13; H, 5.10; N, 11.81%; Found: C, 64.17; H, 5.13; N, 11.79%.
3-(4-Hydroxyphenyl)-4-(5-hydroxy-4_ff-pyrazol-3-yl)-N-phenylbutanamide (4)
m.p. 152 °C; IR (cm1): u 3423 (C-OH), 1649 (CONH), 669 (CH); 1H NMR (DMSO-d6): 8 2.2 (s,1H, OH), 1.66 (s, 2H, CH in pyrazole), 1.82 (d, 2H, CH2), 3.48 (tt, 1H, CH), 2.60 (d, 2H, CH2-CO), 10.21 (s, 1H, CONH), 7.19-7.61 (m, 5H, Ph), 7.58 (d,1H, furyl), 6.42 (dd, 1H, furyl), 6.12 (d,1H, furyl); 13C NMR (DMSO-d6): 155.8 (C-OH), 31.8 (CH2 in pyrazole ring), 164.2 (C-CH2-C-), 39.8 (CH2-CH-), 31.9 (C-CH-), 33.0
(-CH-CH2-), 72.9 (CONH), 138.5, 128.9, 121.8, 128.5 (Ph), 135.0, 115.2, 127.6 (Ph). MS (m/z): 337.37 (M+, 21%), 245.65, 169.36 (100%), 153.25, 110.90, 97.91, 86.01, 67.25. Elemental analysis: Calculated for C, 67.64; H, 5.68; N, 12.46%; Found: C, 67.60; H, 5.69; N, 12.40%.
4-(5-Hydroxy-4_ff-pyrazol-3-yl)-3-(4-nitrophenyl)-N-phenylbutanamide (5)
m.p. 164 °C; IR (cm-1): u 3428 (C-OH), 1652 (CONH), 645 (CH), 1581 (C-NO2); 1H NMR (DMSO-d6): 8 2.19 (s, 1H, OH), 1.65 (s, 2H, CH in pyrazole), 1.88 (d, 2H, CH2), 3.39 (tt, 1H, CH), 2.64 (d, 2H, CH2-CO), 10.11 (s, 1H, CONH), 7.21-7.56 (m, 5H, Ph), 7.56-8.20 (dd, 4H, NO2-Ph); 13C NMR (DMSO-d6): 164.0 (C-OH), 30.3 (CH2 in pyrazole ring), 165.1 (C-CH2-C-), 39.0 (CH2-CH-), 31.7 (C-CH-), 33.6 (-CH-CH2-), 72.2 (CONH), 148.2, 127.2, 123.8 (Ph), 145.7 (C-NO2), 138.4, 128.0, 128.6, 121.1 (-NH-Ph); MS (m/z): 366.41 (M+, 11%), 245.20, 169.36 (100%), 153.10, 110.20, 98.16, 85.95, 68.26. Element al analysis: Calcul at ed for C, 62.29; H, 4.95; N, 15.29%; Found: C, 62.32; H, 4.91; N, 15.32%.
3. 1. 2. 3-(Furan-2-yl)-3-(1H-imidazol-1-yl)-N-phenylpropanamide (6)
To prepare the solution of imidazole (6.8 g, 0.1 mol), acetanilide (13.5 g, 0.1 mol) and furaldehyde (9.6 g, 0.1 mol) in ethanol, the reaction mixture was refluxed for 3 h. The reaction mixture were cooled and poured into ice-cold water. The precipitated material was obtained in a few minutes. The precipitate was collected by filtration, dried and recrystallised from absolute ethanol. Using above procedure was followed by all remaining compounds 7-10.
m.p. 198 °C; IR (cm1): u 3119 ( CH str in Ph ring ), 2781 (CH str in furyl), 1640 (CONH), 641 (CH); 1H NMR (DMSO-d6): 8 6.45 (s, 1H, CH in imidazole ring), 7.84 (s, 1H, CH in imidazole ring), 5.41 (t, 1H, CH), 3.42 (d, 2H, CH2), 10.35 (s, 1H, CONH), 7.19-7.61 (m, 5H, Ph), 7.56 (d, 1H, furyl), 6.54 (dd, 1H, furyl), 6.37 (d, 1H, furyl); 13C NMR (DM-SO-d6): 137.6 (CH2 in imidazole ring), 128.6 (CH in imidazole ring), 53.8 (CH), 38.6 (CH2-CH-), 173.2 (CONH), 138.6, 121.4, 128.2, 128.0 (Ph), 151.9, 141.6, 110.8, 105.2 (furyl ring). MS (m/z): 281.76 (M+, 17%), 190.19, 162.18 (100%), 148.16, 82.10. Elemental analysis: Calculated for C, 68.29; H, 5.37; N, 14.94%; Found: C, 68.29; H, 5.30; N, 14.96%.
3-(1_ff-Imidazol-1-yl)-N,3-diphenylpropanamide (7)
m.p. 195 °C; IR (cm1): u 3156 (CH str in Ph ring ), 1641 (CONH), 654 (CH); 1H NMR (DMSO-d6): 8 6.27 (s, 1H, CH in imidazole ring), 7.64 (s, 1H, CH in imidazole ring), 5.97 (t, 1H, CH), 3.41 (d, 2H, CH2), 10.16 (s, 1H, CONH), 7.43-7.64 (m, 5H, Ph), 7.27-7.240 (m, 5H, Ph); 13C NMR (DMSO-d6): 136.2 (CH2 in imidazole ring), 127.3 (CH in imidazole ring), 53.6 (CH), 37.9 (CH2-CH-), 171.6 (CONH), 140.9, 128.2, 128.8, 125.8 (Ph), 138.1, 121.8, 128.1, 128.6 (-CONH-Ph). MS (m/z): 291.01 (M+,
23%), 215.25, 139.25 (100%), 124.14, 110.15, 82.10. Elemental analysis: Calculated for C, 74.20; H, 5.88; N, 14.42%; Found: C, 74.22; H, 5.80; N, 14.44%.
3-(4-Chlorophenyl)-3-(1#-imidazol-1-yl)-N-phenyl-propanamide (8)
m.p. 210 °C; IR (cm1): u 3121 (CH str in Ph ring), 1664 (CONH), 654 (CH), 847 (C-Cl); 1H NMR (DMSO-d6): 8 6.94 (s, 1H, CH in imidazole ring), 7.41 (s, 1H, CH in imidazole ring), 5.38 (t, 1H, CH), 3.40 (d, 2H, CH2), 10.34 (s, 1H, CONH), 7.43-7.25 (m, 4H, Ph), 7.192-7.66 (dd, 4H, Ph); 13C NMR (DMSO-d6): 137.2 (CH2 in imidazole ring), 127.6 (CH in imidazole ring), 52.9 (CH), 38.3 (CH2-CH-), 173.1 (CONH), 131.2(C-Cl), 131.6, 128.6, 129.0 (Ph), 138.6, 122.2, 124.8, 127.9 (-CONH-Ph). MS (m/z): 325.01 (M+, 46%), 291.34, 139.36 (100%), 124.66, 110.84, 82.41. Elemental analysis: Calculated for C, 66.36; H, 4.95; N, 12.90%; Found: C, 66.32; H, 4.92; N, 12.93%.
3-(4-Hydroxyphenyl)-3-(1_ff-imidazol-1-yl)-N-phenyl-propanamide (9)
m.p. 110 °C; IR (cm1): u 3235 (C-OH), 3210 (CH str in Ph ring), 1652 (CONH), 710 (CH); 1H NMR (DMSO-d6): 8 9.41 (s, 1H, Ph-OH), 6.57 (s, 1H, CH in imidazole ring), 7.95 (s, 1H, CH in imidazole ring), 5.36 (t, 1H, CH), 3.51 (d, 2H, CH2), 10.16 (s, 1H, CONH), 6.69-7.12 (m, 4H, Ph), 7.17-7.65 (dd, 4H, Ph); 13C NMR (DMSO-d6): 136.4 (CH2 in imidazole ring), 128.6 (CH in imidazole ring), 53.9 (CH), 37.6 (CH2-CH-), 172.3 (CONH), 154.6 (C-OH), 136.2, 115.8, 128.5 (Ph), 138.9, 121.0, 128.1, 128.9 (-CONH-Ph). MS (m/z): 307.21 (M+, 56%), 291.45, 139.01 (100%), 124.77, 110.81, 82.36. Elemental analysis: Calculated for C, 70.34; H, 5.55; N, 13.67%; Found: C, 70.37; H, 5.55; N, 13.60%.
3-(1_ff-Imidazol-1-yl)-3-(4-nitrophenyl)-N-phenylpro-panamide (10)
m.p. 122 °C; IR (cm1): u 3108 (CH str in Ph ring), 2766 (CH str in furyl), 1652 (CONH), 669 (CH), 1586 (C-NO2); 1H NMR (DMSO-d6): 8 6.44 (s, 1H, CH in imidazole ring), 7.80 (s, 1H, CH in imidazole ring), 5.46 (t, 1H, CH), 3.47 (d, 2H, CH2), 10.27 (s, 1H, CONH), 7.17-7.61 (m, 4H, Ph), 13C NMR (DMSO-d6): 136.9 (CH2 in imidazole ring), 128.1 (CH in imidazole ring), 53.0 (CH), 37.1 (CH2-CH-), 172.6 (CONH), 139.1, 128.6, 128.9, 121.6 (NO2-Ph), 123.0, 128.4, 128.2 (-CONH-Ph). MS (m/z): 336.28 (M+, 41%), 291.76, 139.87 (100%), 124.13, 110.06, 82.47. Elemental analysis: Calculated for C, 16.66; H, 4.79; N, 64.28%; Found: C, 64.28; H, 4.73; N, 16.60%.
3. 2. Biological Screening
3. 2. 1. In vitro Antibacterial Screening
The compounds 1-10 were screened for in vitro antibacterial activity against S. aureus (ATCC-25923), E.
coli (ATCC-25922), by disc diffusion method37 38 performed using Muelter-Hinton agar (Hi-Media) medium. Each compound was tested at the concentration of 100 lg/mL in DMSO. Ciprofloxacin was used as the standard. The zone of inhibition was measured after 24 h incubation at 37 °C for 24 h.
3. 2. 2. In vitro Antifungal Screening
The compounds 1-10 were screened for in vitro antifungal activity A. niger, C. albicans, using an disc diffusion method39,40 with Sabouraud's dextrose agar (Hi-Media) medium. Each compound was tested at the concentration of 100 lg/mL in DMSO. Clotrimazole was used as the standard. The zone of inhibition was measured after 24 h incubation at 37 °C.
4. Conclusion
New series of pyrazole and imidazole derivatives 1-10 were synthesized by the Mannich base method and screened for antimicrobial activity. Among these, compound 6 has high antibacterial activity against S. aureus compared with the standard ciprofloxacin and high anti-fungal ac ti vity against A. niger compared with the standard clotrimazole. The synthesized compounds could be extended to the testing for various other pharmacological activities.
5. Acknowledgment
We sincerely thank Principal and management of Jamal Mohamed College, for providing laboratory facilities and we wish to thank Department of Microbiology, Bha-rathidasan University, Tamil Nadu, India for help of antimicrobial screening.
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Povzetek
S pomočjo Mannichove metode smo pripravili novi seriji pirazolskih derivatov 3-(furan-2-il)-4-(5-hidroksi-4_ff-pirazol-3-il)-N-fenilbutanamidov 1-5 in imidazolskih derivatov 3-(furan-2-il)-3-(1_ff-imidazol-1-il)-N-fenilpropanamidov 6-10. Strukture pripravljenih spojin 1-10 smo potrdili z IR, 1H NMR, 13C NMR, masno spektroskopijo in z elementno analizo. Spojine smo tudi testirali za morebitne antimikrobne aktivnosti.