CC BY-NC-ND
0Journal of Saudi Chemical Society (2013) 17, 307-313
ORIGINAL ARTICLE
Synthesis, characterization and antimicrobial activity of novel sulphapiperazine containing arylazopyrazoles
Purvesh J. Shah, Hasmukh S. Patel, Bhupendra P. Patel *
Department of Chemistry, Sardar Patel University, Vallabh Vidhyanagar 388 120, India
Received 18 September 2010; accepted 27 April 2011 Available online 6 May 2011
KEYWORDS
Pyrazole; Benzotriazole; Spectral studies; Antibacterial activity; Antifungal activity
Abstract Mannich reaction of benzotriazole (1), ethyl-4-amino benzoate (2) and formaldehyde in eth-anol afforded 4-(1H)-benzotriazoyl methyl amino benzoate (3), which on treatment with hydrazine hydrate results in the 4-(1H)-benzotriazoylmethyl amino benzoyl hydrazide (4). This compound on condensation with pre-prepared various ethyl-2-substituted phenyl hydrazono-3-oxobutyrates (6a-h), furnished 1-(4-((1H-benzo[d][1,2,3]triazol-1-yl) methyl amino) benzoyl)-3-methyl-4-(2-(4-(4-alkylpiperazin-1-ylsulfonyl) phenyl) hydrazono)-1H-pyrazol-5(4H)-ones (7a-h). All these compounds (7a-h) were characterized by spectral studies. The compounds showed significant antimicrobial activity against various bacteria and fungi.
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1. Introduction
Many pyrazoles and substituted pyrazoles derivatives are well known for their biological and pharmacological activities (Bek-hit et al., 2005; Pattan et al., 2009; Scheibye et al., 1982), which exhibit an anti-inflammatory (Hiremith et al., 2002), fungicidal (Dhol et al., 1975), bactericidal (Dhol et al., 1975), antipyretic (Souza et al., 2002; McTavish, 2004), antidepressant (Palaska
* Corresponding author.
E-mail address: drbppatel1948@yahoo.com (B.P. Patel).
1319-6103 © 2011 King Saud University. Production and hosting by Elsevier B.V. All rights reserved.
Peer review under responsibility of King Saud University. doi:10.1016/j.jscs.2011.04.016
et al., 2001; Rajendra et al., 2005; Ozdemir et al., 2007; Ruhogluo et al., 2005) anticonvulsant (Ozdemir et al., 2007; Ruhogluo et al., 2005) and protein kinase inhibitors (Abdallah, 2007). These pyrazolone derivatives were investigated as thermal stabilizers for rigid PVC (Sabaa et al.,2006a,b). Arylazopyrazoles are generally prepared by combination of aryl-azo-ethyl actoacetate derivatives and hydrazine derivatives (Amir et al., 2003; Bhatt et al., 2003; Patel and Singh, 2009; Kartritzky and Rachwal, 1987; Kartritzky et al., 2005). The benzotriazole is found as an important heterocyclic compound. It's prime application is as corrosion inhibitors for copper or copper alloys (Long and Vecek, 1982; Hageolorn and Evertz, 1984). Ciba Geigy has introduced benzotriazole derivative under the trade name Trinvin-P (Ratway, 1981). It is applied as an UV light absorber for stabilizing plastics and other organic materials against discolouration determination. It is employed as photographic emulsion stabilizer (Ullman's, 1984). In the peptide synthesis, it acts in the form of an active ester (Hadson et al., 1990). The area in which the merged molecule like aryl azo pyr-azole-benzotriazole has not been developed in spite of good
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biological properties of both these compounds. The present authors did initial work as this aspect (Patel et al., 2010). In continuation with this work, the present paper comprises the synthesis and characterization of azopyrazole- benzotriazole derivatives shown in Schemes 1 and 2.
2. Experimental
2.1. Materials
All chemicals used were of laboratory grade. Ethyl-4-amino benzoate and Benzotriazole were prepared by reported method (Vogel, 1978). The sulfonamide derivatives 5a-h were prepared by reported method (Patel et al., 2003).
rT"VN*
|l ,,N + H-CHO ■
Benzotriazole Formaldehyde
EtOH reflux
n-ch2-nh
Ethyl-p-amino benzoate 2
N2H4 , EtOH reflux
¿ch2-nh-
2.2. Measurement
Melting points were determined in open capillary tubes and were uncorrected. IR spectra were recorded in KBr pellets on a Nicolet 760D spectrometer. *H NMR and 13C NMR spectra were recorded in DMSO with TMS as internal standard on a Bruker spectrometer at 400 MHz and 100 MHz respectively. LC-MS of selected samples was taken on a LC-MSD-Trap-SL_01046 instrument.
2.3. Synthesis of 4-(1H)-benzotriazolyl methyl amino benzoate
A mixture of 1H-Benzotriazole (1) (0.02 mol), formaldehyde (0.02 mol) and ethyl-4-amino benzoate (2) (0.02 mol) in etha-nol (50 ml) was heated under reflux for 4 h. Subsequently, eth-anol was distilled off and the pasty mass obtained, which was triturated with petroleum ether (40-60 0C). The solid 4-(1H)-benzotriazolyl methyl amino benzoate (3) was isolated and dried.
Yield 68%, m.p. 146-147 oc. IR [v, cm"1, KBr]: 3034-3086 (C-H aromatic), 2965 (CH2), 2910-2890 (C-H), 1725 (C=O of ester), 1456 (C-H), 1255-1197 (C-N). *H NMR [400 MHz, d, ppm, DMSO-d6]: 8.20-6.56 (8H, m, Ar-H, J = 8.2, 7.8, 1.1, 1.0, 0.09, 0.1 Hz), 5.71 (2H, s, CH2), 3.2 (1H, s, NH), 4.32 (2H, q, -O-CH2), 1.32 (3H, t, -CH3). 13C NMR [100 MHz, d, ppm, DMSO]: 170.4 (CO), 145.6,132.9,127.3,120.6,114.3 (benzotriazole Ar-C), 149.1, 130.8, 118.7, 114.5 (Ar-C), 75.7 (CH2), 62.1 (CH2), 13.9 (CH3). LC-MS: m/z 305 (M+). Anal. Calcdfor C16H16N4O2 (296) C, 64.85; H, 5.44; N, 18.91. Found: C, 64.83; H, 5.43; N, 18.90.
2.4. Synthesis of 4-(1H)-benzotriazolyl methyl amino benzoyl hydrazide (4)
4-(1H)-benzotriazolyl methyl amino benzoate (3) (0.05 mol) was refluxed with hydrazine hydrate (0.05 mol) in absolute eth-anol for 8-10 h. It was cooled and kept overnight. The solid so obtained was filtered and recrystallized from ethanol.
Yield 63%, m.p. 77-78 oc. IR [v, cm"1, KBr]: 3450, 1630 (NH2), 3034-3086 (C-H aromatic), 2965 (CH2), 1725 (C=O of ester), 1197-1255 (C-N). *H NMR [400 MHz, d, ppm, DMSO-d6]: 9.66 (1H, s, CONH), 8.21-6.56 (8H, m, Ar-H, J = 8.2, 7.8, 1.1, 1.0, 0.09, 0.1 Hz), 5.7 (2H, s, CH2), 3.95 (2H, s, NH2), 3.2 (1H, s, NH). 13C NMR [100 MHz, d, ppm, DMSO]: 170.4 (CO), 145.6, 132.9, 127.3, 120.6, 114.3 (benzo-
Scheme 1
triazole Ar-C), 149.1, 130.8, 118.7, 114.5 (Ar-C), 75.7 (CH2). LC-MS: m/z 291 (M+). Anal. Calcd for C14H14N6O (282): Calcd.: C, 59.56; H, 5.00; N, 29.77. Found: Calcd.: C, 59.55; H, 4.98; N, 29.75.
2.5. General procedure for the preparation of Synthesis of ethyl-2-substituted phenyl hydrazono-3-oxobutyrates (6a-h)
Sulphonamide derivatives (5a-h) (0.01 mol) were dissolved in a mixture of HCl (8 ml) and water (6 ml) and cooled to 0 oc in ice bath. To it a cold aqueous solution of sodium nitrate (0.03 mol) was added. The diazonium salt solution was filtered into a cooled solution of ethyl actoacetate (0.01 mol) and sodium acetate (0.12 mol) in ethanol (50 ml). The resulting solid was washed with water and recrystallized from EtOH/MeOH.
All the compounds of this series were prepared by adopting similar type of procedures.
2.5.1. Ethyl 2-(2-(3-(4-methylpiperazin-1-ylsulfonyl)phenyl) hydrazono)-3-oxobutanoate (6a)
Yield 75%; m.p. 145-148 oc. IR [v, cm"1, KBr]: 3369 (N-H), 3034-3086 (C-H aromatic), 2920 (CH3, CH2), 1725-1765 (C=O), 1640-1596 (C=N), 1465 (CH3, CH2), 1197-1255 (c-N), 1148 (C-O). *H NMR [400 MHz, d, ppm, DMSO-d6]: 11.62 (1H, s, NH), 7.67-6.90 (4H, s, ArH, J= 7.4, 2.5, 0.1 Hz), 4.29 (2H, q, COCH2), 3.10-2.40 (8H, t, CH2), 2.54 (3H, s, CH3), 2.35 (3H, s, COCH3), 1.34 (3H, t, CH3). 13C NMR [100 MHz, d, ppm, DMSO]: 195.4, 165.4 (CO), 143.6,
R-N N O2S
EAA Sodium acetate
NaNO2/HCl
R-N Vl—O2S-
,/CO2C2H5
R= (a) Methyl; (d) Phenyl;
(g) 2-tetrahydrofuroyl;
(b) Ethyl;
(e) 2,3-dichlorophenyl; (h) hydroxyl ethanol
(c) Benzyl; (f) 3-chlorophenyl;
Scheme 2
138.2, 127.9, 117.6, 114.8 (Ar-C), 61.4 (CH2), 56.6 (CH2), 46.9 (CH3), 48.7 (CH2), 26.9, 14.2 (CH3). LC-MS: m/z 402 (M+). Anal. Calcd for C17H24N4O5S (396): C, 51.50; H, 6.10; N, 14.13; S, 8.09. Found: C, 51.49; H, 6.08; N, 14.11; S, 8.08.
2.5.2. Ethyl 2-(2-(3-(4-ethylpiperazin-1-ylsulfonyl)phenyl) hydrazono)-3-oxobutanoate (6b)
Yield 73%; m.p. 164-166 0C. IR [v, cm"1, KBr]: 3369 (N-H), 3034-3086 (C-H aromatic), 2920, 1465 (CH3, CH2), 17651725 (C=O), 1640-1596 (C=N), 1255-1197 (C-N), 1148 (C-O). NMR [400 MHz, d, ppm, DMSO-d6]: 11.62 (1H, s, NH), 7.67-6.90 (4H, m, ArH, J = 7.3, 2.4, 0.1 Hz), 4.29 (2H, q, COCH2), 3.10-2.40 (8H, t, CH2), 2.43 (1H, q, CH2), 2.35 (3H, s, COCH3), 1.34-1.06 (6H, t, CH3). 13C NMR [100 MHz, d, ppm, DMSO]: 195.4, 165.4 (CO), 143.6, 138.2, 127.9, 117.6, 114.8 (Ar-C), 61.4 (CH2), 56.6 (CH2), 49.7 (CH3), 48.7 (CH2), 26.9, 14.2, 13.6 (CH3). LC-MS: m/z 418(M+). Anal. Calcd for C18H26N4O5S (410): C, 52.67; H, 6.38; N, 13.65; S, 7.81. Found C, 52.65; H, 6.36; N, 13.64; S, 7.80.
2.5.3. Ethyl 2-(2-(3-(4-benzylpiperazin-1-ylsulfonyl)phenyl) hydrazono)-3-oxobutanoate (6c)
Yield 69%; m.p. 170-172 0C. IR [v, cm"1, KBr]: 3369(N-H), 3034-3086 (C-H aromatic), 2920 (CH3, CH2), 1725-1765 (C=O), 1640-1596 (C=N), 1465 (CH3, CH2), 1255-1197 (c-N), 1148 (C-O). NMR [400 MHz, d, ppm, DMSO-d6]: 11.62(1H, s, NH), 7.67-6.90 (9H, m, ArH, J = 7.4, 2.5, 0.1 Hz), 4.29 (2H, q, COCH2), 3.64 (2H, s, CH2), 3.34-2.52 (8H, t, CH2), 2.35 (3H, s, COCH3), 1.34 (3H, t, CH3). 13C NMR [100 MHz, d, ppm, DMSO]: 195.4, 165.4 (CO), 143.6, 138.8, 138.2, 128.4, 127.9, 127.4, 117.6, 114.8 (Ar-C), 64.6 (CH2), 61.4 (CH2), 56.6 (CH2), 48.7 (CH2), 26.9, 14.2 (CH3). LC-MS: m/z 484 (M+). Anal. Calcd for C23H28N4O5S (472): C, 58.46; H, 5.97; N, 11.86; S, 6.79. Found: C, 58.45; H, 5.96; N, 11.84; S, 6.78.
2.5.4. Ethyl 2-(2-(3-(4-phenylpiperazin-1-ylsulfonyl)phenyl) hydrazono)-3-oxobutanoate (6d)
Yield 77%; m.p. 143-145 oc. IR [v, cm"1, KBr]: 3369 (N-H), 3034-3086 (C-H aromatic), 2920 (CH3, CH2), 1725-1765 (C=O), 1640-1596 (C=N), 1465 (CH3, CH2), 1255-1197 (c-N), 1148 (C-O). 1H NMR [400 MHz, d, ppm, DMSO-d6]: 11.62(1H, s, NH), 7.67-6.90(9H, m, ArH, J = 7.6, 2.4, 0.1 Hz), 4.29(2H, q, COCH2), 3.10-2.40(8H, t, CH2), 2.35(3H, s, COCH3), 1.34 (3H, t, CH3). 13C NMR [100 MHz, d, ppm, DMSO]: 195.4, 165.4 (CO), 149.8, 143.6, 138.8, 138.2, 129.9, 128.4, 127.9, 127.4, 122.1, 117.6, 114.8
(Ar-C), 61.4 (CH2), 56.6 (CH2), 48.7 (CH2), 26.9, 14.2 (CH3). LC-MS: m/z 476 (M + ). Anal. Calcd for C22H26N4O5S (458): C, 57.63; H, 5.72; N, 12.22; S, 6.99. Found: C, 57.62; H, 5.70; N, 12.21; S, 6.98.
2.5.5. Ethyl-2-(2-(3-(4-(2,3-dichlorophenyl)piperazin-1-ylsulfo nyl)phenyl)hydrazono)-3-oxo butanoate (6e)
Yield 77%; m.p. 143-145 oc. IR [v, cm"1, KBr]: 3369(N-H), 3034-3086 (C-H aromatic), 2920 (CH3, CH2), 1255-1197 (C-N), 1765-1725 (C=O), 1465 (CH3, CH2), 1148 (C-O), 890-910 (C-Cl). 1H NMR [400 MHz, d, ppm, DMSO-d6]: 11.62 (1H, s, NH), 7.67-6.90 (7H, m, ArH, J= 7.5, 2.2, 0.1 Hz), 4.29 (2H, q, COCH2), 3.10-2.40 (8H, t, CH2), 2.35 (3H, s, COCH3), 1.34 (3H, t, CH3). 13C NMR [100 MHz, d, ppm, DMSO]: 195.4, 165.4 (CO), 149.8, 143.6, 138.8, 133.5, 129.4, 127.9, 127.4, 124.1, 117.8, 117.5, 117.2, 114.8 (Ar-C), 61.4 (CH2), 56.6 (CH2), 48.7 (CH2), 26.9, 14.2 (CH3). LC-MS: m/z 539 (M+). Anal. Calcd for C22H24Cl2N4O5S (526): C, 50.10; H, 4.59; Cl, 13.44; N, 10.62; S, 6.08. Found: C, 50.09; H, 4.58; Cl, 13.43; N, 10.61; S, 6.07.
2.5.6. Ethyl-2-(2-(3-(4-(3-chlorophenyl)piperazin-1-ylsulfonyl) phenyl)hydrazono)-3-oxo butanoate (6f)
Yield 73%; m.p. 133-135 oc. IR [v, cm"1, KBr]: 3369 (N-H), 3034-3086 (C-H aromatic), 2920 (CH3, CH2), 1765-1725 (C=O), 1640-1596 (C=N), 1465 (CH3, CH2), 1255-1197 (c-N), 1148 (C-O), 890-910 (C-Cl). 1H NMR [400 MHz, d, ppm, DMSO-d6]: 11.62 (1H, s, Nh), 7.67-6.90 (8H, m, ArH, J = 7.5, 2.6, 0.1 Hz), 4.29 (2H, q, COCH2), 3.10-2.40 (8H, t, CH2), 2.35 (3H, s, COCH3), 1.34 (3H, t, CH3). 13C NMR [100 MHz, d, ppm, DMSO]: 195.4, 165.4 (CO), 149.8, 143.6, 138.8, 135.4, 131.2, 127.9, 122.1, 117.5, 117.2, 114.8, 112.6, 110.8 (Ar-C), 61.4 (CH2), 56.6 (CH2), 48.7 (CH2), 26.9, 14.2 (CH3). LC-MS: m/z 507(M + ). Anal. Calcd for C22H25ClN4O5S (432): C, 53.60; H, 5.11; Cl, 7.19; N, 11.37; S, 6.50. Found: C, 53.59; H, 5.10; Cl, 7.18; N, 11.36; S, 6.49.
2.5.7. Ethyl-2-(2-(3-(4-(2-tetrahydrofuroyl)piperazin-1-ylsulfo nyl)phenyl)hydrazono)-3-oxo butanoate (6g)
Yield 78%; m.p. 149-152 oC. IR [v, cm"1, KBr]: 3369 (N-H), 3034-3086 (C-H aromatic), 2920 (CH3, CH2), 1725-1765 (C=O), 1640-1596 (C=N), 1465 (cH3, CH2), 1255-1197 (c-N), 1148 (C-O). 1H NMR [400 MHz, d, ppm, DMSO-d6]: 11.62(1H, s, NH), 7.67-6.90(4H, m, ArH, J = 7.4, 2.5, 0.1 Hz), 4.76-1.92 (tetrahydro furan ring CH2), 4.29 (2H, q, COCH2), 3.10-2.40 (8H, t, CH2), 2.35 (3H, s, COCH3), 1.34 (3H, t, CH3). 13C NMR [100 MHz, d, ppm, DMSO]: 195.4, 168.2, 165.4 (CO), 149.8, 143.6, 127.8, 117.5, 117.2, 114.7
(Ar-C), 85.6, 67.8, 32.5, 24.4 (tetra hydro furan ring CH) 61.4, 56.6, 48.7 (CH2), 26.9, 14.2 (CH3). LC-MS: m/z 496 (M+). Anal. Calcd for C21H28N4O7S (480): C, 52.49; H, 5.87; N, 11.66; S, 6.67. Found: C, 52.47; H, 5.86; N, 11.65; S, 6.65.
2.5.8. Ethyl-2-(2-(3-(4-(2-hydroxyl ethanolyl)piperazin-1-ylsulfonyl)phenyl)hydrazono)-3-oxo butanoate (6h) Yield 76%; m.p. 138-140 oc. IR [v, cm"1, KBr]: 3540 (OH), 3369 (N-H), 3034-3086 (C-H aromatic), 2920 (CH3, CH2), 1765-1725 (C=O), 1640-1596 (C=N) 1465 (CH3, CH2), 1197-1255 (C-N), 1148 (C-O). *H NMR [400 MHz, d, ppm, DMSO-d6]: 11.62 (1H, s, NH), 7.67-6.90 (4H, m, ArH, J = 7.4, 2.3, 0.1 Hz), 4.29 (2H, q, COCH2), 3.72 (1H, s, OH), 3.10-2.40 (12H, t, CH2), 2.35 (3H, s, COCH3), 1.34 (3H, t, CH3). 13C NMR [100 MHz, d, ppm, DMSO]: 195.4, 165.4 (CO), 149.8, 143.6, 127.8, 117.5, 117.2, 114.7 (Ar-C), 61.4, 59.8, 59.4, 56.6, 48.7 (CH2), 26.9, 14.2 (CH3). LC-MS: m/z 439 (M+). Anal. Calcd for C18H26N4O6S (426): C, 50.69; H, 6.14; N, 13.14; S, 7.52. Found: C, 50.68; H, 6.13; N, 13.13; S, 7.50.
2.6. General procedure for the preparation of 1-(4-((1H-benzo [d][1,2,3]triazol-1-yl)methylamino)benzoyl)-3-methyl-4-(2-(4-(4-alkylpiperazin-1-ylsulfonyl)phenyl) hydrazono)-1H-pyrazol-5 (4H)-ones (7a-h)
The compounds (6a-h) (0.002 mol) dissolved in glacial acetic acid (20 ml), a solution of 4-(1H)-benzotriazolyl methyl amino benzoyl hydrazide (4) (0.002 mol) in 25 ml of glacial acetic acid was added and the mixture was refluxed 10-12 h. It was then cooled and allowed to stand overnight. The resulting solid was filtered off, dried and crystallized from methanol.
All the compounds of this series were prepared by adopting similar type of procedures.
2.6.1. Synthesis of 1-(4-((1H-benzo[d][1,2,3]triazol-1-yl) met hylamino)benzoyl)-3-methyl-4-(2-(4-(4-methylpiperazin-1-ylsu lfonyl)phenyl) hydrazono)-1H-pyrazol-5(4H)-one (7a) Yield 68%; m.p. 209-211 oc. IR [v, cm-1, KBr]: 3369(N-H), 3034-3086 (C-H aromatic), 2920 (CH3, CH2), 1725-1665 (C,O), 1640-1596 (C=N), 1465 (CH3, CH2), l255-1197 (C-N), 1148 (C-O). NMR [400 MHz, d, ppm, DMSO-d6]: 11.62, 6.97 (2H, s, NH), 7.67-6.90(12H, m, ArH, J = 8.3, 1.1, 1.0 Hz), 5.64 (2H, s, CH2), 3.10-2.40 (8H, t, CH2), 2.352.28 (6H, s, CH3). 13C NMR [100 MHz, d, ppm, DMSO]:
170.1, 164.3 (CO), 151.3, 145.6, 143.6, 138.2, 132.8, 130.3, 127.7, 126.6, 117.5, 117.2, 116.8, 114.8, 113.4, 112.8 (Ar-C), 129.4 (C=N), 59.8, 56.4, 48.7 (CH2), 46.9, 11.6 (CH3). LC-MS: m/z 628 (M+). Anal. Calcd for C29H30N10O4S (614): C, 56.67; H, 4.92; N, 22.79; S, 5.22. Found: C, 56.66; H, 4.90; N, 22.78; S, 5.21.
2.6.2. Synthesis of 1-(4-((1H-benzo[d][1 , 2, 3]triazol-1-yl) met hylamino)benzoyl)-3-methyl-4-(2-(4-(4-ethylpiperazin-1-ylsulf onyl)phenyl) hydrazono)-1H-pyrazol-5(4H)-one (7b)
Yield 64%; m.p. 198-201 oc. IR [v, cm"1, KBr]: 3369 (N-H), 3034-3086 (C-H aromatic), 2920 (CH3, CH2), 1725-1665 (C=O), 1640-1596 (C=N), 1465 (CH3, CH2), 1255-1197 (c-N), 1148 (C-O). NMR [400 MHz, d, ppm, DMSO-d6]: 11.62, 6.97(2H, s, NH), 7.67-6.90 (12H, m, ArH, J = 8.3, 1.1, 0.09 Hz), 5.64 (2H, s, CH2), 3.10-2.40 (8H, t,
CH2), 2.42 (2H, q, CH2), 2.35 (3H, s, CH3), 1.12 (3H, t, CH3). 13C NMR [100 MHz, d, ppm, DMSO]: 170.1, 164.3 (Co), 151.3, 145.6, 143.6, 138.2, 132.8, 130.3, 127.7, 126.6, 117.5,
117.2. 116.8, 114.8, 113.4, 112.8 (Ar-C), 129.4 (C=N), 59.8, 56.4, 49.8, 48.7 (CH2), 13.5, 11.6 (CH3). LC-MS: m/z 636 (M+). Anal. Calcd for C30H32N10O4S (628): C, 57.31; H, 5.13; N, 22.28; S, 5.10. Found: C, 57.30; H, 5.12; N, 22.27; S, 5.09.
2.6.3. Synthesis of 1-(4-((1H-benzo[d][1 , 2, 3]triazol-1-yl)eth ylamino)benzoyl)-3-methyl-4-(2-(4-(4-benzylpiperazin-1-yls ulfonyl)phenyl) hydrazono)-1H-pyrazol-5(4H)-one (7c) Yield 62%; m.p. 205-207 oc. IR [v, cm"1, KBr]: 3369(N-H), 3034-3086 (C-H aromatic), 2920 (CH3, CH2), 1725-1665 (C=O), 1640-1596 (C=N), 1465 (ch3, CH2), 1255-1197 (c-N), 1148 (C-O). NMR [400 MHz, d, ppm, DMSO-d6]: 11.62, 6.97(2H, s, NH), 7.67-6.90(17H, m, ArH, J = 8.3, 1.2, 0.09 Hz), 5.64 (2H, s, CH2), 3.74(2H, s, CH2), 3.10-2.40 (8H, t, CH2), 2.35 (3H, s, CH3). 13C NMR [100 MHz, d, ppm, DMSO]: 170.1, 164.3 (Co), 151.3, 145.6, 143.6, 138.8, 138.2, 132.8, 130.3, 128.9, 128.5, 127.7, 127.4, 126.6, 117.5, 117.2, 116.8, 114.8, 113.4, 112.8 (Ar-C), 129.4 (C=N), 64.8, 59.8, 54.4, 48.7 (CH2), 11.6 (CH3). LC-MS: m/z 703 (M+). Anal. Calcd for C35H34N10O4S (690): C, 60.86; H, 4.96; N, 20.28; S, 4.64. Found: C, 60.85; H, 4.94; N, 20.27; S, 4.62.
2.6.4. Synthesis of 1-(4-((1H-benzo[d][1,2,3]triazol-1-yl)eth ylamino)benzoyl)-3-methyl-4-(2-(4-(4-phenylpiperazin-1-ylsulf onyl)phenyl) hydrazono)-1H-pyrazol-5(4H)-one (7d)
Yield 65%; m.p. 212-214 oc. IR [v, cm"1, KBr]: 3369 (N-H), 3034-3086 (C-H aromatic), 2920 (CH3, CH2), 1725-1665 (C=O), 1640-1596 (C=N), 1465 (CH3, CH2), 1255-1197 (c-N), 1148 (C-O). 1H NMR [400 MHz, d, ppm, DMSO-d6]: 11.62, 6.97(2H, s, NH), 7.67-6.90 (17H, m, ArH, J = 8.3, 1.0, 0.09 Hz), 5.64 (2H, s, CH2), 3.10-2.40 (8H, t, CH2), 2.35 (3H, s, CH3). 13C NMR [100 MHz, d, ppm, DMSO]: 170.1, 164.3 (CO), 151.3, 149.7, 145.6, 143.6, 138.2, 132.8, 130.3, 129.8, 127.7, 126.6, 122.3, 117.5, 114.6, 117.2, 116.8, 114.8, 113.4, 112.8 (Ar-C), 129.4 (C=N), 59.8, 54.4, 48.7 (CH2), 11.6 (CH3). LC-MS: m/z 689 (M+). Anal. Calcd for C34H32N10O4S (676): C, 60.34; H, 4.77; N, 20.70; S, 4.74. Found: C, 60.32; H, 4.73; N, 20.69; S, 4.73.
2.6.5. Synthesis of1-(4-((1H-benzo[d][1,2,3]triazol-1-yl) met hylamino)benzoyl)-4-(2-(4-(4-(2,3-dichlorophenyl) piperazin-1-ylsulfonyl)phenyl)hydrazono)-3-methyl-1H-pyrazol-5(4H)-one (7e)
Yield 61%; m.p. 203-205 oc. IR [v, cm"1, KBr]: 3369(N-H), 3034-3086 (C-H aromatic), 2920 (CH3, CH2), 1725-1665 (C=O), 1640-1596 (C=N), 1465 (CH3, CH2), 1255-1197 (c-N), 1148 (C-O), 890-910 (C-Cl). 1H NMR [400 MHz, d, ppm, DMSO-d6]: 11.62, 6.97 (2H, s, NH), 7.67-6.90 (15H, m, ArH, J =8.4, 1.2, 0.09 Hz), 5.64(2H, s, CH2), 3.10-2.40(8H, t, CH2), 2.35 (3H, s, CH3). 13C NMR [100 MHz, d, ppm, DMSO]: 170.1, 164.3 (CO), 151.3, 150.2, 145.6, 143.6, 138.2, 133.5, 132.8, 130.3, 129.3, 127.7, 127.6, 124.3, 117.8,
114.6. 117.2, 116.8, 114.8, 113.4, 112.8 (Ar-C), 129.4 (C=N), 59.8, 54.4, 48.7 (CH2), 11.6 (CH3). LC-MS: m/z 756 (M+). Anal. Calcd for C34H30Cl2N10O4S (744): C, 54.77; H, 4.06; Cl, 9.51; N, 18.78; S, 4.30. Found: C, 54.75; H, 4.04; Cl, 9.50; N, 18.76; S, 4.28.
2.6.6. Synthesis of 1-(4-((1H-benzo[d][1,2,3]triazol-1-yl) me thylamino)benzoyl)-4-(2-(4-(4-(3-chlorophenyl)piperazin-1-yl sulfonyl)phenyl)hydrazono)-3-methyl-1H-pyrazol-5(4H)-one
Yield 64%; m.p. 202-203 oc. IR [v, cm"1, KBr]: 3369(N-H), 3034-3086 (C-H aromatic), 2920 (CH3, CH2), 1725-1665 (C=O), 1640-1596 (C=N), 1465 (cH3, CH2), 1255-1197 (c-N), 1148 (C-O), 890-910 (C-Cl). 1H NMR [400 MHz, d, ppm, DMSO-d6]: 11.62, 6.97(2H, s, NH), 7.67-6.90 (16H, m, ArH, J = 8.2, 1.3, 1.0 Hz), 5.64 (2H, s, CH2), 3.10-2.40(8H, t, CH2), 2.35 (3H, s, CH3). 13C NMR [100 MHz, d, ppm, DMSO]: 170.1, 164.3 (CO), 151.3, 150.8, 145.6, 143.6, 138.2,
133.5, 132.8, 130.8, 129.3, 129.3, 127.8, 127.6, 124.9, 123.8, 117.8, 114.6, 117.2, 116.8, 114.8, 113.4, 112.8 (Ar-C), 129.4 (C=N), 59.8, 54.4, 48.7 (CH2), 11.6 (CH3). LC-MS: m/z 722(M+). Anal. Calcd for C^H^Cl^^S (710): C, 57.42; H, 4.39; Cl, 4.99; N, 19.69; S, 4.51. Found: C, 57.41; H, 4.38; Cl, 4.97; N, 19.68; S, 4.50.
2.6.7. Synthesis of 1-(4-(( 1H-benzo[d][1,2,3]triazol-1-yl) met hylamino)benzoyl)-3-methyl-4-(2-(4-(4-(2-tetrahydrofu royl)p iperazin-1-ylsulfonyl)phenyl)hydrazono )-1H-pyrazol-5( 4H)-one
Yield 62%; m.p. 214-216 oc. IR [v, cm"1, KBr]: 3369(N-H), 3034-3086 (C-H aromatic), 2920 (CH3, CH2), 1725-1665 (C=O), 1640-1596 (C=N), 1465 (cH3, CH2), 1255-1197 (c-N), 1148 (C-O), 890-910 (C-Cl). 1H NMR [400 MHz, d, ppm, DMSO-d6]: 11.62, 6.97(2H, s, NH), 7.67-6.90 (12H, m, ArH, J = 8.1, 1.0 Hz), 5.64(2H, s, CH2), 4.76-1.92(tetrahydro furan ring CH2), 3.74(2H, s, CH2), 3.10-2.40 (8H, t, CH2), 2.35(3H, s, CH3). 13C NMR [100 MHz, d, ppm, DMSO]: 170.1, 168.2, 164.3 (CO), 151.3, 145.6, 143.6, 138.2, 132.8, 130.3, 127.7, 117.5, 117.2, 116.8, 114.8, 113.4, 112.8 (Ar-C), 129.4 (C=N), 84.8, 68.2, 59.8, 56.4, 48.7, 32.5, 25.4 (CH2), 11.6 (CH3). LC-MS: m/z 722 (M+). Anal. Calcd for C33H34N10O6S (710): C, 56.72; H, 4.90; N, 20.05; S, 4.59. Found: C, 56.71; H, 4.88; N, 19.99; S, 4.58.
2.6.8. Synthesis of 1-(4-(( 1H-benzo[d][1,2,3]triazol-1-yl)meth ylamino)benzoyl) -3-methyl-4- (2-(4-(4-( 2-hydroxyl ethanolyl) pi perazin-1-ylsulfonyl)phenyl)hydrazono)-1H-pyrazol-5( 4H)-one (7h)
Yield 66%; m.p. 201-203 oc. IR [v, cm"1, KBr]: 3540(OH), 3369(N-H), 3034-3086 (C-H aromatic), 2920 (cH3, CH2), 1725-1665 (C=O), 1640-1596 (C=N), 1465 (CH3, CH2), 1197-1255 (C-N), 1148 (C-O), 1H NMR [400 MHz, d, ppm, DMSO-d6]: 11.62, 6.97(2H, s, NH), 7.67-6.90 (12H, m, ArH, J = 8.2, 1.1, 1.0 Hz), 5.64(2H, s, CH2), 3.67 (1H, s, OH) 3.48-2.40 (12H, t, CH2), 2.35 (3H, s, CH3). 13C NMR [100 MHz, d, ppm, DMSO]: 170.1, 164.3 (CO), 151.3, 145.6,
143.6, 138.2, 132.8, 130.3, 127.7, 126.6, 117.5, 117.2, 116.8114.8, 113.4, 112.8 (Ar-C), 129.4 (C=N), 59.8, 59.6, 59.34, 56.4, 48.7 (CH2), 11.6 (CH3). LC-MS: m/z 662(M+). Anal. Calcd for C30H32N10O5S (644): C, 55.89; H, 5.00; N, 21.73; S, 4.97. Found: C, 55.87; H, 4.99; N, 21.72; S, 4.96.
3. Results and discussion
3.1. Chemistry
The compound 4 (hydrazide) has been synthesized successfully as the Mannich reaction reported previously (Amir et al., 2003;
Bhatt et al., 2003; and Singh, 2009; Kartritzky and Rachwal, 1987; Kartritzky et al., 2005). The synthesis of 5a-h has been performed based on the method reported (Patel et al., 2003). From these compounds the novel compounds 6a-h has been synthesized. The compounds 6a-h reacted with 4 to give the corresponding compounds 7a-h. All the compounds were confirmed on the basis of the elemental analysis and spectro-scopic investigation. IR spectrum of 4 revealed characteristic bands at 3450, 1630 (NH2) and confirmatory by 1H NMR d 3.95 (2H, s, NH2). Further, IR spectroscopic investingation of 6a-h reveals bands at 1640-1596 (C=N) and 1H NMR d 11.62 (1H, s, NH).
IR spectra of compounds 7a-h shows 3369 (N-H), 16401596 (C=N), 1255-1197 (C-N) and 1H NMR 11.62 (1H, s, NH). The examination of these data reveals that the IR band and 1H NMR signals are appropriate to the corresponding structure of compound.
The final structure of all compounds was confirmed by 13C NMR and LC-MS data, i.e., The compounds 7a show the molecular ion peak m/z 628 gives the molecular weight of 7a, i.e., 614. All these facts confirm the structures 7a-h.
3.2. Biological screening
3.2.1. Antibacterial activities
Antibacterial activities of all the compounds were studied against Gram-positive Bacteria (Bacilus subtilis and Staphylococcus aureus) and Gram-negative Bacteria (E. coil, Salmonella typhi and Klebsiella promioe) at a concentration of 50 ig/ml by Agar cup plate method. Methanol system was used as control in this method. Under similar condition using sulphonamide as a standard for comparison carried out the control experiment. The area of inhibition of zone was measured in mm. Compound 7c was found more active against the above microbes. Other compounds were found more active against the above microbes. The antibacterial activities all compounds are shown in Table 1.
3.2.2. Antifungal activity
The fungicidal activity of all the compounds was studied at 1000 ppm concentration in vitro. Plant pathogenic organisms are listed in Table 2. The antifungal activities of all the samples were measured by cup plate method (Baily and Scott, 1966; Banty, 1976; Simoncini et al., 1968). Each of the plant pathogenic strains on potato dextrose agar (PDA) medium. Such a PDA medium contained potato 200 g, dextrose 20 g, agar 20 g and water 1 l. Five days old cultures were employed. The compounds to be tested were suspended (1000 ppm) in a PDA medium and autoclaved at 120 oc for 15min, at 15 atm pressure. These medium were poured into sterile Petri plate and the organisms were inoculated after cooling the Petri plate. The percentage inhabitation for fungi was calculated after five days using the formula given below.
Percentage of inhibition = 100(X - Y)/X
where X is the area of colony in control plate and Y the area of colony in test plate.
The fungicidal activity all compounds are shown in Table 2. The antifungal activity of all the compounds measured for various plant pathogens. Inspection of the result shown in Table 2 indicates that all compounds are good toxic for fungi.
Table 1 Antibacterial activity of 1-(4-((1H-benzo[d][1,2,3]triazol-1-yl)methyl amino) benzoyl)-3-methyl-4-(2-(4-(4-alkylpiperazin-1-ylsulfonyl)phenyl)hydrazono)-1H-pyrazol-5(4H)-ones (7a-h).
Compounds Zone of Inhibition (mm) (activity index)std
Gram +ve Gram -ve
Bacillus Subtilis Staphylococcus Aureus Kllebsiella promioe Salmonella typhl E. coil
7a 53(0.62) 46(0.83) 66(0.80) 61(0.88) 67(0.93)
7b 46(054) 50(0.90) 75(0.91) 63(0.91) 65(0.90)
7c 80(0.94) 46(0.83) 76(0.92) 64(0.92) 62(0.86)
7d 81(0.95) 49(0.89) 74(0.90) 61(0.88) 67(0.93)
7e 84(0.98) 54(0.98) 80(0.97) 67(0.97) 70(0.97)
7f 82(0.96) 52(0.94) 78(0.95) 65(0.94) 69(0.95)
7g 78(0.91) 49(0.89) 74(0.90) 60(0.86) 66(0.91)
7h 80(0.94) 48(0.87) 76(0.92) 63(0.91) 64(0.88)
Sulphonamide 85 55 82 69 72
(Activity index)std = zone of inhibition of the sample/zone of inhibition of the standard.
Table 2 Antifungal activity of 1-(4-((1H-benzo[d][1,2,3]triazol-1-yl)methyl amino) benzoyl)-3-methyl-4-(2-(4-(4-alkylpiperazin-1-ylsulfonyl)phenyl)hydrazono)-1H-pyrazol-5(4H)-ones (7a-h).
Zone of inhibition at 1000 ppm (%)
Compound no. Penicillium Expansum Botrydepladia Thiobromine Nigrosspora Sp. Trichothesium Sp. Rhizopus Nigricuns
7a 75 65 73 54 48
7b 66 72 66 56 66
7c 62 73 65 54 65
7d 64 68 65 61 60
7e 78 76 77 66 64
7f 76 74 76 64 63
7g 64 73 65 54 60
7h 61 70 65 52 63
These compounds almost inhibit the fungi about 60%. Hence produced compounds can be employed as garden fungicides. Further work in the direction is in progress.
4. Conclusion
The present study reports the synthesis of novel heterocyclic pyrazolinone from the corresponding precursors ethyls-substituted phenyl hydrazono-3-oxobutyrates (6a-h) and 4-(lH)-benzotriazolyl methyl amino benzoyl hydrazide (4). The antimicrobial activity of 1-(4-((1H-benzo[d][1,2,3]triazol-1-yl)-methyl amino)benzoyl)-3-methyl-4-(2-(4-(4-alkyl piperazin-1-yl sulfonyl)phenyl) hydrazono)-1H-pyrazol-5(4H)-ones (7a-h) was carried out against some strain bacteria. The results show that the synthesized compounds were toxic against the bacteria. The investigation of antibacterial screening reveals that the compounds 4e and 4f have exhibited good antibacterial activity comparable to the standard drugs, while compounds 4e and 4f display better antifungal activity.
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