Synthesis and antitubercular activity of pyridazinone derivatives

Article abstract of DOI:10.4067/S0717-97072011000300013

Two series of pyridazinone derivatives (19-34) were synthesized and evaluated for antitubercular activities against Mycobacterium tuberculosis H37Rv strain. The results illustrated that among the synthesized compounds, compound 25, 5-(4-hydroxy-3-methoxybenzyl)-3-(4-chloro-phenyl)-1,6-dihydro-6-pyridazinone emerged as a lead compound with good antitubercular activity. Four more compounds, (21, 22, 29 & 33) were significant in their antitubercular action.

Full text of DOI:10.4067/S0717-97072011000300013

J. Chil. Chem. Soc., 56, Nº 3 (2011)
SYNTHESIS AND ANTITUBERCULAR ACTIVITY OF PYRIDAZINONE DERIVATIVES
ASIF HUSAIN1*, AFTAB AHMAD2, ANIL BHANDARI2, VEERMA RAM2
1Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hamdard University, New Delhi-110062, India; 2Faculty of Pharmaceutical Sciences,
Jodhpur National University, Jodhpur, Rajasthan-342001, India
(Received: January 24, 2011 - Accepted: June 26, 2011)
ABSTRACT
Two series of pyridazinone derivatives (19-34) were synthesized and evaluated for antitubercular activities against Mycobacterium tuberculosis H37Rv strain.
The results illustrated that among the synthesized compounds, compound 25, 5-(4-hydroxy-3-methoxybenzyl)-3-(4-chloro-phenyl)-1,6-dihydro-6-pyridazinone
emerged as a lead compound with good antitubercular activity. Four more compounds, (21, 22, 29 & 33) were significant in their antitubercular action.
Key words: Pyridazinone, antitubercular, mycobacteria, furanone.
After refluxing reaction mixture was poured onto crushed ice, a precipitate
was obtained, which was filtered, dried and recrystallized from methanol to
give TLC pure 5-(substituted benzyl)-3-aryl-1,6-dihydro-6-pyridazinone
derivatives.
5-Benzyl-3-(4-chlorophenyl)-1,6-dihydro-6-pyridazinone (19): Yield:
59%; m.p. 174 ºC; 1H-NMR (CDCl3, δ, ppm): 3.78 (s, 2H, CH2), 7.16 (s, 1H,
H-4, pyridazinone ring), 7.14-7.48 (m, 5H, benzyl ring), 7.42 and 7.73 (d, each,
J=8.1 Hz, 2xA2B2, p-substituted phenyl ring), 10.72 (s, 1H, NH); MS (m/z):
296(M+); IR (cm-1, KBr): 3186 (NH), 2949 (CH), 1683 (CO), 718 (C-Cl); Anal
calcd. for C17H13ClN2O: C, 68.81; H, 4.42; N, 9.44. Found: C, 68.93; H, 4.45;
N, 9.43.
5-(4-Chlorobenzyl)-3-(4-chlorophenyl)-1,6-dihydro-6-pyridazinone (20):
Yield: 58%; m.p. 196 ºC; 1H-NMR (CDCl3, δ, ppm): 3.95 (s, 2H, CH2), 7.11
(s, 1H, H-4, pyridazinone ring), 7.23 (m, 4H, H-2,3,5,6, benzyl ring), 7.32 and
7.41 (d, each, J=8.1 Hz, 2xA2B2, p-substituted phenyl), 10.97 (s, 1H, NH); MS
(m/z): 330(M+); IR (cm-1, KBr): 3179 (NH), 2942 (CH), 1688 (CO), 726 (C-
Cl); Anal calcd. for C17H12Cl2N2O: C, 61.65; H, 3.65; N, 8.46. Found: C, 61.55;
H, 3.67; N, 8.47.
5-(4-Nitrobenzyl)-3-(4-chlorophenyl)-1,6-dihydro-6-pyridazinone (21):
Yield: 53%; m.p. 197 ºC; 1H-NMR (CDCl , δ, ppm): 3.71 (s, 2H, CH2), 6.78
(s, 1H, H-4, pyridazinone ring), 7.37 (m,34H, H-2,3,5,6, benzyl ring), 7.53
and 7.62 (d, each, J=8.4 Hz,2xA2B2, p-substituted phenyl), 10.93 (s, 1H, NH);
MS (m/z): 341(M+); IR (cm-1, KBr): 3173 (NH), 2936 (CH), 1672 (CO), 707
(C-Cl); Anal calcd. for C H12ClN3O3: C, 59.75; H, 3.54; N, 12.30. Found: C,
59.63; H, 3.57; N, 12.31. 17
INTRODUCTION
During recent years pyridazinones have been a subject of intensive
research owing to their wide spectrum of pharmacological activities.
Differently substituted pyridazinones have been found to have potential
antibacterial, antifungal and antiviral including anti-HIV activities [1-4].
Various 3-(2H)-pyridazinone derivatives have shown anticancer [4], analgesic
& anti-inflammatory [4-6], anticonvulsant [7], cardiotonic & hypotensive [8,9]
and antiulcer activities [10].
Resistance of Mycobacterium tuberculosis strains to antitubercular agents
is an increasing problem worldwide. However, potent new antimycobacterial
drugs with new mechanism of action have not been developed in the last forty
years [11]. TB is considered by the WHO to be the most important chronic
communicable disease in the world. About 32% of the world’s population is
currently infected with TB. The emergence of AIDS, decline of socioeconomic
standards and a reduced emphasis on tuberculosis control programs contribute
to the disease’s resurgence in industrialized countries [12]. If the present trend
continues, tuberculosis is likely to claim more than 30 million lives within the
new decade.
Now research effort towards the development of novel antitubercular
agents is in the direction of discovering new classes of compounds, which are
structurally different from known anti-tubercular drugs [13,14]. The current
work describes the synthesis of newer 2(3H)-pyridazinones with encouraging
antitubercular activity.
5-(4-Hydroxybenzyl)-3-(4-chlorophenyl)-1,6-dihydro-6-pyridazinone
(22): Yield: 57%, m.p. 192 ºC; 1H-NMR (CDCl3, δ, ppm): 3.59 (s, 2H,
CH2), 6.11 (m, 1H, OH), 7.06 (m, 2H, H-2,6, benzyl ring), 7.31 (s, 1H, H-4,
pyridazinone ring), 7.47 and 7.71 (d, each, J=7.8 Hz, 2xA2B2, p-substituted
phenyl), 7.49 (m, 2H, H-3,5, benzyl ring), 9.41 (s, 1H, NH); MS (m/z): 312(M+);
IR (cm-1, KBr): 3178 (NH), 2942 (CH), 1686 (CO), 722 (C-Cl); Anal calcd. for
C17H13ClN2O2: C, 65.29; H, 4.19; N, 8.96. Found: C, 65.39; H, 4.17; N, 8.97.
5-(4-Methylbenzyl)-3-(4-chlorophenyl)-1,6-dihydro-6-pyridazinone (23):
Yield: 59%; m.p. 186 ºC; 1H-NMR (CDCl , δ, ppm): 2.27 (s, 3H, CH3), 3.51
(s, 2H, CH2), 6.60 (s, 1H, H-4, pyridazin3one ring), 7.13 and 7.36 (d, each,
J=7.8 Hz, 2xA2B2, p-substituted benzyl ring), 7.34 (m, 2H, H-3,5, phenyl ring),
7.61 (m, 2H, H-2,4, phenyl ring), 10.93 (s, 1H, NH); MS (m/z): 310(M+); IR
(cm-1, KBr): 3173 (NH), 2939 (CH), 1684 (CO), 708 (C-Cl); Anal calcd. for
C18H15ClN2O: C, 69.57; H, 4.86; N, 9.01. Found: C, 69.53; H, 4.87; N, 9.03.
5-(4-Methoxybenzyl)-3-(4-chlorophenyl)-1,6-dihydro-6-pyridazinone
(24): Yield: 61%; m.p. 169 ºC; 1H-NMR (CDCl , δ, ppm): 3.42 (s, 2H, CH2),
3.71 (s, 3H, OCH ), 6.81 (s, 1H, H-4, pyridazi3none ring), 7.13 and 7.36 (d,
each, J=8.1 Hz, 2x3A2B2, p-substituted benzyl ring), 7.59 (m, 2H, H-3,5, phenyl
ring), 7.68 (m, 2H, H-2,4, phenyl ring), 10.73 (s, 1H, NH); MS (m/z): 326(M+);
IR (cm-1, KBr): 3167 (NH), 3002 (CH), 1675 (CO), 717 (C-Cl); Anal calcd. for
C18H15ClN2O : C, 66.16; H, 4.63; N, 8.57. Found: C, 66.23; H, 4.61; N, 8.55.
5-(4-Hy2droxy-3-methoxybenzyl)-3-(4-chlorophenyl)-1,6-dihydro-6-
EXPERIMENTAL
Chemistry
Melting points were determined in open capillary tubes and are uncorrected.
Thin-layer chromatography was carried out to monitor the reactions using
silica gel G plates. The IR spectra were recorded in potassium bromide pellets
using a Perkin-Elmer 1725X spectrophotometer. Elemental analyses were
performed on a Perkin-Elmer 240 analyzer and the values were in range of
±0.4% theoretical value for the element analyzed (C, H, N). 1H-NMR spectra
were recorded on Bruker spectropsin DPX-300 MHz in CDCl3; chemical
shift (δ) values are reported in parts per million (ppm). The splitting pattern
abbreviations are as follows: s, singlet; d, doublet; m, multiplet. Mass spectra
under electron impact conditions (EI) were recorded at 70 eV ionizing voltage
with a VG Prospec instrument and are presented as m/z. Spectral data are
consistent with the assigned structures.
Preparation of 3-(4-Chloro/methyl benzoyl)propionic acid (1,2). The
compounds, 1 and 2, were synthesized according to the reported method [14].
Preparation of 3-Arylidene-5-(4-chloro/methyl phenyl)-2(3H)-furanones
(3-18). Compounds (3-18) were synthesized from 3-(4-chloro/methyl benozyl)
propionic acid (1,2) following literature method [14].
General Procedure for the synthesis of 5-(substituted benzyl)-3-aryl-1,6-
dihydro-6-pyridazinones (19-34). 2(3H)-Furanones (3-18) (0.005 mol) and
hydrazine hydrate (1-2 mL) in n-propanol (5-6 mL) were refluxed for 3h.
1
pyridazinone (25): Yield: 53%; m.p. 191 ºC; H-NMR (CDCl3, δ, ppm): 3.48
e-mail: drasifhusain@yahoo.com
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J. Chil. Chem. Soc., 56, Nº 3 (2011)
(s, 2H, CH2), 3.64 (s, 3H, OCH3), 6.53 (s, 1H, H-4, pyridazinone ring), 7.07-
7.29 (m, 3H, H-2,5,6, disubstituted benzyl ring), 7.46 and 7.71 (d, each, J=8.1
Hz, 2xA2B2, p-substituted phenyl ring), 10.92 (s, 1H, NH); MS (m/z): 342(M+);
IR (cm-1, KBr): 3173 (NH), 2951 (CH), 1680 (CO), 713 (C-Cl); Anal calcd. for
C18H15ClN2O3: C, 63.07; H, 4.41; N, 8.17. Found: C, 62.97; H, 4.39; N, 8.19.
5-(4-Fluorobenzyl)-3-(4-chlorophenyl)-1,6-dihydro-6-pyridazinone
(26): Yield: 57%; m.p. 190 ºC; 1H-NMR (CDCl , δ, ppm): 3.61 (s, 2H,
CH2), 7.05 (s, 1H, H-4, pyridazinone ring), 7.10 an3d 7.26 (d, each, J=7.5 Hz,
2xA2B2, p-substituted benzyl ring), 7.41 and 7.60 (d, each, J=7.8 Hz, 2xA2B2,
p-substituted phenyl ring), 11.14 (s, 1H, NH); MS (m/z): 314(M+); IR (cm-
1, KBr): 3191 (NH), 2944 (CH), 1682 (CO), 719 (C-Cl); Anal calcd. for
C17H12ClFN2O: C, 64.87; H, 3.84; N, 8.90. Found: C, 64.93; H, 3.85; N, 8.91.
5-Benzyl-3-(4-methylphenyl)-1,6-dihydro-6-pyridazinone (27): Yield:
53%; m.p. 168 ºC; 1H-NMR (CDCl3, δ, ppm): 2.36 (s, 3H, CH3), 3.59 (s, 2H,
CH ), 6.86 (s, 1H, H-4, pyridazinone ring), 7.02-7.43 (m, 5H, benzyl ring), 7.46
and27.79 (d, each, J=7.8 Hz, 2xA2B2, p-substituted phenyl ring), 8.92 (s, 1H,
NH); MS (m/z): 276(M+); IR (cm-1, KBr): 3185 (NH), 2952 (CH), 1676 (CO);
Anal calcd. for C18H16N2O: C, 78.24; H, 5.84; N, 10.14. Found: C, 78.23; H,
5.87; N, 10.17.
tuberculosis H37Rv (ATCC 27294) in Middle brook 7H11 agar medium
with OADC (oleic acid albumin dextrose catalase) growth supplement. 10
fold serial dilutions of each test compound/drug (in DMSO/Water mixture)
were incorporated into the agar medium. Inoculum of M. tuberculosis H37Rv
were prepared from fresh Middlebrook 7H11 agar slants with OADC growth
supplement adjusted to 1 mg/mL (wet weight) in Tween 80 (0.05%) saline
diluted to 10-2 to give a concentration of approximately 107 cfu/mL. A 5 µL
amount of bacterial suspension was spotted into 7H11 agar tubes containing
10-fold serial dilutions of drugs per mL. The tubes were incubated at 37 °C,
and final readings were recorded after 30 days. The minimum inhibitory
concentration (MIC) is defined as the minimum concentration of compound
required to give complete inhibition of bacterial growth. The MIC of the
standard drug streptomycin was 10 µg/mL. The results of the pharmacological
evaluation have been listed in Table 1.
RESULT AND DISCUSSION
Chemistry
2(3H)-Furanones (3-18) on reaction with hydrazine hydrate in n-propanol
gave 16 title compounds i.e. 5-(substituted benzyl)-3-aryl-1,6-dihydro-6-
pyridazinone derivatives (19-34). 2(3H)-Furanones (3-18) were prepared
using 3-(4-substituted benzoyl)propionic acid (1-2) following the previously
reported methods of modified Perkin’s reaction in higher yields [14]. The
3-(4-substituted benzoyl)propionic acid (1, 2) was synthesized according to
Friedel Craft’s acylation reaction condition using chlorobenzene or toluene
(Scheme-1).
5-(4-Chlorobenzyl)-3-(4-methylphenyl)-1,6-dihydro-6-pyridazinone (28):
Yield: 48%; m.p. 188 ºC; 1H-NMR (CDCl , δ, ppm): 2.38 (s, 3H, CH3), 3.94 (s,
2H, CH2), 7.24 (s, 1H, H-4, pyridazinone3ring), 7.26 and 7.56 (d, each, J=7.8
Hz, 2xA2B2, p-substituted benzyl ring), 7.28-7.35 (m, 4H, H-2,3,5,6, phenyl
ring), 10.69 (s, 1H, NH); MS (m/z): 310 (M+); IR (cm-1, KBr): 3174 (NH), 2939
(CH), 1683 (CO), 718 (C-Cl); Anal calcd. for C18H15ClN2O: C, 69.57; H, 4.86;
N, 9.01. Found: C, 69.53; H, 4.87; N, 8.99.
5-(4-Nitrobenzyl)-3-(4-methylphenyl)-1,6-dihydro-6-pyridazinone (29):
Yield: 47%; m.p. 189 ºC; 1H-NMR (CDCl , δ, ppm): 2.37 (s, 3H, CH3), 3.41 (s,
2H, CH2), 7.13 (s, 1H, H-4, pyridazinone3ring), 7.31 and 8.01 (d, each, J=8.1
Hz, 2xA2B2, p-substituted benzyl ring), 7.48 (m, 2H, H-3,5, phenyl ring), 7.81
(m, 2H, H-2,4, phenyl ring), 11.13 (s, 1H, NH); MS (m/z): 321(M+); IR (cm-
1, KBr): 3183 (NH), 2948 (CH), 1679 (CO); Anal calcd. for C18H15N3O3: C,
67.28; H, 4.70; N, 13.08. Found: C, 67.23; H, 4.71; N, 13.07.
5-(4-Hydroxybenzyl)-3-(4-methylphenyl)-1,6-dihydro-6-pyridazinone
(30): Yield: 47%; m.p. 196 ºC; 1H-NMR (CDCl3, δ, ppm): 2.54 (s, 3H, CH3),
3.43 (s, 2H, CH2), 6.40 (s, 1H, H-4, pyridazinone ring), 6.63 (m, 2H, H-2,6,
phenyl ring), 6.66 (m, 2H, H-2,6, benzyl ring), 6.79 (m, 2H, H-3,5, phenyl
ring), 6.81 (m, 2H, H-3,5, benzyl ring), 12.25 (s, 1H, NH); MS (m/z): 291(M+);
IR (cm-1, KBr): 3173 (NH), 2957 (CH), 1685 (CO); Anal calcd. for C18H16N2O2:
C, 73.96; H, 5.52; N, 9.58. Found: C, 73.98; H, 5.51; N, 9.57.
5-(4-Methylbenzyl)-3-(4-methylphenyl)-1,6-dihydro-6-pyridazinone (31):
Yield: 48%; m.p. 182 ºC; 1H-NMR (CDCl , δ, ppm): 2.29 and 2.31 (s, each, 6H,
2xCH3), 3.67 (s, 2H, CH2), 6.51 (s, 1H, H3-4, pyridazinone ring), 7.31 and 7.85
(d, each, J=7.8 Hz, 2xA2B2, p-substituted benzyl ring), 7.37 (m, 2H, H-3,5,
phenyl ring), 7.59 (m, 2H, H-2,6, phenyl ring), 10.51 (s, 1H, NH); MS (m/z):
289(M+); IR (cm-1, KBr): 3182 (NH), 2940 (CH), 1676 (CO); Anal calcd. for
C19H18N2O: C, 78.59; H, 6.25; N, 9.65. Found: C, 78.53; H, 6.27; N, 9.67.
5-(4-Methoxybenzyl)-3-(4-methylphenyl)-1,6-dihydro-6-pyridazinone
(32): Yield: 43%; m.p. 192 ºC; 1H-NMR (CDCl , δ, ppm): 2.37 (s, 3H, CH3),
3.67 (s, 3H, OCH3), 3.97 (s, 2H, CH2), 6.79 (s,31H, H-4, pyridazinone ring),
7.37 and 7.82 (d, each, J=8.1 Hz, 2xA B2, p-substituted benzyl ring), 7.49 (m,
2H, H-3,5, phenyl ring), 7.72 (m, 2H, 2H-2,6, phenyl ring), 11.15 (s, 1H, NH);
MS (m/z): 305(M+); IR (cm-1, KBr): 3186 (NH), 2944 (CH), 1682 (CO); Anal
calcd. for C19H18N2O2: C, 74.49; H, 5.92; N, 9.14. Found: C, 74.53; H, 5.91;
N, 9.13.
5-(4-Hydroxy-3-methoxy-benzyl)-3-(4-methylphenyl)-1,6-dihydro-6-
1
pyridazinone (33): Yield: 51%; m.p. 180 ºC; H-NMR (CDCl3, δ, ppm):) δ
2.39 (s, 3H, CH3), 3.25 (s, 3H, OCH3), 3.92 (s, 2H, CH2), 6.82 (s, 1H, H-4,
pyridazinone ring), 7.04 (m, 1H, H-6, benzyl ring), 7.25 (m, 2H, H-3,5, phenyl
ring), 7.53 (m, 1H, H-2, benzyl ring), 7.68 (m, 2H, H-2,6, phenyl ring), 7.75
(m, 1H, H-5, benzyl ring), 10.73 (s, 1H, NH); MS (m/z): 321(M+); IR (cm-
1, KBr): 3189 (NH), 2952 (CH), 1687 (CO); Anal calcd. for C19H18N2O3: C,
70.79; H, 5.63; N, 8.69. Found: C, 70.83; H, 5.65; N, 8.67.
5-(4-Fluorobenzyl)-3-(4-methylphenyl)-1,6-dihydro-6-pyridazinone (34):
Yield: 49%; m.p. 174 ºC; 1H-NMR (CDCl , δ, ppm): 2.36 (s, 3H, CH3), 3.95 (s,
2H, CH2), 7.01 (s, 1H, H-4, pyridazinone3ring), 7.05 and 7.55 (d, each, J=7.5
Hz, 2xA2B2, p-substituted benzyl ring), 7.21-7.29 (m, 4H, H-2,3,6,5, phenyl
ring), 11.42 (s, 1H, NH); MS (m/z): 293(M+). IR (cm-1, KBr): 3183 (NH),
2948(CH), 1672 (CO); Anal calcd. for C18H15FN2O: C, 73.45; H, 5.14; N, 9.52.
Found: C, 73.43; H, 5.17; N, 9.53.
Antitubercular activity [15,16]
The antitubercular screening was carried out against Mycobacterium
Scheme 1: Protocol for synthesis of pyridazinones.
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J. Chil. Chem. Soc., 56, Nº 3 (2011)
Antitubercular evaluation
The antitubercular screening was carried out against Mycobacterium
tuberculosis H37Rv (ATCC 27294) (Table 1). The results illustrated
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pyridazinone (25) showed best antitubercular activity among the synthesized
compounds with MIC-12.5 µg/mL. Four compounds, 5-(4-nitrobenzyl)-3-
(4-chloro-phenyl)-1,6-dihydro-6-pyridazinone (21), 5-(4-hydroxybenzyl)-
3-(4-chlorophenyl)-1,6-dihydro-6-pyridazinone (22), 5-(4-nitrobenzyl)-3-
(4-methylphenyl)-1,6-dihydro-6-pyridazinone (29) and 5-(4-hydroxy-3-
methoxybenzyl)-3-(4-methylphenyl)-1,6-dihydro-6-pyridazinone (33) were
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4-chloro-furanones were found to have better activity than those derived from
4-methyl-furanones. Disubstituted phenyl rings (25 & 33) at 5th position of
pyridazinone ring showed better antitubercular activity than unsubstituted or
mono-substituted phenyl rings. Among the mono-substituted phenyl rings at
5th position of pyridazinone ring, presence of nitro group (21 & 29) showed
significant antitubercular activity. (Table 1).
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Table 1: Antitubercular activity of the Pyridazinone derivatives 19-34.
Compound
R
R`
MIC values (µg/mL)
19
4-Cl
4-Cl
H
4-Cl
50
50
25
25
100
50
12.5
50
50
50
25
50
50
50
25
50
10
20
21
4-Cl
4-NO2
4-OH
22
4-Cl
23
4-Cl
4-CH3
4-OCH3
4-OH; 3-OCH3
4-F
24
4-Cl
25
4-Cl
26
4-Cl
27
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
-
H
28
4-Cl
29
4-NO2
4-OH
30
31
4-CH3
4-OCH3
4-OH; 3-OCH3
4-F
32
33
34
Streptomycin
-
CONCLUSIONS
To sum up, among the synthesized 16 newer pyridazinones, compound
5-(4-hydroxy-3-methoxybenzyl)-3-(4-chlorophenyl)-1,6-dihydro-6-
25,
pyridazinone emerged as lead compound with good antitubercular activity. The
study showed the antitubercular potential of pyridazinones.
Acknowledgements: The authors are thankful to UGC for financial
assistance under major-research project scheme. We are thankful to Prof.
MSY Khan, Professor Emeritus, Jamia Hamdard, New Delhi for his valuable
suggestions.
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