Synthesis, antiviral and antimicrobial screening of some new 2-oxoindoline derivatives

Article abstract of DOI:10.1007/s10593-009-0301-z

New 3-(2-(5-(aryldiazenyl)-4-methylthiazol-2-yl)hydrazono)indolin-2-ones were prepared by the reaction of isatin β-thiosemicarbazone with different hydrazonoyl chlorides. Imide derivatives were prepared by the reaction of isatin hydrazone with various anh

Full text of DOI:10.1007/s10593-009-0301-z

Chemistry of Heterocyclic Compounds, Vol. 45, No. 5, 2009
SYNTHESIS, ANTIVIRAL AND ANTIMICROBIAL
SCREENING OF SOME NEW 2-OXOINDOLINE
DERIVATIVES
Madiha Farghaly1, Bakr F. Abdel-Wahab1*, Essam M. Ahmed2
New 3-(2-(5-(aryldiazenyl)-4-methylthiazol-2-yl)hydrazono)indolin-2-ones were prepared by the
reaction of isatin β-thiosemicarbazone with different hydrazonoyl chlorides. Imide derivatives were
prepared by the reaction of isatin hydrazone with various anhydrides, and a series of new sulfonimides
was also synthesized. All new compounds were tested for their biological activities.
Keywords: isatin, 2-oxoindolinylidenaminobenzenesulfonamide, phthalic anhydride, thiazolyl-
hydrazone, antimicrobial and antiviral activities.
Isatins (1H-indole-2,3-dione) are synthetically versatile substrates, useful for the synthesis of a large
variety of heterocyclic compounds [1]. The synthetic versatility of isatin has stemmed from the interest in the
biological and pharmacological properties of its derivatives. In nature, isatin is found in plants of the genus
Isatis [2], in Calanthe discolor LINDL. [3], and Couroupita guianensis Aubl. [4], and has been also found as a
component of the secretion from the parotid gland of Bufo frogs [5], and in humans as a metabolic adrenaline
derivative [6−8]. Several authors found that isatin β-thiosemicarbazone and its N-Mannich bases were active
against various viruses [9−11]. The first clinically approved antiviral agent, N-methylisatin β-thio-
semicarbazone (methisazone 1), and isatin β-thiosemicarbazone (2) are active against poxviruses [12]. Antiviral
S
NH2
HN
N
O
N
R
1, 2
1 R = Me, 2 R = H
_______
* To whom correspondence should be addressed, e-mail: Bakrfatehy@yahoo.com.
1Applied Organic Chemistry Department, National Research Center, Dokki, Giza, Egypt.
2Natural and Microbial Products Chemistry Department, National Research Center, Dokki, Giza, Egypt.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 689-694, May, 2009. Original
article submitted May 5, 2008.
0009-3122/09/4505-0539©2009 Springer Science+Business Media, Inc.
539

properties of certain semicarbazone derivatives have been reported, in which the antiviral effect is attributed to
the presence of the NHC(=S)NH group [13−15]. Prompted by these observations, we report here the synthesis of
the new 2-oxoindoline derivatives with the hope to get better antimicrobial and antiviral molecules. All new
compounds have been screened for their antibacterial, antifungal, and antiviral activities.
N-(1-Arylethylidene)-N'-[4-(indan-5-yl)thiazol-2-yl]hydrazones have been synthesized by the reaction
of acetophenone derivatives with thiosemicarbazide followed by the treatment with 2-bromo-1-(5-indanyl)-
ethanone [16]. We used this pathway to prepare thiazoles 4a-d.
3-[2-(5-Aryldiazenyl-4-methylthiazol-2-yl)hydrazono]indolin-2-ones 4a-d were prepared according to
Scheme 1 by the reaction of thiosemicarbazone 2 with hydrazonyl chlorides 3. The reaction of hydrazone 5 with
phthalic anhydride and tetrachlorophthalic anhydride afforded 2-(2-oxoindolin-3-ylideneamino)isoindoline-
1,3-diones 6a,b (Scheme 1).
Scheme 1
2
O
Cl
H2N
Me
N
N
HN
3
Ar
O
X
N
Ar
H
N
5
Me
N
O
X
X
OH
NH
S
O
HN
O
X
N
X
X
O
X
N
O
H
X
N
– H2O
S
O
N
Ar
N
N
O
N
Me
H
HN
N
N
6a,b
N
H
O
4a–d
4 a Ar = Ph, b Ar = 4-ClC6H4, c 4-BrC6H4, d Ar = 2,4-Cl2C6H3;
6 a X = H, b X = Cl
Since sulfonamides are used in the treatment of infections, especially for patients intolerant to antibiotics
[17], we synthesized new sulfonimides 8a-d for biological evaluation using the reaction of 3-(4-
sulfonamidophenylimino)indolin-2-ones 7a,b with phthalic and tetrachlorophthalic anhydrides (Scheme 2).
540

Scheme 2
X
X
X
O
S
H2N
O
O
S
X
O
X
N
O
X
X
O
O
O
N
O
X
N
O
N
O
R
N
7a,b
R
8a–d
7 a R = H, b R = Ac; 8 a R = X = H; b R = H, X = Cl; c R = Ac, X = H;
d R = Ac, X = Cl
1
The H NMR spectra of compounds 4a-d displayed a singlet at about 2.4 ppm attributed to the methyl
groups. The IR spectra of compounds 6a,b showed absorption bands in the region of 1750-1625 cm−1 indicating
the presence of the C=O groups. Physical data are given in Table 1.
The IR spectra of compounds 8a-d showed sharp stretching bands at about 1714 cm−1 for the carbonyl
groups. The mass spectra of all new compounds in each case revealed a peak corresponding to their molecular
ion peaks.
TABLE 1. Physical and analytical data for the compounds 4, 6, and 8
Found, %
Calculated, %
——————
Com-
pound*
Empirical
formula
mp, °C
Yield, %
83
C
H
N
S
4a
C18H14N6OS
59.68
59.65
3.85
3.89
23.24
23.19
8.91
8.85
279-280
4b
4c
4d
6a
6b
8a
8b
8c
8d
C18H13ClN6OS
C18H13BrN6OS
C18H12Cl2N6OS
C16H9N3O3
54.52
54.48
49.21
48.99
50.34
50.13
66.09
65.98
45.02
44.79
61.43
61.25
46.65
46.42
61.02
60.88
3.29
3.30
3.12
2.97
2.97
2.80
3.19
3.11
1.22
1.17
3.29
3.04
1.98
1.59
3.29
3.19
21.28
21.18
18.99
19.04
19.71
19.49
14.71
14.43
9.98
9.79
9.77
9.74
7.51
7.38
8.89
8.88
8.22
8.08
7.52
7.27
7.61
7.43
300-302
282-283
262-263
>300
79
81
84
74
76
62
66
70
67
—
—
C16H5Cl4N3O3
C22H13N3O5S
C22H9Cl4N3O5S
C24H15N3O6S
C24H11Cl4N3O6S
>300
7.68
7.43
5.64
5.63
6.89
6.77
5.41
5.25
>300
>300
>300
47.32
47.16
1.99
1.81
7.03
6.87
>300
_______
* Color: red (compounds 4a-c), yellow (compound 4d), colorless
(compounds 6a,b, 8a-d).
541

The antimicrobial and antiviral activities were studied for all new compounds. Amoxicillin
(antibacterial) and fluconazole (antifungal) were used as references. Among all the tested compounds only
compound 6b showed antibacterial activity against Bacillus subtilis in about 25 mm inhibition zone. No antiviral
activities were found for any of the compounds examined.
EXPERIMENTAL
Melting points were determined on a Gallenkamp apparatus and are uncorrected. The IR spectra were
1
recorded in potassium bromide using Perkin Elmer 1650 and Pye-Unicam SP300 IR spectrophotometers. The H
NMR spectra were recorded in DMSO-d6 with TMS as an internal standard using a Varian Gemini 300 NMR
spectrometer (300 MHz). Mass spectra were recorded on a GCMS-QP 1000 EX Shimadzu and GCMS 5988-A HP
spectrometers. Elemental analyses were carried out in the Micro-analytical Laboratory of Cairo University, Giza,
Egypt. 1-(2-Oxoindolin-3-ylidene)thiosemicarbazide 2 [18], 3-(4-sulfonamidophenylimino)indolin-2-one deriva-
tives 7a,b [19], and 3-hydrazonoindolin-2-one 5 [20] were prepared according to the methods reported.
3-(2-(5-(Aryldiazenyl)-4-methylthiazol-2-yl)hydrazono)indolin-2-ones 4a-d. A mixture of 1-(2-
oxoindolin-3-ylidene)thiosemicarbazide 2 (2.2 g, 10 mmol) and the appropriate hydrazonyl chloride (10 mmol)
in ethanol (100 ml) containing a few drops of triethylamine was refluxed for 1.5 h, left to cool at room
temperature, and the products were separated by filtration, vacuum dried, and recrystallized from ethanol/DMF.
3-(2-(4-Methyl-5-(phenyldiazenyl)thiazol-2-yl)hydrazono)indolin-2-one (4a). IR spectrum, ν, cm−1:
1
1692 (C=O, st.); 3251 (NH, st.). H NMR spectrum, δ, ppm: 2.39 (3H, s, CH3); 6.82−7.45 (9H, m, H Ar); 8.12
(1H, s, NH); 8.36 (1H, s, NH). Mass spectrum, m/z (I, %): 363 [M++1] (3.5); 362 [M+] (100).
3-(2-(5-[(4-Chlorophenyl)diazenyl]-4-methylthiazol-2-yl)hydrazono)indolin-2-one (4b). IR spectrum,
ν, cm−1: 1690 (C=O, st.); 3221 (NH, st.). 1H NMR spectrum, δ, ppm: 2.41 (3H, s, CH3); 6.91−7.45 (8H, m, H Ar);
8.22 (1H, s, NH), 8.42 (2H, 2s, 2NH). Mass spectrum, m/z (I, %): 398 [M++2] (3); 397 [M++1] (14); 396 [M+] (100).
3-(2-(5-[(4-Bromophenyl)diazenyl]-4-methylthiazol-2-yl)hydrazono)indolin-2-one (4c). IR spectrum, ν,
cm−1: 1690 (C=O, st.); 3198 (NH, st.). 1H NMR spectrum, δ, ppm: 2.42 (3H, s, CH3); 6.83−7.23 (8H, m, H Ar); 8.15
(1H, s, NH); 8.42 (1H, s, NH). Mass spectrum, m/z (I, %): 442 [M++2] (18); 441 [M++1] (89); 440 [M+] (100).
3-(2-(5-[(2,4-Dichlorophenyl)diazenyl]-4-methylthiazol-2-yl)hydrazono)indolin-2-one
(4d).
IR
spectrum, ν, cm−1: 1688 (C=O, st.); 3219 (NH, st.). 1H NMR spectrum, δ, ppm: 2.44 (3H, s, CH3); 6.87−7.33 (7H,
m, H Ar); 8.17 (1H, s, NH); 8.40 (1H, s, NH). Mass spectrum, m/z (I, %): 432 [M++1] (34); 431 [M+] (17.5); 430
(100).
2-(2-Oxoindolin-3-ylideneamino)isoindoline-1,3-diones 6a,b. A mixture of 3-hydrazonoindolin-2-one 5
(0.48 g, 3 mmol) and the appropriate phthalic anhydride (3 mmol) in 50 ml of glacial acetic acid was heated under
reflux for 6 h. The reaction mixture was evaporated under reduced pressure; the obtained residue was solidified with
ether, filtered off, and crystallized from acetic acid–water to yield compounds 6a,b.
2-(2-Oxoindolin-3-ylideneamino)isoindoline-1,3-dione (6a). IR spectrum, ν, cm−1: 1751 (C=O, st.);
1
1625 (C=O, st.); 3235 (NH, st.). H NMR spectrum, δ, ppm: 7.11−8.02 (8H, m, H Ar); 8.45 (1H, s, NH). Mass
spectrum, m/z (I, %): 291 [M+] (22); 132 (100).
4,5,6,7-Tetrachloro-2-(2-oxoindolin-3-ylideneamino)isoindoline-1,3-dione (6b). IR spectrum, ν,
1
cm−1: 1750 (C=O, st.); 1631 (C=O, st.); 3241 (NH, st.). H NMR spectrum, δ, ppm: 6.99−7.34 (4H, m, H Ar);
8.32 (1H, s, NH). Mass spectrum, m/z (I, %): 430 [M+] (0.45); 429 [M+ +1] (1.9); 132 (100).
2-(4-(2-Oxoindolin-3-ylideneamino)arylsulfonyl)isoindoline-1,3-diones 8a-d. A mixture of 3-(4-
sulfonamidophenylimino)indolin-2-one 7a or 1-acetyl-3-(4-sulfonamidophenylimino)indolin-2-one 7b (3 mmol) and
the appropriate phthalic anhydride (3 mmol) in 50 ml of glacial acetic acid was heated under reflux for 8 h. The
obtained solid product was filtered off and crystallized from acetic acid–water to yield compounds 8a-d.
542

−
1
2-(4-(2-Oxoindolin-3-ylideneamino)phenylsulfonyl)isoindoline-1,3-dione (8a). IR spectrum, ν, cm :
1718 (C=O, st.); 1621 (C=O, st.); 3190 (NH, st.). 1H NMR spectrum, δ, ppm: 6.89−7.98 (12H, m, Ar-H); 8.45 (1H, s,
NH). Mass spectrum, m/z (I, %): 432 [M++1] (0.45); 431 [M+] (1.9); 285 (100).
4,5,6,7-Tetrachloro-2-(4-(2-oxoindolin-3-ylideneamino)phenylsulfonyl)isoindoline-1,3-dione (8b).
1
IR spectrum, ν, cm−1: 1714 (C=O, st.); 1625 (C=O, st.); 3252 (NH, st.). H NMR spectrum, δ, ppm: 7.11−7.68
(8H, m, H Ar); 8.21 (1H, s, NH). Mass spectrum, m/z (I, %): 569 [M+] (12); 285 (100).
2-(4-(1-Acetyl-2-oxoindolin-3-ylideneamino)phenylsulfonyl)isoindoline-1,3-dione (8c). IR spectrum, ν,
cm−1: 1714 (C=O, st.); 1638 (C=O, st.); 3254 (NH, st.). 1H NMR spectrum, δ, ppm: 2.39 (3H, s, CH3); 7.11−8.03
(12H, m, H Ar). Mass spectrum, m/z (I, %): 473 [M+] (3.5); 327 (100).
2-(4-(1-Acetyl-2-oxoindolin-3-ylideneamino)phenylsulfonyl)-4,5,6,7-tetrachloroisoindoline-1,3-dione (8d).
1
IR spectrum, ν, cm−1: 1714 (C=O, st.); 1625 (C=O, st.); 3243 (NH). H NMR spectrum, δ, ppm: 2.38 (3H, s,
CH3); 6.88−7.76 (8H, m, H Ar). Mass spectrum, m/z (I, %): 612 (0.4); 611 [M+] (2.4); 327 (100).
Antimicrobial Activities. Escherichia coli, Bacillus subtilis, Pseudomonas aeruginosa, Candida
albicans, and Aspergillus fulvous were used to verify the antimicrobial activity of the synthesized compounds.
The bacterial strains were cultivated on nutrient agar medium, while the fungal strains were cultivated on potato
dextrose agar medium. The antimicrobial activities of the tested compounds were investigated by the disk
diffusion methods [21].
Antiviral Activity. All the prepared compounds were submitted to test for antiviral activity against
HBV (hepatitis B viruses). The test was carried out according to the method [22].
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