Synthesis of 5-(4-aminophenyl)-2-(arylamino)-1,3,4-thiadiazoles and their schiff base derivatives as antimycobacterial agents

Article abstract of DOI:10.1007/s10593-012-0998-y

The condensation reaction of 5-(4-aminophenyl)-N-aryl-1,3,4-thiadiazol-2- ylamines with salicylaldehyde, 3-hydroxybenzaldehyde, 4-hydroxybenzaldehyde, 5-bromosalicylaldehyde, 5-chlorosalicylaldehyde, 4-methoxybenzaldehyde, 3-nitrobenzaldehyde, and 4-nitro

Full text of DOI:10.1007/s10593-012-0998-y

Chemistry of Heterocyclic Compounds, Vol. 48, No. 2, May, 2012 (Russian Original Vol. 48, No. 2, February, 2012)
SYNTHESIS OF 5-(4-AMINOPHENYL)-2-(ARYLAMINO)-
1,3,4-THIADIAZOLES AND THEIR SCHIFF BASE
DERIVATIVES AS ANTIMYCOBACTERIALAGENTS
K. A. Dilmaghani1*, N. H. Jazani2, F. Nasuhi Pur1, N. Shokoufeh1,
F. Ghadiri1, and F. M. Fakhraee3
The condensation reaction of 5-(4-aminophenyl)-N-aryl-1,3,4-thiadiazol-2-ylamines with salicyl-
aldehyde, 3-hydroxybenzaldehyde, 4-hydroxybenzaldehyde, 5-bromosalicylaldehyde, 5-chlorosalicyl-
aldehyde, 4-methoxybenzaldehyde, 3-nitrobenzaldehyde, and 4-nitrobenzaldehyde results in series of new
Schiff bases. The synthesized compounds were tested for their antimicrobial efficiency against
Mycobacterium smegmatis PTCC 1307 in vitro. All compounds showed significant antiproliferative
activity against M. smegmatis.
Keywords: salicylaldehyde, 1,3,4-thiadiazole, in vitro, Mycobacterium smegmatis, Schiff base.
Tuberculosis is responsible for nearly three million deaths and eight million new patients annually [1].
This situation has worsened because of emergence of drug-resistant isolates of Mycobacterium tuberculosis.
Therefore there is a need for identification of new drugs possessing positive therapeutic effects towards this
pathogen. A common drawback of the most available methods is that they require the use of virulent M.
tuberculosis. Mycobacterium smegmatis is a nonpathogenic, fast-growing Mycobacterium species that could
serve as a model for evaluation of antimycobacterial effects of different drug candidates, and it shows higher
resistance to antituberculosis drugs among the other fast growing genera [2].
A wide variety of heterocyclic systems has been utilized for designing pharmaceutically active
molecules. Among them the derivatives of thiadiazoles and oxadiazoles have played an important role in
medicinal chemistry. The 1,3,4-thiadiazole derivatives have attracted continuing interest over the years due to
their varied biological activities [3–5], such as anticancer [6–10], antimicrobial [11], antibacterial [12],
antitubercular [13], anti-inflammatory [14, 15], antifungal [16], antihypertensive [17], antidepressant [18],
antileishmanial [19], and antimycobacterial [20–24] properties.
On the other hand, Schiff bases containing the azomethine group have attracted much interest due to
their synthetic availability along with antibacterial [25–27], anti-inflammatory [28], antitumor [29], and
antimycobacterial [30] properties.
_______
*To whom correspondence should be addressed, e-mail: kadilmaghani@yahoo.com.
1Urmia University, Urmia 57159, Iran; e-mail: fazelnasuhi@gmail.com
2Urmia Medical Science University, Urmia 57159, Iran; e-mail: n_jazani@yahoo.com.
3Institute of Standard and Industrial Research of Iran, Urmia 57159, Iran; e-mail: fm_fakhraee@yahoo.com.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 384-389, February, 2012. Original
article submitted February 1, 2011; revision submitted May 24, 2011.
362
0009-3122/12/4802-0362©2012 Springer Science+Business Media, Inc.

In this paper we report the synthesis of 2,5-disubstituted 1,3,4-thiadiazole Schiff base derivatives and
their antimycobacterial and antimicrobial activity. 5-(4-Aminophenyl)-2-(arylamino)-1,3,4-thiadiazoles and their
Schiff base derivatives were obtained by a versatile and efficient synthetic route outlined in scheme below.
The reaction of benzoyl chloride and benzocaine in diethyl ether gave ethyl 4-(benzoylamino)benzoate
(1). The hydrazide 2 was prepared by refluxing compound 1 with hydrazine hydrate [31]. The resulting
compound was treated with aryl isothiocyanate providing 4-aryl-1-[4-(benzoylamino)benzoyl]thiosemicarba-
zides 3a,b, which were cyclized in sulfuric acid into 5-(4-aminophenyl)-2-(arylamino)-1,3,4-thiadiazoles 4a,b [32].
Schiff bases 5a–h, 6a–d were synthesized by the reaction of the corresponding 1,3,4-thiadiazoles 4a,b and
benzaldehyde derivatives in MeOH.
NH2
O
CO2Et
N
H
COCl
NH2
NH2NH2
EtOH
R1NCS
EtOH
+
O
O
Et2O
N
H
N
H
CO2Et
O
Ph
Ph
1
2
H
N
R1
H
N
H
N
N
N
H
N
R1
R1
N
N
S
S
N
H
S
R2CHO
MeOH
H2SO4
R2
H

O
H2N
N
N
H
3a,b
4a,b
5a–h, 6a–d
Ph
3a, 4a, 5a–h R1 = 4-BrC6H4; 3b, 4b, 6a–d R1 = 4-O2NC6H4; 5a R2 = 2-HO-5-ClC6H3,
5d R2 = 3-HOC6H4, 5e R2 = 4-HOC6H4, 5f R2 = 4-MeOC6H4; 5c, 6a R2 = 2-HOC6H4;
5b, 6b R2 = 2-HO-5-B-C6H3; 5g, 6c R2 = 3-O2NC6H4; 5h, 6d R2 = 4-O2NC6H4
The structure of the Schiff bases was confirmed by 1H NMR, 13C NMR, IR, and mass spectroscopy. The
chemical shifts of imine (CH=N) and N–H protons were observed as singlets at 8.50–10.50 and 9.70-11.35
ppm, respectively, in the 1H NMR spectra. Hydroxyl protons of the derivatives 5a–e and 6a,b showed resonance
within the range of 10.65–12.85 ppm as a result of the intramolecular hydrogen bond between the hydroxyl
proton and the imine group nitrogen [34]. The imine group stretching vibration in the Schiff bases 5 and 6 was
indicated by the 1616–1644 cm–1 band in the IR spectra. Compounds 5h and 6d had poor solubility in DMSO;
therefore their 13C NMR spectra could not be recorded.
The antimycobacterial activity of the synthesized compounds was tested against Mycobacterium
smegmatis PTCC 1307 (CIP 73.26) from the Persian Type Culture Collection (Shahriar, Iran). Escherichia coli
ATCC 25922 and Staphylococcus aureus ATCC 25923 were also used for determinating of antimicrobial
activity of the compounds. The antimycobacterial activity of the tested compounds was compared with that of
the known chemotherapeutic ciprofloxacin (Table 1).
Thus, compounds 4–6 were not active against E. coli and S. aureus at concentrations up to 50 µg/ml.
However, they were active against M. smegmatis with minimum inhibitory concentration (MIC) values in the range
of 1.6–12.5 µg/ml (Table).
In general, the antimycobacterial activity of all the tested compounds was slightly lower compared to
ciprofloxacin (0.5 μg/ml), whereas compounds 5, having the 4-bromoanilino substituent at the thiadiazole ring,
tend to have slightly higher activity than compounds 6 that have the 4-nitroanilino substituent in the same
position. Compounds 5g and 5c showed the highest effect against the test species. In addition, the MIC values
363

for compounds 6 showed no difference or even an increase with respect to the "parent" amine 4b, whereas
Schiff bases 5 showed a tendency to lower MIC values compared to free amine 4a.
TABLE 1. Antibacterial activity of synthesized compounds against
Mycobacterium smegmatis PTCC 1307
Compound
MIC, µg/ml
Compound
MIC, µg/ml
6.2
1.6
2.9
3.1
12.5
3.1
6.2
3.1
0.5
4a
5a
5b
5c
5d
5e
5f
5g
3.1
6.2
1.9
3.1
3.1
3.1
5h
4b
6a
6b
6c
6d
Ciprofloxacin
EXPERIMENTAL
IR spectra were recorded on a Thermo Nicolet 610 Nexus FT-IR spectrometer in KBr disks. 1H and 13C
NMR spectra were recorded on a Bruker Avance-300 spectrometer at 300 and 75 MHz, respectively, in DMSO-
d6 using TMS as internal standard. High resolution mass spectra were obtained with an HPLC-Q-TOF system
equipped with a Q-TOF micromass spectrometer (dual ESI). Melting points were measured on a Philip Harris
C4954718 apparatus without calibration. Thin layer chromatography (TLC) analyses were carried out on silica
gel plates. All chemicals were purchased from Merck and used as received.
Ethyl 4-(benzoylamino)benzoate (1), 4-(benzoylamino)benzoylhydrazine (2), and 1-(4-benzoylamino)-
benzoyl-4-arylthiosemicarbazides 3a,b were prepared by the previously reported methods [31].
Synthesis of Thiadiazoles 4a,b. A mixture of corresponding compound 3a,b (6 mmol) in 50% aq.
H2SO4 (15.0 ml) was refluxed for 6 h. The mixture was cooled to room temperature and then neutralized with
2 N NaOH (pH 1). The precipitate that formed was filtered, washed with water, and recrystallized from ethanol
[32-34].
Synthesis of Schiff Bases 5a–h and 6a–d. The respective compound 4a,b (1 mmol) and aldehyde
(1 mmol) were dissolved in methanol (10 ml), and the reaction mixture was refluxed for 8 h. After cooling, the
resulting precipitate was recrystallized from methanol.
2-{[(4-{5-[(4-Bromophenyl)amino]-1,3,4-thiadiazol-2-yl}phenyl)imino]methyl}-4-chlorophenol
(5a).
Yield 49%. Orange powder, mp 230-232°C. IR spectrum, ν, cm-1: 3338 (OH, NH), 1619 (C=N). H NMR
spectrum, δ, ppm (J, Hz): 7.00 (1H, d, J = 9.0, H Ar); 7.45 (1H, d, J = 9.0, H Ar); 7.52 (4H, d, J = 8.4, H Ar);
7.63 (2H, d, J = 8.4, H Ar); 7.70 (1H, s, H Ar); 7.93 (2H, d, J = 8.4, H Ar); 8.98 (1H, s, CH=N); 10.68 (1H, s,
NH); 12.72 (1H, s, OH). 13C NMR spectrum, δ, ppm: 113.8; 119.2; 119.9; 121.2; 122.8; 123.2; 128.4; 129.3;
131.3; 132.3; 133.5; 140.2; 150.0; 157.9; 159.3; 162.8; 164.2. Found, m/z: 484.9920 [M+H]+. C21H14BrClN4OS.
Calculated, m/z: 484.9838.
1
4-Bromo-2-{[(4-{5-[(4-bromophenyl)amino]-1,3,4-thiadiazol-2-yl}phenyl)imino]methyl}phenol
(5b).
Yield 42%. Orange powder, mp 211-214°C. IR spectrum, ν, cm-1: 3242 (NH), 1616 (C=N). 1H NMR spectrum,
δ, ppm (J, Hz): 6.96 (1H, d, J = 8.7, H Ar); 7.53 (4H, d, J = 9.0, H Ar); 7.57 (1H, dd, J = 8.7, J = 2.7, H Ar);
7.64 (2H, d, J = 8.7, H Ar); 7.90 (1H, d, J = 2.7, H Ar); 7.94 (2H, d, J = 8.7, H Ar); 8.98 (1H, s, CH=N); 10.70
(1H, s, NH); 12.76 (1H, s, OH). 13C NMR spectrum, δ, ppm: 110.5; 113.8; 119.6; 119.9; 121.8; 122.8; 128.5;
129.3; 132.3; 134.3; 136.3; 140.2; 150.0; 159.5; 159.8; 162.7; 164.2. Found, m/z: 528.9419 [M+H]+.
C21H14Br2N4OS. Calculated, m/z: 528.9333.
364

2-{[(4-{5-[(4-Bromophenyl)amino]-1,3,4-thiadiazol-2-yl}phenyl)imino]methyl}phenol (5c). Yield 44%.
1
Orange powder, mp 218-220°C. IR spectrum, ν, cm-1: 3311 (NH), 1621 (C=N). H NMR spectrum, δ, ppm (J,
Hz): 6.97 (2H, d, J = 8.1, H Ar); 7.43 (1H, t, J = 7.5, H Ar); 7.53 (4H, d, J = 6.3, H Ar); 7.60-7.74 (3H, m,
H Ar); 7.93 (2H, d, J = 8.1, H Ar); 9.01 (1H, s, CH=N); 10.70 (1H, s, NH); 12.85 (1H, s, OH). 13C NMR
spectrum, δ, ppm: 113.8; 117.1; 119.7; 119.8; 119.9; 122.8; 128.4; 129.0; 132.3; 133.1; 134.1; 140.2; 150.1;
158.0; 160.8; 164.1; 164.5. Found, m/z: 451.0310 [M+H]+. C21H15BrN4OS. Calculated, m/z: 451.0228.
3-{[(4-{5-[(4-Bromophenyl)amino]-1,3,4-thiadiazol-2-yl}phenyl)imino]methyl}phenol (5d). Yield 47%.
1
Orange powder, mp 208-209°C. IR spectrum, ν, cm-1: 3421 (NH), 1623 (C=N). H NMR spectrum, δ, ppm (J,
Hz): 6.95 (1H, d, J = 7.5, H Ar); 7.27-7.40 (4H, m, H Ar); 7.45-7.57 (3H, m, H Ar); 7.65 (2H, d, J = 9.0, H Ar),
7.90 (2H, d, J = 8.4, H Ar); 8.57 (1H, s, CH=N); 9.72 (1H, s, NH); 10.67 (1H, s, OH). 13C NMR spectrum,
δ, ppm: 114.9; 119.6; 119.9; 121.0; 122.4; 128.2; 128.3; 128.6; 130.4; 132.2; 132.3; 137.6; 140.3; 153.5; 158.2;
162.2; 164.0. Found, m/z: 451.0314 [M+H]+. C21H15BrN4OS. Calculated, m/z: 451.0228.
4-{[(4-{5-[(4-Bromophenyl)amino]-1,3,4-thiadiazol-2-yl}phenyl)imino]methyl}phenol (5e). Yield 50%.
1
Orange powder, mp 210-212°C. IR spectrum, ν, cm-1: 3432 (NH), 1623 (C=N). H NMR spectrum, δ, ppm (J,
Hz): 6.88 (2H, d, J = 7.8, H Ar); 7.32 (2H, d, J = 7.8, H Ar); 7.52 (2H, d, J = 8.7, H Ar); 7.64 (2H, d, J = 8.7,
H Ar); 7.79 (2H, d, J = 7.8, H Ar), 7.86 (2H, d, J = 7.8, H Ar); 8.51 (1H, s, CH=N); 10.18 (1H, s, NH); 10.65
(1H, s, OH). 13C NMR spectrum, δ, ppm: 113.7; 116.2; 119.9; 122.3; 127.8; 128.3; 128.6; 131.4; 132.3; 140.3;
154.0; 158.3; 161.3; 161.4; 163.9. Found, m/z: 451.0311 [M+H]+. C21H15BrN4OS. Calculated, m/z: 451.0228.
N-(4-Bromophenyl)-5-(4-{[(4-methoxyphenyl)methylidene]amino}phenyl)-1,3,4-thiadiazol-2-amine
(5f). Yield 61%. Yellowish-white powder, mp 258°C. IR spectrum, ν, cm-1: 3335 (NH), 1621 (C=N). 1H NMR
spectrum, δ, ppm (J, Hz): 3.83 (3H, s, CH3O); 7.06 (2H, d, J = 8.7, H Ar); 7.33 (2H, d, J = 8.7, H Ar); 7.51 (2H,
d, J = 8.7, H Ar); 7.64 (2H, d, J = 8.7, H Ar); 7.87 (2H, d, J = 9.0, H Ar); 7.90 (2H, d, J = 9.0, H Ar); 8.56 (1H,
s, CH=N); 10.64 (1H, s, NH). 13C NMR spectrum, δ, ppm: 55.9; 113.7; 114.8; 119.9; 122.3; 127.8; 128.3;
129.2; 131.2; 132.3; 140.3; 153.8; 158.3; 161.2; 162.6; 163.9. Found m/z: 465.0469 [M+H]+. C22H17BrN4OS.
Calculated, m/z: 465.0385.
N-(4-Bromophenyl)-5-(4-{[(3-nitrophenyl)methylidene]amino}phenyl)-1,3,4-thiadiazol-2-amine (5g).
Yield 57%. Yellow powder, mp 246-248°C. IR spectrum, ν, cm-1: 3244 (NH), 1623 (C=N). 1H NMR spectrum,
δ, ppm (J, Hz): 7.43 (2H, d, J = 8.1, H Ar); 7.50 (2H, d, J = 8.1, H Ar); 7.63 (2H, d, J = 8.1, H Ar); 7.81 (1H, t,
J = 8.1, H Ar); 7.90 (2H, d, J = 8.1, H Ar); 8.36 (2H, d, J = 8.1, H Ar); 8.73 (1H, s, H Ar); 8.85 (1H, s, CH=N);
13
10.66 (1H, s, NH). C NMR spectrum, δ, ppm: 113.8; 119.9; 122.6; 123.4; 126.4; 128.3; 128.9; 131.0; 132.3;
135.2; 137.8; 140.2; 148.7; 152.4; 158.0; 160.2; 164.1. Found, m/z: 480.0217 [M+H]+. C21H14BrN5O2S.
Calculated, m/z: 480.0130.
N-(4-Bromophenyl)-5-(4-{[(4-nitrophenyl)methylidene]amino}phenyl)-1,3,4-thiadiazol-2-amine (5h).
Yield 45%. Yellow powder, mp 242-244°C. IR spectrum, ν, cm-1: 3238 (NH), 1625 (C=N). 1H NMR spectrum,
δ, ppm (J, Hz): 7.45 (2H, d, J = 8.4, H Ar); 7.78 (2H, d, J = 8.1, H Ar); 7.89 (2H, d, J = 8.1, H Ar); 8.16-8.28
(4H, m, H Ar); 8.36 (2H, d, J = 9.0, H Ar); 8.85 (1H, s, CH=N); 11.09 (1H, s, NH). Found, m/z: 480.0213
[M+H]+. C21H14BrN5O2S. Calculated, m/z: 480.0130.
2-{[(4-{5-[(4-Nitrophenyl)amino]-1,3,4-thiadiazol-2-yl}phenyl)imino]methyl}phenol (6a). Yield
54%. Orange powder, mp 263-265°C. IR spectrum, ν, cm-1: 3448 (OH, NH), 1623 (C=N). 1H NMR spectrum, δ,
ppm (J, Hz): 6.96 (2H, d, J = 8.6, H Ar); 7.42 (1H, t, J = 7.5, H Ar); 7.52 (2H, d, J = 8.4, H Ar); 7.66 (1H, d,
J = 7.5, H Ar); 7.78-7.89 (2H, m, H Ar); 7.94 (2H, d, J = 8.4, H Ar); 8.23 (2H, d, J = 8.6, H Ar); 8.99 (1H, s,
CH=N); 11.24 (1H, s, NH); 12.81 (1H, s, OH). 13C NMR spectrum, δ, ppm: 114.1; 117.1; 117.5; 119.7; 122.8;
126.0; 128.6; 128.8; 133.0; 134.1; 141.4; 146.6; 150.4; 151.8; 160.8; 163.4; 164.5. Found, m/z: 418.1057
[M+H]+. C21H15N5O4S. Calculated, m/z: 418.0974.
4-Bromo-2-{[(4-{5-[(4-nitrophenyl)amino]-1,3,4-thiadiazol-2-yl}phenyl)imino]methyl}phenol
(6b).
Yield 47%. Yellow powder, mp 278-279°C. IR spectrum, ν, cm-1: 2920 (NH), 1619 (C=N). 1H NMR spectrum,
δ, ppm (J, Hz): 6.95 (1H, d, J = 8.7, H Ar); 7.52 (2H, d, J = 8.4, H Ar); 7.56 (1H, dd, J = 8.7, J = 2.1, H Ar);
365

7.84–7.91 (3H, m, H Ar); 7.87 (2H, d, J = 9.3, H Ar); 7.97 (2H, d, J = 8.4, H Ar); 8.26 (2H, d, J = 9.3, H Ar);
8.98 (1H, s, CH=N); 11.30 (1H, s, NH); 12.72 (1H, s, OH). 13C NMR spectrum, δ, ppm: 110.5; 114.1; 117.2;
117.5; 119.6; 121.8; 122.9; 126.0; 128.7; 134.3; 136.3; 141.4; 146.6; 150.3; 159.7; 162.8; 163.5. Found, m/z:
496.0167 [M+H]+. C21H14BrN5O3S. Calculated, m/z: 496.0079.
N-(4-Nitrophenyl)-5-(4-{[(3-nitrophenyl)methylidene]amino}phenyl)-1,3,4-thiadiazol-2-amine
(6c).
Yield 42%. Orange powder, mp 231-234°C. IR spectrum, ν, cm-1: 3265 (NH), 1644 (C=N). 1H NMR spectrum,
δ, ppm (J, Hz): 7.56 (4H, m, H Ar); 7.91 (6H, m, H Ar); 8.20–8.29 (2H, m, H Ar); 10.49 (1H, s, CH=N); 11.23
13
(1H, s, NH). C NMR spectrum, δ, ppm: 117.4; 120.9; 122.6; 125.4; 126.0; 128.0; 128.2; 128.5; 128.9; 132.2;
135.1; 141.3; 141.8; 146.7; 159.9; 163.0; 166.3. Found, m/z: 447.0964 [M+H]+. C21H14N6O4S. Calculated, m/z:
447.00875.
N-(4-Nitrophenyl)-5-(4-{[(4-nitrophenyl)methylidene]amino}phenyl)-1,3,4-thiadiazol-2-amine
(6d).
Yield 43%. Orange powder, mp 240-242°C. IR spectrum, ν, cm-1: 3421 (NH), 1624 (C=N). 1H NMR spectrum,
δ, ppm (J, Hz): 7.50 (2H, d, J = 8.4, H Ar); 7.89 (2H, d, J = 9.0, H Ar); 7.99 (2H, d, J = 9.0, H Ar); 8.20–8.31
(4H, m, H Ar); 8.38 (2H, d, J = 9.0, H Ar); 8.89 (1H, s, CH=N); 11.34 (1H, s, NH). Found, m/z: 447.0961
[M+H]+. C21H14N6O4S. Calculated, m/z: 447.00875.
Preparation of Test Compounds and Antibacterial and Antimycobacterial Activity Assays. Stock
solutions of compounds were prepared in DMSO at an initial concentration of 1 mg/ml. The susceptibility of
Mycobacterium smegmatis to the test compounds was determined using the microdilution method, and the MIC
values for the compounds were determined using MB 7H10 agar medium for Mycobacterium smegmatis [2].
500 μl of serial twofold dilutions of the stock solution (1 mg/ml) of each compound were incorporated in 9.5 ml
of medium (initial concentration 50 µg/ml and final concentration 0.39 µg/ml of culture media). The tubes were
kept in slanting position until the medium solidified. 10 μl of M. smegmatis (2×107 CFU/ml) were spread on the
medium in each tube, and the tubes were incubated at 37°C. Results were available within 3 days. The lowest
concentration of a compound that inhibited the growth of the bacterium was taken as its (MIC). Experiments
were performed at least three times [2]. The susceptibility of E. coli and S. aureus to the compounds was
determined using the microdilution method in Mueller–Hinton broth [35].
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