Antileishmanial, antimicrobial and antifungal activities of some new aryl azomethines

Article abstract of DOI:10.3390/molecules15020660

A series of eighteen azomethines has been synthesized by the reaction of appropriate primary aromatic amines with aryl and/or heteroaryl carboxaldehydes. The synthesized azomethines have been evaluated for their in vitro antileishmanial, antibacterial and antifungal activities. The results revealed some antifungal activity of most of the synthesized compounds, whereas the antileishmaniasis activity results highlighted that all synthesized azomethines inhibited parasite growth and most of them showed highly potent action towards Leishmania major promastigotes. No remarkable bactericidal activities were observed.

Full text of DOI:10.3390/molecules15020660

Molecules 2010, 15, 660-671; doi:10.3390/molecules15020660
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Antileishmanial, Antimicrobial and Antifungal Activities of
Some New Aryl Azomethines
Yasser M.S.A. Al-Kahraman 1, Hassan. M.F. Madkour 1,2, Dildar Ali 1 and Masoom Yasinzai 1,*
1
Institute of Biochemistry, University of Balochistan, Quetta, Pakistan
2
Synthetic Organic Chemistry Lab., Chemistry Department, Faculty of Science, Ain Shams
University, Cairo, Egypt
* Author to whom correspondence should be addressed; E-Mail: yasinzai_masom@yahoo.com.
Received: 5 December 2009; in revised form: 28 December 2009 / Accepted: 8 January 2010 /
Published: 28 January 2010
Abstract: A series of eighteen azomethines has been synthesized by the reaction of
appropriate primary aromatic amines with aryl and/or heteroaryl carboxaldehydes. The
synthesized azomethines have been evaluated for their in vitro antileishmanial,
antibacterial and antifungal activities. The results revealed some antifungal activity of most
of the synthesized compounds, whereas the antileishmaniasis activity results highlighted
that all synthesized azomethines inhibited parasite growth and most of them showed highly
potent action towards Leishmania major promastigotes. No remarkable bactericidal
activities were observed.
Keywords: azomethines; primary aromatic amines; hetaryl carboxyladehyes;
antileishmanial activity; antifungal activity; antibacterial activity
Introduction
Although the last century has been characterized by a drastic lowering in the mortality caused by
infectious diseases, some diseases still represent a dreadful menace to human health and therefore, for
a more efficient control, require the steady development of new, more powerful and inexpensive drugs.
Leischmaniasis, considered a serious public health concern in many countries, is one of these diseases.
It is now endemic in many parts of Pakistan and Balochistan and the Upper Sindh are vulnerable to
cutaneous leishmaniasis. The World Health Organization (WHO) has identified leishmaniasis as a

Molecules 2010, 15
661
major and increasing public health problem [1]. In spite of the social and economic importance of
leishmaniasis as a tropical infectious disease, efforts directed towards the discovery of new drugs
against it remain undeveloped [2,3]. Moreover, the drugs currently in use are expensive, require long-
term treatment [4], display high liver and heart toxicities, develop clinical resistance after few weeks of
treatment and currently contribute to increase leishmaniasis-AIDS co-infections in some countries
[5,6]. Azomethines are characterized by the –CH=N- (imino group) which has special importance in
elucidating the mechanism of transmination and racemization in biological system [7–9]. Azomethines
have high potential chemical permutation possibilities and show diuretic [10], anticancer [11–14],
antibacterial [15–19], and antifungal activities [20–22]. This class of compounds has also exhibited
activity against a wide range of organisms and is known to have medicinal importance and is used in
drug design [23–25]. It has been also reported that when some aldehydes were functionalized by
condensation with various amines, the resulting azomethines had antiparasitic activities [26].
Results and Discussion
The present work is a continuation of our ongoing programme devoted to the utilization of simple
and readily obtainable materials in the synthesis of different biologically active compounds [27–33],
aiming at the same time to seek a cure for the cutaneous antileishmaniasis facing our society in
Pakistan by presenting some cheap azomethines that might be useful in antileishmanial and antifungal
drug development.
Reaction of various substituted anilines with aromatic and/or heterocyclic aldehydes in hot
methanol containing a catalytic amount of glacial acetic acid afforded the target azomethines 1-18 in
good yields (55–87%). (cf. Scheme 1).
The structural features of the synthesized azomethines were determined from the corresponding IR,
1H-NMR, 13C-NMR and mass spectroscopy data, listed in Tables 1-4. All compounds showed in the IR
spectra a strong absorption band at 1,592–1,637 cm-1, typical of the stretching vibrations of the C=N
functionality, as well as the bands corresponding to C-H stretching vibrations.
1
The H-NMR spectra of compounds 1-18 contained multiple signals in the δ 6.90 to 8.08 ppm
regions due to aromatic protons and a singlet at 8.43-9.75 ppm from the C-H protons of the CH=N
groups. In the spectra of compounds 5, 6, 11, 12, 13 and 14, signals between δ 3.50 and 4.0 ppm were
attributed to –OCH3 groups. The signals at δ 2.36 and 2.33 ppm which appeared as singlets in
compounds 15 and 16 were assigned for methyl groups. In the DEPT spectra of compounds 1-18, there
are no peaks at 189.0-196.0 ppm due to CHO group and the observed peaks were shifted to ~160.0-
163.0 ppm which were attributable to HC=N group.
Scheme 1. General synthetic route.
NH2
R2
R1
R1
H
AcOH
+
Ar
C
Ar
CH
N
R3
O
R2
1-18
R3

Molecules 2010, 15
662
Scheme 1. Cont.
Compd. No. Ar
R1
H
H
R2
H
H
R3
H
NO2
1
2
C6H4(Cl)-4
C6H4(Cl)-4
3
H
H
H
O
4
H
H
NO2
O
5
6
7
8
C6H3(OH)(OCH3)-3,4
C6H3(OH)(OCH3)-3,4
C6H5CH=CH-
C6H5CH=CH-
C6H4(OH)-2
C6H4(Cl)-4
C6H3(OH)(OCH3)-3,4
C6H4(Cl)-4
C6H3(OH)(OCH3)-3,4
C6H4(OH)-2
C6H4(Cl)-4
C6H4(OH)-2
C6H5CH=CH-
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
NO2
H
NO2
H
9
H
NO2
10
11
12
13
14
15
16
17
-CH=CH-CH=CH-
-CH=CH-CH=CH-
H
H
H
H
H
H
OCH3
OCH3
OCH3
CH3
CH3
CH3
18
H
H
NO2
S
Table 1. Physical and select IR data of the synthesized azomethines 1-18.
IR (cm-1)
Azomethine
C-H
Moleculara
formula
(Mol. Mass)
C13H10ClN [34]
(215.05)
Mp (C)
(recryst.
solvent)b
72-4
Yield
(%)
Compd. Color
N=C
1621
1625
1605
1592
Substituent
Pale
2874,
1
82
74
79
68
-
yellow
(L.P)
1352
C13H9ClN2O2 [35]
(260.04)
140-42
(L.P)
1505,
2
3
4
Yellow
Brown
Brown
1333
2850, 1328
1285
1376(NO2)
C11H9NO [36]
(171.07)
106 d
3360(OH)
(B)
C11H8N2O3 [37]
(216.05)
196-98
(EtOH)
1535,
1339(NO2)
3354–3480(OH)
1544, 1342
(NO2)
Pale
C14H12N2OH
(272.08)
148-50
(L.P)
5
64
1628
1325
orange
Pale
C14H13NO2
(227.09)
155-57
(L.P)
3088
6
7
72
65
1621
1592
1388
1300
yellow
broad(OH)
1512,
C15H12N2O2
(252.09)
133d
Orange
(MeOH)
1335(NO2)

Molecules 2010, 15
663
Table 1. Cont.
Pale
C15H13N
(207.10)
100-02
8
66
59
1623
1632
1375
1338
-
brown
(MeOH)
1562, 1347
C13H10N2O3
(242.07)
162-64
(L.P)
9
Orange
(NO2), 3150
(OH)
Pale
C17H12ClN
(265.07)
107-09
(MeOH)
114-16
(B)
10
11
12
78
76
87
1637
1621
1629
1391
1381
-
brown
C18H15NO2
(277.11)
Brown
3048(OH)
Pale
C14H12ClNO
(245.06)
136-37
(MeOH)
2838, 2895
(CH3)
2838, 1364
Brown
3000 (broad
OH), 2954,
2982 (CH3)
3610(OH),
2964, 2996
(CH3)
Pale
C15H15NO3
( 257.11)
257-59
13
14
70
67
1621
1637
2954, 1378
2964, 1362
Brown
(MeOH)
Greenish
White
C14H13NO2
(227.09)
85-87
(MeOH)
C14H12ClN
(229.07)
127-29
(MeOH)
96-98
2854, 2925
(CH3)
15
16
17
White
White
79
67
71
55
1622
1615
1627
2929, 1354
2920, 1366
2912, 1379
1323
C14H13NO
(211.10)
3100 (OH),
2920 (CH3)
(MeOH)
76-77
Pale
C16H15N [38]
(221.12)
2912 (CH3)
Orange
Pale
(MeOH)
135-37
(MeOH)
C11H8N2O2S [39]
(232.03)
1543, 1341
(NO2)
18
1612
Yellow
a
b
references are given for known products, the others are new; L.P = Light Petroleum b.p. 60–80
C, B = benzene, EtOH = ethanol, MeOH = methanol.
Table 2. 1H-NMR of azomethines 5-16 (DMSO-d6) (δ, ppm).
Compd.
5
1H-NMR
9.45 (s, 1H, -OH, exchangeable), 8.36 (s, 1H, benzylidenimine H), 8.08-6.90 (m, 7H, Ar-H),
3.80 (s, 3H, -OCH3).
9.75 (s, 1H, -OH, exchangeable), 8.43 (s, 1H, -CH=N), 7.52-6.88 (m, 8H, Ar-H), 3.84 (s, 3H,
-OCH3).
6
7
8
9
8.10 (m, 1H, -CH=N), 7.60-6.95 (m, 11H, Ar-H and olefinic H).
8.25 (d, 1H, benzylideimin H, J = 5.36 Hz), 7.54-7.07 (m, 12H, Ar-H and olefinic H).
12.27 (s, 1H, OH, exchangeable), 8.99 (s, 1H, -CH=N), 8.32-6.98 (m, 7H, Ar-H).
8.73 (s, 1H, benzylidenimine H), 8.09-7.23 (m, 11H, Ar-H).
9.76 (s, 1H, OH, exchangeable), 8.53 (s, 1H, benzylidenimine H), 8.29-6.92 (m, 10H, Ar-H),
3.89 (s, 3H, -OCH3).
8.64 (s, 1H, -CH=N), 7.93-6.97 (m, 8H, Ar-H), 3.77 (s, 3H, -OCH3).
9.60 (s, 1H, OH, exchangeable), 8.44 (s, 1H, -CH=N), 7.49-6.86 (m, 7H, Ar-H), 3.83 and 3.76
(2s, 6H, 2 -OCH3).
10
11
12
13

Molecules 2010, 15
664
Table 2. Cont.
13.38 (s, 1H, OH, exchangeable), 8.59 (s, 1H, benzylidenimine H), 7.36-6.89 (m, 7H, Ar-H),
3.82 (s, 3H, -OCH3)
8.41 (s, 1H, -CH=N),7.83-7.11 (m, 8H, Ar-H), 2.36 (s, 3H, -CH3)
13.19 (s, 1H, OH, exchangeable), 8.94 (s, 1H, -CH=N), 7.63-6.93 (m, 7H, Ar-H), 2.33 (s, 3H,
-CH3).
14
15
16
Table 3. 13C-NMR (DMSO-d6) ( δ, ppm) of azomethines 5-16.
Compd
13C-NMR
5
6
160.0, 154.2, 152.4, 147.3, 146.3, 131.0, 125.5, 125.2, 123.2, 115.9, 112.3, 56.1.
160.2, 152.4, 152.0, 147.3, 131.1, 129.9, 127.2, 125.5, 122.3, 115.9, 112.3, 56.1.
163.7, 158.6, 146.4, 135.2, 133.3, 128.5, 128.5, 127.9, 125.2, 123.2, 119.8.
163.7, 152.4, 135.2, 133.3, 130.0, 128.6, 128.5, 127.9, 127.2, 122.3, 119.9.
161.1, 160.0, 154.2, 146.4, 132.4, 132.1, 125.2, 123.2, 121.4, 120.5, 117.8.
160.0, 151.9, 136.6, 135.0, 134.5, 130.5, 128.9, 128.6, 128.3, 127.8, 126.8, 126.3, 115.2.
7
8
9
10
160.0, 152.2, 151.9, 147.9, 147.3, 135.0, 131.1, 128.5, 128.3, 127.8, 126.7, 126.3, 125.5, 115.9, 115.1,
112.3, 56.1.
11
12
13
14
15
16
160.0, 159.1, 144.3, 136.5, 134.5, 130.6, 128.8, 122.1, 115.6, 55.8.
159.9, 159.1, 152.4, 147.3, 144.3, 131.1, 125.5, 115.9, 115.6, 122.1, 112.3, 56.1, 55.8.
161.1, 160.1, 159.1, 144.3, 132.4, 132.1, 122.1, 121.4, 120.4, 117.8, 115.5, 55.8.
160.1, 149.1, 136.9, 136.5, 134.5, 130.6, 130.3, 128.9, 122.2, 21.3.
161.1, 159.9, 149.1, 136.8, 132.4, 132.1, 130.3, 122.2, 121.4, 120.5, 117.7, 21.3.
Table 4. Mass spectra of azomethines 5-16.
Compd.
m/z (% Relative abundance)
5
6
272 (M+., 4.25), 227 (2.34), 139 (4.85), 138 (70.25), 107 (76.60), 92 (48.80), 91 (6.91), 65 (100.00).
227 (M+., 98.26), 211 (21.66), 166 (14.45), 154 (7.12), 139 (5.12), 104 (22.42), 77 (100.00)
252 (M+., 27.28), 251 (M-1+., 83.41), 205 (56.73), 178 (4.88), 149 (4.88), 138 (54.55), 115 (70.16), 92
(48.50), 91 (47.95), 65 (100.00)
7
8
9
207 (M+., 33.52), 206 (M-1+., 100.00), 178 (3.25), 128 (13.57), 115 (18.72), 77 (90.33).
242 (M+., 96.65), 212 (13.38), 195 (37.11), 167 (29.72), 151 (5.91), 120 (44.48), 76 (100.00)
267 (M+2+., 20.42), 266 (M+1+., 20.79), 265 (M+., 60.68), 230 (2.89), 202 (3.48), 154 (23.00), 127
(100.00), 77 (29.47), 51 (9.14).
10
11
12
13
14
277 (M+., 100.00), 261 (7.13), 216 (6.07), 204 (5.90), 178 (3.99), 154 (19.97), 127 (80.53), 101 (11.97),
85 (44.01), 83 (69.57), 77 (27.60).
247 (M+2+., 26.19), 246 (M+1+., 15.23), 245 (M+., 77.99), 230 (100.00), 201 (10.17), 167 (27.80), 149
(5.64), 139 (10.67), 114 (4.26), 77 (35.29), 63 (45.11).
257 (M+., 100.00), 242 (85.72), 227 (3.73), 198 (5.24), 170 (15.75), 154 (7.33), 134 (6.16), 115 (7.02), 77
(4.02), 64 (19.33).
228 (M+1+., 16.62), 227 (M+., 100.00), 212 (71.79), 183 (4.33), 154 (3.40), 128 (5.33), 105 (3.08), 77
(55.04), 65 (38.15).
231 (M+2+., 30.49), 230 (M+1+., 33.41), 229 (M+., 90.60), 193 (2.89), 165 (4.57), 150 (2.05), 118
15
16
(22.99), 91 (100.00), 77 (9.79), 65 (61.60).
211 (M+., 100.00), 210 (M-1+., 76.87), 167 (6.29), 120 (12.86), 118 (8.68), 91 (80.65), 65 (74.49).

Molecules 2010, 15
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Antileishmaniasis activity
Antileishmanial activity of the compounds (1-18) was assayed by Zhai’s method [40] using a pre-
established culture of L. major (Table 5) Parasites were cultured in medium M199 with 10% foetal
bovine serum; 25 mM of HEPES, and 0.22 µg of penicillin and streptomycin, respectively, at 24 °C in
a shaking incubator. Compounds 1, 6 and 16 have moderate activity against L major. Azomethines 4,
10, 14, 15, and 17 show good activity against L major and azomethines 9 and 12 show significant
activity. The high in vitro antileishmaniasis activity of these compounds makes them promising leads
for development of effective therapeutic agents.
Table 5. % Inhibition of azomethines against L. major leishmania.
Compound
L. major a
1
2
0.77 ± 0.09
-
3
-
4
0.65 ± 0.01
-
5
6
0.73 ±0.16
-
7
8
-
9
0.59 ± 0.07
0.61 ± 0.27
-
10
11
12
13
14
15
16
17
18
0.57 ±0.11
0.63 ± 0.04
0.68 ±0.12
0.66 ±0.18
0.81 ± 0.03
0.62 ± 0.08
-
Standard Drug IC50 (µg/mL± S.D)
Amphotericin B 0.56 ± 0.20
percentage inhibition activity: 100 = (non-significant; 0.95−0.80 = low; 0.79−0.70 = Moderate;
0.69−0.60 = Good; below 0.59-0.56 = Significant activity).
a
Antifungal activity
The antifungal bioassay is screened by the Agar Tube Dilution Method [41–42], in which the test
compounds were screened for activity against the following organisms: Candida albicans, Aspergillus
flavus, Microsportum canis, Fusarium solani and Candida glabrata. Table 6 shows % inhibition of the
synthesized azomethines. In all tests the linear growth in control was 100 mm. It is evident from the
antifungal screening that:
(i) None of the compounds are inactive against C. albicans or C. glabrata.
(ii) Only compound 17 has moderate activity against A. flavus.

Molecules 2010, 15
666
(iii) Azomethines 4, 5, 12 and 14 have low activity against M. canis, whereas compound 9 has
good antifungal activity against the same fungus.
(iv) Azomethine 9 shows moderate activity against F. solani, whereas azomethines 4, 11, 17
and 18 have low activity against the same fungus.
Table 6. % inhibition of azomethines against different types of fungi.
Compound
C. albicans
A. flavus
M. canis
F. solani
C. glabrata
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
40
0
0
0
0
0
0
0
35
0
0
0
0
40
0
35
0
0
0
0
0
15
20
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
20a
30
0
0
0
60
0
0
35
0
20
0
0
0
0
Std. Drug MIC (mg/mL)
Miconazole
110.8
-
-
98.4
-
73.25
-
110.28
-
Amphotericin B
20.0
a
percentage inhibition activity: 0-39 = low (non-significant); 40-59 = Moderate;
60-69 = Good; Above 70 = Significant activity.
Antibacterial activity
The antibacterial activity of the synthesized azomethines was screened by the agar well diffusion
method [43–44] against Gram-negative and Gram-positive bacteria, namely Escherchia coli, Bacillus
subtilis, Shigella flexen ari, Staphylococcus aureus, Pseudomonas aeruginosa and Salmonella typhi.
Only compound 4 showed significant activity (25 mm inhibition zone) against E. coli and moderate
activity (14 mm zone) against B. subtilis.
Experimental
General
All aromatic and heterocyclic aldehydes as well as primary aromatic amines were obtained
commercially from the Aldrich Chemical Company. Solvents used were of analytical grade. M.p. were
measured using a Stuart (UK) electric melting point apparatus. IR spectra were recorded with a
Thermo 330 FTIR spectrometer. Mass spectra were measured on a MAT 312 Finnigan instrument

Molecules 2010, 15
667
operating at 70 eV. 1H- and 13C-NMR spectra were recorded on a Avance 400 Bruker instrument using
TMS as internal standard and DMSO-d6 as solvent.
Chemistry: General procedure for synthesis of azomethines
An equimolar mixture of aryl and/or hetaryl carboxaldehyde with selected primary aryl amine in
methyl alcohol (30 mL) containing few drops of glacial acetic acid was heated to reflux temperature
for 3-4 hours then left overnight until the product precipitated. The product was filtered off, washed
with light petroleum and recrystallized from the suitable solvent [cf. Table 1]. It is worthy to mention
that anhydrous dry solvents for recrystallization were essential to avoid decomposition by hydrolysis.
The crystalline solid that separated out was filtered by suction using water pump and washed with light
petrol to afford the desired azomethines 1-18 in pure state.
Biological Screening: Antileishmaniasis Activity - Preparation of Samples
Each compound (1 mg) was dissolved in DMSO (1 mL) and Amphotercin B (1 mg) was also
dissolved in DMSO (1 mL) as positive control. Parasites at log phase were centrifuged at 3,000 rpm
for 3 minutes. Parasites were diluted in fresh culture medium to a final density of 2 × 106 cells/mL. In
96-well plates, 180 µL of medium was added in different wells. Twenty µL of the compound was
added in medium and serially diluted. Parasite culture (100 µL) was added in all wells. Three rows
were left for negative and positive controls. In the negative controls, DMSO was serially diluted in
medium while the positive control contained varying concentrations of the standard antileishmanial
compound Amphotercin B. The plates were incubated for 72 hours at 24 °C. The culture was examined
microscopically on an improved neubaur counting chamber and IC50 values of compounds possessing
antileishmanial activity were calculated. All assays were run in duplicate. IC50 of samples was
determined by using the Prism software.
Antifungal activity
The concentration of the tested compounds was 200 ug/mL of DMSO. A reference antifungal and
DMSO were used as positive and negative control, respectively. Incubation temperature was 27 C and
time 7 days. The inculation of fungus was carried out with a 4 mm diameter piece of fungus removed
from a seven-day-old culture. The growth in the compound-amended media was determined by
measuring linear growth (mm) and growth inhibition calculated with reference to the negative control
and calculating the % inhibition of fungal growth:
linear growth in test (mm)
100 
100
% Inhibition =
linear growth in control (mm)
Antibacterial Activity
The concentration of tested compound was 1 mg/mL of DMSO, whereas the concentration of the
reference antibacterial drug imipenem was 10 mg/disc. Blank test showed that DMSO in the
preparations of the test solutions does not affect the test organisms.

Molecules 2010, 15
668
Conclusion
Eighteen azomethines were prepared by reacting an aromatic or heterocyclic aldehyde and an
aromatic primary amine compound in a protic solvent like ethanol or methanol heated to reflux
temperature in presence of few drops of acetic acid as a catalyst. The acidic catalyst leads to the
increase of the electrophilicity of the caronyl function of the carboxalehyde containing reactant. The
results revealed some order of fungicidal activities of most of the synthesized compounds whereas the
results of leishmanicidal activity highlighted that all synthesized azomethines inhibited the growth of
parasite and most of them showed high potent action towards leishmania major promastigotes. No
remarkable bactericidal activities have been recorded. Azomethines are characterized by the –CH=N-
(imino group) which has special importance in elucidating the mechanism of transmination and
racemization in biological system. Azomethines have high potential chemical permutation and show
diuretic, anticancer, antibacterial, and antifungal activities. This class of compounds also exhibited
activity against a wide range of organisms and are known to have medicinal importance and used in
drugs design. It has been also reported that some aldehydes when were functionalized by condensation
with various amines, the produced azomethines had antiparasitic activities. It is evident that
Azomethine compounds 1, 6 and 16 have moderate activity against L major. Azomethines 4, 10, 14,
15, and 17 show good activity against L major and azomethine 9 and 12, shows significant activity
against L.major. The high in vitro Anti leishmaniasis activity of these compounds makes them a
promising lead for development of effective therapeutic agents.It is clear that the synthesize of
Azomethines showed only compound 17 has moderated activity against A flavus. Azomethine 4,5,12
and 14 have low activity against M. Canis whereas compound 9 has good anti fungal activity against
same fungus. Azomethine 9 shows a moderate activity against F. Solani whereas azomehtines 4,11,17
and 18 have low activity against the same fungus. In bacteria among the 18 synthesize of azomethines
tested only compound 4 showed significant activity against E.coli and low activity against B. subtilis.
Acknowledgments
This work was supported by University of Balochistan, Quetta and Higher Education Commission
(HEC), Islamabad, Pakistan.
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Sample Availability: Samples of the compounds 1-18 are available from the authors.
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