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. 2010 Jan 28;15(2):660–671. doi: 10.3390/molecules15020660

Antileishmanial, Antimicrobial and Antifungal Activities of Some New Aryl Azomethines

Yasser MSA Al-Kahraman 1, Hassan MF Madkour 1,2, Dildar Ali 1, Masoom Yasinzai 1,*
PMCID: PMC6256931  PMID: 20335936

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 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 [7,8,9]. Azomethines have high potential chemical permutation possibilities and show diuretic [10], anticancer [11,12,13,14], antibacterial [15,16,17,18,19], and antifungal activities [20,21,22]. 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 [23,24,25]. 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 [27,28,29,30,31,32,33], 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).

Scheme 1.

Scheme 1

Scheme 1

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General synthetic route.

The structural features of the synthesized azomethines were determined from the corresponding IR, 1H-NMR, 13C-NMR and mass spectroscopy data, listed in Table 1, Table 2, Table 3 and Table 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.

Table 1.

Physical and select IR data of the synthesized azomethines 1-18.

Compd. Color Moleculara formula
(Mol. Mass)		 Mp (°C) (recryst. solvent)b Yield
(%)		 IR (cm−1)
N=C Azomethine
C-H		 Substituent
1 Pale yellow C13H10ClN [34]
(215.05)		 72-4
(L.P)		 82 1621 2874,
1352		 ­-
2 Yellow C13H9ClN2O2 [35]
(260.04)		 140-42
(L.P)		 74 1625 1333 1505, 1376(NO2)
3 Brown C11H9NO [36]
(171.07)		 106 d
(B)		 79 1605 2850, 1328 3360(OH)
4 Brown C11H8N2O3 [37]
(216.05)		 196-98
(EtOH)		 68 1592 1285 1535, 1339(NO2)
5 Pale orange C14H12N2OH
(272.08)		 148-50
(L.P)		 64 1628 1325 3354–3480(OH)
1544, 1342 (NO2)
6 Pale yellow C14H13NO2
(227.09)		 155-57
(L.P)		 72 1621 1388 3088 broad(OH)
7 Orange C15H12N2O2
(252.09)		 133d
(MeOH)		 65 1592 1300 1512, 1335(NO2)
8 Pale brown C15H13N
(207.10)		 100-02
(MeOH)		 66 1623 1375 -
9 Orange C13H10N2O3
(242.07)		 162-64
(L.P)		 59 1632 1338 1562, 1347 (NO2), 3150 (OH)
10 Pale brown C17H12ClN
(265.07)		 107-09
(MeOH)		 78 1637 1391 -
11 Brown C18H15NO2
(277.11)		 114-16
(B)		 76 1621 1381 3048(OH)
12 Pale Brown C14H12ClNO
(245.06)		 136-37
(MeOH)		 87 1629 2838, 1364 2838, 2895 (CH3)
13 Pale Brown C15H15NO3
( 257.11)		 257-59
(MeOH)		 70 1621 2954, 1378 3000 (broad OH), 2954, 2982 (CH3)
14 Greenish White C14H13NO2
(227.09)		 85-87
(MeOH)		 67 1637 2964, 1362 3610(OH), 2964, 2996 (CH3)
15 White C14H12ClN
(229.07)		 127-29
(MeOH)		 79 1622 2929, 1354 2854, 2925 (CH3)
16 White C14H13NO
(211.10)		 96-98
(MeOH)		 67 1615 2920, 1366 3100 (OH), 2920 (CH3)
17 Pale Orange C16H15N [38]
(221.12)		 76-77
(MeOH)		 71 1627 2912, 1379 2912 (CH3)
18 Pale Yellow C11H8N2O2S [39]
(232.03)		 135-37
(MeOH)		 55 1612 1323 1543, 1341 (NO2)
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a references are given for known products, the others are new; b 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. 1H-NMR
5 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).
6 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).
7 8.10 (m, 1H, -CH=N), 7.60-6.95 (m, 11H, Ar-H and olefinic H).
8 8.25 (d, 1H, benzylideimin H, J = 5.36 Hz), 7.54-7.07 (m, 12H, Ar-H and olefinic H).
9 12.27 (s, 1H, OH, exchangeable), 8.99 (s, 1H, -CH=N), 8.32-6.98 (m, 7H, Ar-H).
10 8.73 (s, 1H, benzylidenimine H), 8.09-7.23 (m, 11H, Ar-H).
11 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).
12 8.64 (s, 1H, -CH=N), 7.93-6.97 (m, 8H, Ar-H), 3.77 (s, 3H, -OCH3).
13 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).
14 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)
15 8.41 (s, 1H, -CH=N),7.83-7.11 (m, 8H, Ar-H), 2.36 (s, 3H, -CH3)
16 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).
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Table 3.

13C-NMR (DMSO-d6) ( δ, ppm) of azomethines 5-16.

Compd 13C-NMR
5 160.0, 154.2, 152.4, 147.3, 146.3, 131.0, 125.5, 125.2, 123.2, 115.9, 112.3, 56.1.
6 160.2, 152.4, 152.0, 147.3, 131.1, 129.9, 127.2, 125.5, 122.3, 115.9, 112.3, 56.1.
7 163.7, 158.6, 146.4, 135.2, 133.3, 128.5, 128.5, 127.9, 125.2, 123.2, 119.8.
8 163.7, 152.4, 135.2, 133.3, 130.0, 128.6, 128.5, 127.9, 127.2, 122.3, 119.9.
9 161.1, 160.0, 154.2, 146.4, 132.4, 132.1, 125.2, 123.2, 121.4, 120.5, 117.8.
10 160.0, 151.9, 136.6, 135.0, 134.5, 130.5, 128.9, 128.6, 128.3, 127.8, 126.8, 126.3, 115.2.
11 160.0, 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.
12 160.0, 159.1, 144.3, 136.5, 134.5, 130.6, 128.8, 122.1, 115.6, 55.8.
13 159.9, 159.1, 152.4, 147.3, 144.3, 131.1, 125.5, 115.9, 115.6, 122.1, 112.3, 56.1, 55.8.
14 161.1, 160.1, 159.1, 144.3, 132.4, 132.1, 122.1, 121.4, 120.4, 117.8, 115.5, 55.8.
15 160.1, 149.1, 136.9, 136.5, 134.5, 130.6, 130.3, 128.9, 122.2, 21.3.
16 161.1, 159.9, 149.1, 136.8, 132.4, 132.1, 130.3, 122.2, 121.4, 120.5, 117.7, 21.3.
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Table 4.

Mass spectra of azomethines 5-16.

Compd. m/z (% Relative abundance)
5 272 (M+., 4.25), 227 (2.34), 139 (4.85), 138 (70.25), 107 (76.60), 92 (48.80), 91 (6.91), 65 (100.00).
6 227 (M+., 98.26), 211 (21.66), 166 (14.45), 154 (7.12), 139 (5.12), 104 (22.42), 77 (100.00)
7 252 (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)
8 207 (M+., 33.52), 206 (M-1⎤+., 100.00), 178 (3.25), 128 (13.57), 115 (18.72), 77 (90.33).
9 242 (M+., 96.65), 212 (13.38), 195 (37.11), 167 (29.72), 151 (5.91), 120 (44.48), 76 (100.00)
10 267 (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).
11 277 (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).
12 247 (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).
13 257 (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).
14 228 (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).
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 (22.99), 91 (100.00), 77 (9.79), 65 (61.60).
16 211 (M+., 100.00), 210 (M-1⎤+., 76.87), 167 (6.29), 120 (12.86), 118 (8.68), 91 (80.65), 65 (74.49).
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The 1H-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.

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 0.77 ± 0.09
2 -
3 -
4 0.65 ± 0.01
5 -
6 0.73 ±0.16
7 -
8 -
9 0.59 ± 0.07
10 0.61 ± 0.27
11 -
12 0.57 ±0.11
13 0.63 ± 0.04
14 0.68 ±0.12
15 0.66 ±0.18
16 0.81 ± 0.03
17 0.62 ± 0.08
18 -
Standard Drug IC50 (µg/mL± S.D)
Amphotericin B 0.56 ± 0.20
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a 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).

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.

  • (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 0 0 0 0 0
2 0 0 0 0 0
3 0 0 0 0 0
4 0 0 20a 35 0
5 0 0 30 0 0
6 0 0 0 0 0
7 0 0 0 0 0
8 0 0 0 0 0
9 0 0 60 40 0
10 0 0 0 0 0
11 0 0 0 35 0
12 0 0 35 0 0
13 0 0 0 0 0
14 0 0 20 0 0
15 0 0 0 0 0
16 0 0 0 0 0
17 0 40 0 15 0
18 0 0 0 20 0
Std. Drug MIC (mg/mL)
Miconazole 110.8 - 98.4 73.25 110.28
Amphotericin B - 20.0 - - -
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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 flexenari, 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 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:

% Inhibition=100−linear growth in test (mm)linear growth in control (mm)×100

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.

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.

Footnotes

Sample Availability: Samples of the compounds 1-18 are available from the authors.

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