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Synthesis, antifungal evaluation and in silico study of novel Schiff bases derived from 4-amino-5(3,5-dimethoxy-phenyl)-4H-1,2,4-triazol-3-thiol
⁎Corresponding author at: School of Pharmaceutical Sciences, Rajiv Gandhi Proudyogiki Vishwavidyalaya, Airport Bypass Road, Gandhi Nagar, Bhopal 462036, Madhya Pradesh, India. Tel.: +91 755 2678883; fax: +91 755 2742006. nshnm06@yahoo.co.in (N.S. Hari Narayana Moorthy)
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Received: ,
Accepted: ,
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.
Abstract
A novel series of Schiff bases based on of 4-amino-5-(3,5-dimethoxy-phenyl)-4H-1,2,4-triazol-3-thiol scaffold was prepared by heating thiocarbohydrazide and 3,5,-dimethoxy benzoic acid at the temperature above its meting point, and subsequently, treating with substituted benzaldehydes. The chemical constituents in the synthesized compounds were confirmed by IR, Mass, 1H NMR spectroscopy and elemental analysis and the antifungal activity was evaluated against Candida albicans. The structure activity relationship analysis shows that the chloride substituted derivatives possess promising activity in micromolar concentration and also the hydroxy phenyl derivatives exhibited considerable activity at 128 μg/ml. But other compounds with amino, furan and methoxy substitutions did not show antifungal activity till the concentration of 512 μg/ml. In silico pharmacokinetic prediction shows that all the compounds obeyed Lipinski rule of 5 and are free of toxicity and metabolically stable. Pharmacophore analysis revealed that the aromatic/hydrophobic and aromatic/acceptor/donor features in the compounds are essential for the activity. The predicted cardiotoxicity (hERG) and lethal effect of the synthesized compounds will permit us to carry out further in vitro and in vivo toxicity studies.
Keywords
Triazole
Schiff base
Antifungal activity
3,5-Dimethoxyphenyl moiety
In silico
1 Introduction
The 1,2,4-triazole, a heterocyclic derivative exhibits important pharmacological activities such as antifungal (Tsukuda et al., 1998), anticonvulsant (Küçükgüzel et al., 2004; Klimesová et al., 2004), anti-tubercular (Husain and Amir, 1986), antioxidant (Valentina et al., 2009), anti-inflammatory (Sahin et al., 2001), COX-2 inhibition (Navidpour et al., 2006), HIV-I reverse transcriptase inhibition (Rosa et al., 2006), cytochrome P450 inhibition (Sun et al., 2007), anticancer (Demirbas et al., 2002; Olcay et al., 2006; Holla et al., 2001), antimicrobial activity (Holla et al., 2001; Mithun et al., 2007; Karthikeyan et al., 2006; Vicentini et al., 1998; Bayrak et al., 2009a,b), Aggrecanase-2 (Maingot et al., 2010), etc. Furthermore, 1,2,4-triazole nucleus has been incorporated into a wide variety of therapeutically interesting molecules that act as better drugs like Ribavirin (antiviral agent), Rizatriptan (antimigrane agent), Alprazolam (anxiolytic agent) and Fluconazole, Itraconazole (antifungal agent) (Holla et al., 2006; Jack et al., 1976). Consequently, there is continuing drive to explore these pharmacophores for the development of novel molecules with diverse activities.
Fungal infections have become an important complication and major cause of morbidity and mortality in immunocompromised individuals suffering from tuberculosis, cancer, AIDS and in organ transplant cases (Pridkin and Jarvis, 1996; Wingard and Leather, 2004). Triazole antifungals (e.g. fluconazole, lanosterol and voriconazole), act by inhibiting cytochrome P450 14α-desmethylase (CYP51) and recently became the most rapidly expanding group of antifungal compounds (Sun et al., 2007). However, their clinical value has been limited by their relative high risk of toxicity, the emergence of drug resistance, pharmacokinetic deficiencies and insufficiencies in their antifungal activities. There is still a need for genuinely broad-spectrum and low toxic antifungal agents for the therapy.
Prompted by these observations, it was contemplated to synthesize some new Schiff bases of 5-aryl-4H-1,2,4-triazole-3-thiol derivatives with a view to explore their potency as better chemotherapeutic agents. Presence of thiol group in the compounds can bind to the cationic functional group or metal ion in the active site of the target (Maingot et al., 2010). Schiff bases derived from various heterocycles were reported to have cytotoxic, anticonvulsant, antiproliferative, anticancer and antifungal activities (Karthikeyan et al., 2006; Vicentini et al., 1998; Bayrak et al., 2009a). In this investigation, all newly synthesized Schiff bases of 5-aryl-4H-1,2,4-triazole-3-thiol compounds were evaluated for the antifungal activity along with their in silico pharmacophore, pharmacokinetic and toxic properties.
2 Material and methods
2.1 Materials
Reagents, starting materials and solvents were purchased from common commercial suppliers. The melting points were determined in open capillary method on a Jindal melting point apparatus and are reported uncorrected. 1H NMR spectra were recorded on the Bruker NMR using DMSO-d6, TMS (tetramethylsilane) as an internal standard. The FAB mass spectra were recorded on a JEOL SX 102 Mass spectrometer/data system using argon/xenon (6KV, 10 mA) as the FAB gas, m-nitrobenzyl alcohol (NBA) was used as matrix. IR absorption spectra were recorded on Jasco FT/IR-470 Plus, using KBr by the diffuse reflectance method. Elemental analysis was performed on Elementar system. The purity and the progress of reactions were monitored by thin layer chromatography using silica gel-G on glass plate as stationary phase and ethyl acetate and n-heptane as mobile phase. Visualization was accomplished with UV light and/or iodine vapour.
2.2 Synthesis of 4-amino-5-(3,5-dimethoxy-phenyl)-4H-[1,2,4]triazole-3-thiol (3)
A mixture of 3,5-dimethoxy benzoic acid (0.01 mol) and thiocarbohydrazide (0.01 mol) was placed in a round-bottom flask, heated until it melted. The mixture was consistently maintained at 225 °C for 20 min. The product obtained on cooling was treated with sodium bicarbonate solution to neutralize the unreacted carboxylic acid if any. The product was then washed with water and collected by filtration. The solid product was recrystallized from a mixture of dimethylformamide and ethanol. Yield 56%; mp 168–170 °C; IR (KBr) υ/cm−1: 1204 (C—O—C), 1647 (C⚌N), 3295 (N—H), 2960 (CH3C—H), 1540 (Ar C⚌C), 1346 (C⚌N), 1158 (C—S); 1H NMR (400 MHz, δ, DMSO-d6): 3.7 (s, 3H (OCH3)), 3.8 (s, 3H (OCH3)), 5.2 (s, 2H (NH2)), 6.9–7.3 (t, 3H (Ar—H)), 13.7 (s, 1H (SH)); Mass (m/z): 252.1 [M+H]+.
2.3 General procedure for the preparation containing Schiff base derivatives
To a suspension of substituted benzaldehyde (2) (0.2 mol) in ethanol (1 ml), an equimolar amount of corresponding amino mercaptotriazole (3) was added. The suspension was heated until a clear solution was obtained. Then few drops of concentrated sulphuric acid were added and the solution was heated under reflux for 4 h on a water-bath. The precipitated solid was filtered off and recrystallized from a mixture of ethanol and dimethylformamide.
2.3.1 Compound 5a
IR (KBr) υ/cm−1: 1207 (C—O—C), 1647 (C⚌N), 3346 (N—H), 2956 (CH3C—H), 1541 (Ar C⚌C), 1365 (C⚌N), 1159 (C—S), 1051 (C—Cl); 1H NMR (400 MHz, δ, DMSO-d6): 3.8 (s, 3H (OCH3)), 3.9 (s, 3H (OCH3)), 6.57–7.8 (m, 7H (Ar—H)), 10.0 (s, 1H. (HC⚌N)), 13.7 (s, 1 H (SH)); Mass (m/z): 375.1 [M+H]+.
2.3.2 Compound 5b
IR (KBr) υ/cm−1: 1204 (C—O—C), 1647 (C⚌N), 3647 (N—H), 1541 (Ar C⚌C), 1358 (C⚌N), 1165 (C—S), 1051 (C—Cl); 1H NMR (400 MHz, δ, DMSO-d6): 3.7 (s, 3H (OCH3)), 3.8 (s, 3H (OCH3)), 6.5–8.1 (m, 6H (Ar—H)), 10.7 (s, 1H (HC⚌N)), 13.9 (s, 1H (SH)); Mass (m/z): 410.1 [M+H]+.
2.3.3 Compound 5c
IR (KBr) υ/cm−1: 1202 (C—O—C), 1647 (C⚌N), 3295 (N—H), 2959 (CH3C—H), 1540 (Ar C⚌C), 1367 (C⚌N), 1159 (C—S); 1H NMR (400 MHz, δ, DMSO-d6): 3.7–3.9 (tris s, 9H, (OCH3)), 6.5–7.8 (m, 7H. (Ar—H)), 9.7 (s, 1H. (HC⚌N)), 13.9 (s, 1 H (SH)); Mass (m/z): 371.1 [M+H]+.
2.3.4 Compound 5d
IR (KBr) υ/cm−1: 1205 (C—O—C), 1688 (C⚌N), 3648 (N—H), 2941 (CH3C—H), 1540 (Ar C⚌C), 1342 (C⚌N), 1157 (C—S); 1H NMR (400 MHz, δ, DMSO-d6): 3.7 (s, 3H (OCH3)), 3.9 (s, 3H (OCH3)), 6.5–7.3 (m, 6H (Ar—H)), 9.9 (s, 1H (HC⚌N)), 13.8 (s, 1H (SH)); Mass (m/z): 349.1 [M+H]+.
2.3.5 Compound 5e
IR (KBr) υ/cm−1: 1207 (C—O—C), 1647 (C⚌N), 3648 (N—H), 2932 (CH3C—H), 1540 (Ar C⚌C), 1375 (C⚌N), 1167 (C—S); 1H NMR (400 MHz, δ, DMSO-d6): 2.5, s, 3H (CH3), 2.7 (s, 3H (CH3)), 3.1 (s, 2H (NH2)), 3.8 (s, 3H (OCH3)), 3.9 (s, 3H (OCH3)), 6.5–9.7 (m, 5H (Ar—H)), 9.5 (s, 1H (HC⚌N)), 13.8 (s, 1H (SH)); Mass (m/z): 385.4 [M+2].
2.3.6 Compound 5f
IR (KBr) υ/cm−1: 1209 (C—O—C), 1647 (C⚌N), 3647 (N—H), 2939 (CH3C—H), 1541 (Ar C⚌C), 1367 (C⚌N), 1165 (C—S), 1165–1209 (C—OH), 3613 (O—H); 1H NMR (400 MHz, δ, DMSO-d6): 2.8 (s, 1H (OH)), 3.7 (s, 3H (OCH3)), 3.8 (s, 3H (OCH3)), 6.5–7.7 (m, 7H (Ar—H)), 9.8 (s, 1H (HC⚌N)), 13.7 (s, 1H (SH)); Mass (m/z): 357.1 [M+H]+.
2.4 Antifungal studies
Antifungal activity of the compounds was performed by the broth dilution method (MIC method).
2.4.1 Preparation of solution
DMSO stock solutions (1 mg/ml) of all compounds were prepared with 50% DMSO in a screw capped vial. They were stored at 40 °C in the dark.
2.4.2 Preparation of inoculums
Sland culture of Candida albicans was inoculated into a SDB (Sabour and Dextrose Broth) medium in a conical flask and incubated at 35 °C for 24 h in a shaker. After incubation, the turbidity was compared with 0.5 Mc Farland Nephalometric standards (1.5 × 108 CFU) and adjusted with sterile saline.
2.4.3 Preparation of medium
Yeast Nitrogen Base (YNB) (HiMedia) with added agar (1.7%) and glucose (0.5%) were prepared and poured into petri plates. A well mixed standardized inoculum was uniformly spread over the surface of the nutrient broth agar plates with the help of sterile swab. After 15 min of inoculum, 6–7 mm diameter wells were made by well puncture and were filled with 100 μl of each sample stock solution and the control wells were filled with 50% DMSO. Then the plates were incubated at 35 °C for 24 h. After incubation, the zone of inhibition around the well was measured including the diameter of the wells.
2.4.4 Broth dilution method/micro dilution
The synthetic compounds that showed considerable antifungal activities were selected for the study. By this microdilution method, minimal inhibitory concentration (MIC) was found out using Amphotericin-B (potency 750 μg/mg) as a standard drug. All stock solutions (100 μg/ml) were prepared in 100% DMSO. 102 μl of stock solution was taken in a sterile test tube and made up to 2 ml with sterile YNB (0.5%) medium, which gave 512 μg/ml concentration. This content was serially diluted with 1 ml of sterile YNB broth taken in a test tube to 1 μg/ml concentration of drug. Experimental tubes were inoculated with 1 μl of standardized inoculum of C. albicans. Control tubes with DMSO (51 μg/ml) without drug and medium were also inoculated with C. albicans. The tubes were incubated at 35 °C for 24 h and the concentration of drugs were determined (measured the turbidity of the medium).
2.5 In silico ADME-Tox study
The Pentium IV work station and Pallas 6.1.1, q-hERG and q-Tox softwares were used to predict the ADME-T properties of the molecules (Pallas, 2000; q-Tox, 2008). Chemdraw ultra software was used to draw the structure of the compounds to be analysed and was saved as MDL file.
2.6 Pharmacophore study
The Molecular Operating Environment (MOE) software (MOE, 2007) was used to optimize the energy of the synthesized molecules before undergoing conformational analysis (by stochastic search method). The conformers were flexialigned and its pharmacophore sites were investigated.
3 Result and discussions
4-Amino-5(3,5-dimethoxy-phenyl)-4H-1,2,4-triazol-3-thiol (3) derivatives were synthesized from 3,4-dimethoxy benzoic acid (1) and thiocarbohydrazide (2) as per the literature (Pridkin and Jarvis, 1996; Wingard and Leather, 2004; Bayrak et al., 2009a). Intermediate compound 3 was treated with substituted aromatic aldehydes (4) in the presence of concentrated H2SO4, yielded Schiff bases (5) (Fig. 1). The envisaged structures of the synthesized compounds were confirmed by (Table 1) NMR, IR, Mass and elemental analysis. All the synthesized compounds underwent antifungal evaluation against C. albicans strains up to 512 μg/ml concentration. The results obtained from the evaluation study are provided in Table 2 and it explains that the monochloro and dichlorophenyl (5a and 5b) substituents on parent nucleus have significant antifungal activity at 64 μg/ml against C. albicans. The hydroxy phenyl derivatives (5f) also have considerable activity at 128 μg/ml, but other substituents such as amino phenyl, furan and methoxy phenyl derivatives (5c) did not possess antifungal activity till 512 μg/ml concentration.
Scheme for synthesis of Schiff bases of 4-amino-5(3,5-dimethoxy-phenyl)-4H-1,2,4-triazole-3-thiol derivatives.
Compound No.
Molecular formula
Melting point (°C)
Yield (%)
Elemental analysis
C
H
N
Exp
Calc
Exp
Calc
Exp
Calc
5a
C17H15ClN4O2S
212–213
60.19
54.42
54.47
4.05
4.03
14.97
14.95
5b
C17H14Cl2N4O2S
222–223
66.65
49.95
49.89
3.43
3.45
13.65
13.69
5c
C18H18N4O3S
198–201
76.59
58.39
58.36
4.91
4.90
15.07
15.12
5d
C15H14N4O3S
188–190
68.40
54.50
54.53
4.28
4.27
16.98
16.96
5e
C19H21N5O2S
225–228
50.56
59.57
59.51
5.50
5.52
18.24
18.26
5f
C17H16N4O3S
218–219
64.99
57.35
57.29
4.50
4.52
15.69
15.72
Compound No.
Molecular weight
Log P
HBD
HBA
Score
5a
374.87
5.14
1
5
1
5b
409.31
5.81
1
5
1
5c
370.46
4.48
1
6
0
5d
348.46
2.98
1
6
0
5e
383.51
4.34
2
5
0
5f
356.43
4.13
2
6
0
In order to predict the drug likeliness of the synthesized compounds, Lipinski rule of 5 was tested (Molecular weight > 500, Log P > 5, HBD > 5 and HBA > 10), on the synthesized compounds using Pallas 3.1.1.2 software (Pallas, 2000; Oprea, 2002; Moorthy et al., 2006, 2010). The predicted properties such as Log P, drug likeliness of the compounds (Table 2) revealed that the molecules passed Lipinski’s rule of 5. The results showed that molecular weight plays an important role and causes the bulkiness of the molecules. It explains that, if the molecular weight increases beyond a limit, the bulkiness of the compounds also increases, which affects the drug action. Molecular weight of the synthesized compounds lying between 348 and 410 shows that it follows Lipinski rule of 5. The lipophilicity (Log P) is also an important parameter for drug action (membrane transport) (Oprea, 2002). It is interesting that the Log P values of chloro and dichlorophenyl substituted compounds are more than 5, but both are having better antifungal activity than rest of the compounds which have Lipinski score 1.
The cardiotoxicity (hERG) and the LD50 values calculated with q-hERG and q-Tox software and the results are provided in Table 3. The predicted toxicity (LD50) described that the dichloro substituted compound (5b) has comparatively more toxicity than other compounds in the series, it may be caused by a high lipophilic property of the molecules. The furan substituted compound (5d) has less toxicity and free from antifungal activity. The human ether a go-go related gene (hERG) cause sudden death (prolongation of QT interval) of patient when non-antiarrhythmic drugs administered that is a major pharmacological safety issue (Aronov, 2005; Choe et al., 2006; Moorthy et al., 2012, 2013). Hence, the evaluation of hERG blocking effect of the molecules in the early stage of drug discovery provides safe drugs. The results derived from these studies show that the furan ring containing compounds have less hERG blocking activity than other aryl ring substituted compounds. It reveals that the presence of aromatic rings with flexible bonds makes π–π interaction with the aromatic residues present in the protein which provides hydrophobicity to the molecules. Unfortunately, the compound with furan ring (5d) posses no antifungal activity till 512 μg/ml. The compound substituted with dichloro substituents (5b) on the phenyl ring exhibits significant antifungal activity at 64 μg/ml and this compound has lethal effect at high concentration. These results also confirm that the chlorine substituents (5a and 5b) in molecule have significant activity with optimized pharmacokinetic properties.
Compound No.
Concentration (μg/ml)
Growth inhibition (mm)
Predicted hERG (−log IC50)
Predicted (−log LD50)
5a
64
34
6.3
1.6
5b
64
30
6.6
1.3
5c
512
–
6.2
1.3
5d
512
–
4.6
1.5
5e
512
–
6.6
1.7
5f
128
20
6.8
1.7
DMSO
Nil
–
The pharmacophore contour of the flexialigned compounds are provided in Fig. 2, which showed that the aromatic/hydrophobic and aromatic/acceptor/donor contours are important pharmacophore contours for the activities. This result also reveals that the hydrophobicity plays an important role for the activity. The molecular surface (Fig. 3) properties of the molecule also confirm the same result that the hydrophobicity is distributed throughout the surface areas (grey colour).
Pharmacophore and SAR of the flexialigned structure of the compounds.
Molecular surface property of the flexialigned compounds.
4 Conclusion
From the study, it has been concluded that some of the 4-amino-5(3,5-dimethoxy-phenyl)-4H-1,2,4-triazole-3-thiol derivatives have considerable antifungal activity against C. albicans, and are free from toxicity. Hence, it may be the better pharmacophore to explore the development of new bioactive moieties. The in silico predicted toxicity (hERG and LD50) guides us for further in vitro and in vivo toxicity studies.
Acknowledgments
The authors are thankful to The Vice Chancellor, RGPV, Bhopal for providing laboratory facility. The authors are grateful to Head, SAIF, IIT Mumbai, RSIC, Punjab University, Chandigarh, for providing MS and 1H NMR spectral services. Authors (NSHNM and UBV) are grateful to AICTE New Delhi for providing Research Fellowship and Career Award grant during this project.
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