A facile iodine(III)-mediated synthesis of 3-(3-aryl-1-phenyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridines via oxidation of 2-((3-aryl-1-phenyl-1H-pyrazol-4-yl)methylene)-1-(pyridin-2-yl)hydrazines and their antimicrobial evaluations
Fused heterocyclic 1,2,4-triazoles have acquired much importance because of their interesting biological properties. Although a number of methods have been reported in the literature which includes oxidation with phosphorus oxychloride, lead tetraacetate, bromine, etc., hypervalent iodine reagents have emerged as reagents of choice for various synthetically useful transformations due to their low toxicity, ready availability and ease of handling.
Results
A series of new 3-(3-aryl-1-phenyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridines 4 has been conveniently synthesized by oxidative cyclization of 2-(3-aryl-1-phenyl-1H-pyrazol-4-yl)methylene)-1-(pyridin-2-yl)hydrazines 3 promoted with iodobenzene diacetate under mild conditions (up to 90% isolated yields). All the new compounds were tested in vitro for their antimicrobial activity.
Conclusions
Iodine(III)-mediated oxidative approach has offered an easy access to new 3-(3-aryl-1-phenyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridines 4. The antibacterial and antifungal activities of newly synthesized compounds have proved them potent antimicrobial agents.
Fused heterocyclic 1,2,4-triazoles have acquired much importance because of their CNS depressant [1], antiallergy [2], antimicrobial [3] and anti-inflammatory [4] properties. Most methods for the preparation of fused 1,2,4-triazole derivatives are based on the oxidation of heterocyclic hydrazones or hydrazides with phosphorus oxychloride [5], lead tetraacetate [5, 6], bromine [6, 7], etc., which are associated with toxic properties. Therefore, alternative approach avoiding these reagents is always preferred.
Organohypervalent iodine reagents have emerged as reagents of choice for various synthetically useful transformations due to their low toxicity, ready availability and ease of handling [8–17]. We have recently reported the usefulness of iodobenzene diacetate (IBD) to effect oxidative cyclization of benzalhydrazones to 1,2,4-triazoles [18–22].
Pyrazoles form an integral part of many natural products of therapeutic importance and possess potentially reactive sites for a variety of chemical reactions to generate molecular diversity. (S)-3-Pyrazolylalanine [23], lonazolac [24], difenamizole [25], mepirizole [26], metamizol [27] and 4,5-dihydro-3-phenyl-6H-pyrrolo[1,2-b]pyrazole are some of the biologically active compounds endowed with antimicrobial [28], hypoglycaemic [29] and non-nucleoside HIV-1 reverse transcriptase inhibitor properties [30].
Our ongoing programme on the development of hypervalent iodine-mediated methodologies in heterocyclic synthesis coupled with the significant biological importance of fused 1,2,4-triazole derivatives and pyrazole derivatives, prompted us to undertake the synthesis of hitherto unknown fused 1,2,4-triazolopyridines. We report in this study on the synthesis of fused 3-(3-aryl-1-phenyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridines 4 by the oxidation of 2-((3-aryl)-1-phenyl-1H-pyrazol-4-yl)methylene)-1-(pyridin-2-yl)hydrazines 3 using IBD in dichloromethane with an expectation to find new and more potent antibacterial and antifungal agents.
Results and discussion
Chemistry
First, we synthesized a series of 2-((3-aryl-1-phenyl-1H-pyrazol-4-yl)methylene)-1-(pyridin-2-yl)hydrazines 3 needed for their oxidative cyclization. These substrates were easily accessible in high yields (88-96%) and purity from the reaction of 2-pyridyllhydrazine 1 and 3-aryl-1-phenyl-1H-pyrazole-4-carbaldehydes 2 in ethanol (Scheme 1) [31]. Then, the reaction of 2-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)-1-(pyridin-2-yl)hydrazine (3a) (see Additional file 1) was carried out with 1.1 equivalents of IBD in dichloromethane by stirring at room temperature overnight. The usual work-up of the reaction afforded the expected product, 3-(1,3-diphenyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridine (4a) (see Additional file 2) in 90% yield (Scheme 1). To study the scope of reaction, we carried out oxidation of a wide range of substituted 2-((3-aryl-1-phenyl-1H-pyrazol-4-yl)methylene)-1-(pyridin-2-yl)hydrazines (3b-g) (see Additional files 3, 4, 5, 6, 7 and 8) under similar conditions. It was observed that IBD-mediated oxidative approach worked nicely to give the desired products 4b-g (see Additional files 9, 10, 11, 12, 13 and 14) in all cases in 82-90% yields.
Scheme 1
Synthesis of title compound 4viaoxidation of 3. Ar: Phenyl (a); 4-methylphenyl (b); 4-methoxyphenyl (c); 4-fluorophenyl (d); 4-chlorophenyl (e); 4-bromophenyl (f); 4-nitrophenyl (g).
The structures of all the compounds 3 and 4 were confirmed by their spectral (IR, 1H NMR, Mass) and elemental analytical data. For example, the IR spectrum of the compound 3a exhibited characteristic absorption band at 3190 cm-1 due to NH functional group. The 1H NMR spectrum of the product 3a showed two singlets due to C(5)-H of pyrazole ring and N=CH at δ 8.93 and δ 8.17, respectively, and also a broad singlet due to NH at δ 10.66 which disappeared on the addition of D2O. Other protons appeared as multiplet in the aromatic regions. Mass spectrum of the compound 3a exhibited molecular ion peak at m/z 340.06 [M + 1]+.
The characterization of products 4 was based upon a careful comparison of their IR and 1H NMR spectra with those of 3. IR spectra of 4 were found to be transparent in the region of NH stretch, thus confirming the oxidation of 3 into 4. An important characteristic feature in the 1H NMR spectra of 4 was the disappearance of the singlet due to N=CH around δ 8.12-8.93, which was present in the spectra of 3. The plausible mechanism for the oxidation of 3 to 4 is analogous to our earlier reports [18, 19] and given in Scheme 2.
Scheme 2
Mechanism for the oxidation of 3 to 4.
Pharmacology
In vitro antibacterial activity
All the synthesized compounds, 3a-g and 4a-g were evaluated in vitro for their antibacterial activity against two Gram-positive bacterial strains, Staphylococcus aureus and Bacillus subtilis and two Gram-negative bacteria namely, Escherichia coli and Pseudomonas aeruginosa, and their activity was compared to a well-known commercial antibiotic, ciprofloxacin. All the compounds possessed variable antibacterial activity against Gram-positive bacteria, S. aureus and B. subtilis. Results of antibacterial evaluation are summarized in Table 1 and Figure 1. Compounds 3a-g and 4a-g showed zone of inhibition ranging between 12.8 and 24.6 mm. On the basis of zone of the inhibition produced against the test bacteria, compound 3d was found to be the most effective against S. aureus and B. subtilis showing the maximum zone of inhibition of 18.6 and 19.3 mm, respectively, when compared with commercial antibiotic ciprofloxacin, which showed maximum zone of inhibition of 27.6 and 26.3 mm against Gram-positive bacteria, S. aureus and B. subtilis, respectively. Compounds 4a, 4b, 4c and 4f were found to be the most effective against both Gram-positive bacteria showing maximum zone of inhibition ranging between 20.3 and 22.6 mm. Rest of compounds showed fair activity against Gram-positive bacterial strains (Table 1, Figure 1). All the synthesized compounds showed fair activity against both Gram-negative bacterial strains. In the whole series, the MIC value of various synthesized compounds (3 and 4) ranges between 16 and 256 μg/mL against Gram-positive and Gram-negative bacteria (Table 2, Figure 2). Out of compounds 3a-3g, compound 3d was found to be the most effective against both Gram-positive bacteria having the lowest MIC value 64 μg/mL when compared with commercial antibiotic ciprofloxacin, which showed MIC value 5 μg/mL for both Gram-positive bacteria. Out of compounds 4a-4g, compounds 4a, 4b, 4c and 4f possessed good antibacterial activity against B. subtilis with MIC of 16, 16, 32 and 32 μg/mL, respectively (Table 2, Figure 2).
Table 1
In vitro antibacterial activity of compounds 3 and 4
Compounds
Diameter of growth of inhibition zone (mm)a
Staphylococcus aureus
Bacillus subtilis
Escherichia coli
Pseudomonas aeruginosa
3a
17.3
19.3
13.3
15.6
3b
16.6
17.3
-
13.2
3c
17.3
18.6
13.0
12.8
3d
18.6
19.3
14.3
15.0
3e
16.3
17.6
14.2
-
3f
16.3
17.6
-
13.5
3g
17.0
18.3
13.8
14.3
4a
22.6
24.6
19.6
17.3
4b
21.3
24.6
18.0
16.6
4c
20.3
21.6
16.3
15.3
4d
17.0
18.6
15.6
13.6
4e
15.5
16.0
-
16.2
4f
21.6
22.6
17.3
15.6
4g
18.6
19.3
14.6
15.3
Ciprofloxacin
27.6
26.3
25.0
25.3
-, no activity
aValues including diameter of the well (8 mm), are means of three replicates
Figure 1
Comparison of diameter of growth of inhibition of compounds (3 and 4) and standard drug.
Table 2
Minimum inhibitory concentration (μg/mL) of compounds 3 and 4
Compounds
Minimum inhibitory concentration (μg/mL)
Staphylococcus aureus
Bacillus subtilis
Escherichia coli
Pseudomonas aeruginosa
3a
128
64
256
128
3b
128
128
NT
256
3c
128
64
256
256
3d
64
64
256
256
3e
128
128
256
NT
3f
128
128
NT
256
3g
128
64
256
256
4a
32
16
64
64
4b
32
16
64
128
4c
64
32
128
128
4d
128
64
128
256
4e
128
128
256
128
4f
32
32
64
128
4g
64
64
256
256
Ciprofloxacin
5
5
5
5
NT, not tested.
Figure 2
Comparison of MIC of compounds (3 and 4) and standard drug.
In vitro antifungal activity
All the newly synthesized compounds (3 and 4) were also tested in vitro for their antifungal activity against two fungi, namely Aspergillus niger and Aspergillus flavus. Standard antibiotic fluconazole was used for comparison with antifungal activity shown by compounds 3a-g and 4a-g. A careful analysis of percentage mycelial growth inhibition revealed that compounds 3a, 3b, 3c and 3d exhibit good antifungal activity against both A. flavus and A. niger. Out of compounds 4a-g, compounds 4a, 4b, 4c and 4f showed excellent activity against both antifungal strains as shown in Table 3 and Figure 3. It indicates that fused triazoles 4a-g containing electron-releasing substituents (4a, 4b and 4c) at para position of aryl ring of pyrazole moiety are more antifungal than triazoles having electron-withdrawing groups (4d, 4e, 4f and 4g) at the same position.
Table 3
In vitro antifungal activity of compounds 3 and 4
Compounds
Mycelial growth of inhibition (%)
Aspergillus niger
Aspergillus flavus
3a
52.5
51.1
3b
51.1
50.6
3c
52.5
51.1
3d
50.0
49.8
3e
44.4
45.5
3f
45.5
44.4
3g
47.7
45.5
4a
66.5
58.8
4b
62.3
62.5
4c
60.5
60.6
4d
52.5
51.1
4e
48.8
50.0
4f
69.5
68.5
4g
51.1
50.0
Fluconazole
81.1
77.7
Figure 3
Comparison of antifungal activity of compounds (3 and 4) and standard drug.
A careful analysis of MIC data revealed some interesting results ( Table 2) which are as follows
(i)
Compounds 3a-g have shown marginal activity, but after oxidative cyclization of these compounds, it was found that antibacterial activity has been increased.
(ii)
Inhibitory data of compounds 4a-g suggested that the replacement of para proton of aryl ring of pyrazole moiety (at 3-position) in 3-(3-aryl-1-phenyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridines (4a-g) with electron-releasing groups the antibacterial activity increases while replacing the same aryl proton with electron-withdrawing group the antibacterial activity decreases. In compound 4b, the proton at para position of aryl ring of pyrazole moiety is replaced with methyl group, and in compound 4c, the proton at para position of aryl ring of pyrazole moiety is replaced with methoxy group, both of these compounds exhibited significant level of antibacterial activity. Compounds 4d, 4e, 4f (containing halogen at para position of aryl ring of pyrazole moiety) and 4g (containing nitro group at para position of aryl ring of pyrazole moiety) have shown marginal activities against all four bacteria.
Conclusions
We have described in this study an efficient and convenient synthesis of some new 3-(3-aryl-1-phenyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridines (4a-g)via the oxidative cyclization of hydrazones 3, thereby emphasizing the increasing utility of hypervalent iodine(III)-mediated methods. The antibacterial and antifungal activities of newly synthesized compounds 3 and 4 have proven them potent antibacterial and antifungal agents.
Compounds 3a-3g have shown marginal activity. Inhibitory data of compounds 4a-4g suggested that by the replacement of para proton of aryl ring of pyrazole moiety in 3-(3-aryl-1-phenyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridines (4a-g) with electron-releasing groups the antibacterial activity increased while as the para proton of aryl ring of pyrazole moiety is replaced with electron-withdrawing group, the antibacterial activity decreases.
Triazoles 4 having electron-releasing substituents at para position of aryl ring of pyrazole moiety (4a, 4b and 4c) are more antifungal than triazoles containing electron-withdrawing groups (4a, 4e, 4f and 4g) at the same position.
Experimental
Melting points were taken on slides in an electrical apparatus Labindia visual melting range apparatus and are uncorrected. The IR spectra were obtained with a Buck Scientific IR M-500 spectrophotometer. The 1H NMR spectra were recorded on a Bruker (300 MHz) spectrometer using tetramethylsilane as an internal standard. All the compounds gave satisfactory analytical results (within 0.4% of the theoretical values). The starting material 4-formylpyrazoles 2 were prepared by the literature method [32].
General procedure: To the ethanolic solution of 2-pyridylhydrazine (1, 0.01 mol) was added appropriate 4-formylpyrazole (2, 0.01 mol), and the solution was refluxed for 4-5 min. The solvent was evaporated in vacuo to half its volume and cooled to room temperature. The solid obtained was filtered and washed with ethanol.
Yield 92%, Mp 234°C, IR (νmax, in KBr): 3195 cm-1 (-NH str.) 1335, 1504 (-NO2); 1H NMR (DMSO-d6 , 300 MHz): δ 6.72-6.76 (m, 1H), 7.12-7.15 (m, 1H), 7.38-7.42 (m, 1H), 7.54-7.63 (m, 3H), 8.00-8.03 (m, 2H, J = 9 Hz), 8.08-8.11 (m, 3H), 8.20 (s, 1H, N=CH), 8.36-8.39 (d, 2H, J = 9 Hz), 9.01 (s, 1H), 10.76 (bs, 1H, exchangeable with D2O); Anal. Calculated for C21H16N6O2: C 65.62, H 4.20, N 21.86; Found: C 65.64, H 4.26, N 21.85; ESI-MS m/z: 267.06 [M + 1]+.
Synthesis of 3-(3-aryl-1-phenyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridines (4)
General procedure: To a suspension/solution of 3 (0.010 mol) in dichloromethane (25 mL), IBD (0.011 mol) was added in small portions, and the reaction mixture was stirred overnight. Then, the solvent was evaporated on water bath. To the resulting residue was added ethanol (5-10 mL), and the mixture was warmed to obtain a clear solution. On cooling at room temperature, solid separated out was filtered and washed with cold alcohol to give pure fused 1,2,4-triazole derivatives 4a-g.
Yield 89%, Mp 242°C, IR (νmax, KBr): transparent in the region of -NH str.; 1H NMR (DMSO-d6 , 300 MHz): δ 6.82-6.86 (m, 1H), 7.34-7.41 (m, 1H), 7.44-7.46 (m, 1H), 7.55-7.60 (m, 3H), 7.83-7.87 (m, 3H), 7.92-7.94 (d, 2H, J = 6 Hz), 8.14-8.17 (d, 2H, J = 9 Hz), 8.71 (s, 1H); Anal. Calculated for C21H14N6O2: C 65.96, H 3.69, N 21.98; Found: C 65.97, H 3.67, N 21.94; ESI-MS m/z: 383.10 [M + 1]+.
Biological assay
Test microorganisms
Total six microbial strains were selected on the basis of their clinical importance in causing diseases in humans. Two Gram-positive bacteria (Staphylococcus aureus MTCC 96 and Bacillus subtilis MTCC 121); two Gram-negative bacteria (Escherichia coli MTCC 1652 and Pseudomonas aeruginosa MTCC 741) and two fungi, Aspergillus niger and A. flavus, the ear pathogens isolated from the patients of Kurukshetra, were used in the present study for the evaluation of antimicrobial activity of the compounds [33]. All the cultures were procured from Microbial Type Culture Collection (MTCC), IMTECH, Chandigarh. The bacteria were subcultured on nutrient agar, whereas fungi on Sabouraud dextrose.
In vitro antibacterial activity
The antibacterial activity of chemical compounds was evaluated by the agar well diffusion method. All the cultures were adjusted to 0.5 McFarland standards, which is visually comparable to a microbial suspension of approximately 1.5 × 108 cfu/mL. 20 mL of Mueller Hinton agar medium was poured into each Petri plate, and the agar plates were swabbed with 100 μL inocula of each test bacterium and kept for 15 min for adsorption. Using sterile cork borer of 8 mm diameter, wells were bored into the seeded agar plates, and these were loaded with a 100 μL volume with concentration of 2.0 mg/mL of each compound reconstituted in the dimethylsulphoxide (DMSO). All the plates were incubated at 37°C for 24 h. Antibacterial activity of each compound was evaluated by measuring the zone of growth inhibition against the test organisms with zone reader (Hi Antibiotic zone scale). The DMSO was used as a negative control, whereas ciprofloxacin was used as a positive control. This procedure was performed in three replicate plates for each organism [34].
Determination of minimum inhibitory concentration (MIC)
The MIC is the lowest concentration of an antimicrobial compound that will inhibit the visible growth of a microorganism after overnight incubation. The MIC of all the synthesized compounds (3 and 4) against bacterial strains was tested through a modified agar well-diffusion method [35]. In this method, a twofold serial dilution of each compound was prepared by first reconstituting the compound in DMSO followed by dilution in sterile, distilled water to achieve a decreasing concentration range of 256-0.5 μg/mL. A 100 μL volume of each dilution was introduced into wells (in triplicate) in the agar plates already seeded with 100 μL of standardized inoculum (106 cfu/mL) of the test microbial strain. All test plates were incubated aerobically at 37°C for 24 h and observed for the inhibition zones. The MIC, taken as the lowest concentration of the chemical compound that completely inhibited the growth of the microbe, showed by a clear zone of inhibition, was recorded for each test organism. Ciprofloxacin was used as positive control while DMSO as negative control.
In vitro antifungal activity
The antifungal activity of the newly synthesized compounds was evaluated by poison food technique. The moulds were grown on Sabouraud dextrose agar (SDA) at 25°C for 7 days and used as inocula. 15 mL of molten SDA (45°C) was poisoned by the addition of 100 μL volume of each compound having concentration of 4.0 mg/mL, reconstituted in the DMSO, poured into a sterile Petri plate and allowed to solidify at room temperature. The solidified poisoned agar plates were inoculated at the centre with fungal plugs (8 mm diameter), obtained from the actively growing colony and incubated at 25°C for 7 days. The DMSO was used as the negative control, whereas fluconazole was used as the positive control. The experiments were performed in triplicates. Diameter of the fungal colonies was measured and expressed as percent mycelial inhibition determined by applying the following formula [36]:
dc, average diameter of fungal colony in negative control plates; dt average diameter of fungal colony in experimental plates.
Abbreviations
DMSO:
dimethylsulphoxide
IBD:
iodobenzene diacetate
MIC:
minimum inhibitory concentration
MTCC:
microbial type culture collection
SDA:
sabouraud dextrose agar.
Declarations
Acknowledgements
The authors are thankful to the CSIR and the UGC, New Delhi for the award of Junior Research Fellowship to Khalid Hussain and Deepak K. Aneja. Thanks are also due to the RSIC, CDRI Lucknow, India, for providing mass and elemental analyses.
Authors’ Affiliations
(1)
Institute of Pharmaceutical Sciences, Kurukshetra University
(2)
Department of Chemistry, Kurukshetra University
(3)
Department of Microbiology, Kurukshetra University
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