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In present chapter we have reported green and highly efficient method for synthesize novel series of substituted -1H-indazol-3-amine derivative (3a-h) by cyclocondensation reaction of substituted benzonitrile (1a-h) and substituted Hydrazine (2a-h) using ceric (IV) ammonium nitrate (CAN) as a catalyst, EtOH-H2O as a ecofriendly media and reaction was carried out under ultrasound irradiation green method. The structures of newly synthesized indazole derivative (3a-h) were corroborated through spectral investigation such as elemental analysis and spectral studies like IR, C13 NMR, Mass spectra and 1H NMR. The compounds were assessed for their in-vitro antimicrobial activity with pathogenic microbe comprising Gram positive bacterial strains, S. aureus and Gram negative strains E.coli, P.vulgaris, and S. typhi at different concentration. The consequence of bioassay is compared with standard drug Chloramphenicol.
Indraraj Arts, Commerce and Science College, India
Satish Kola
M.G. Arts, Science and Late N.P Commerce College, India
Mohammad Idrees
Department of Chemistry, Institute of Science, India
Naqui J. Siddiqui
Department of Chemistry, Institute of Science, India
Roshan D. Nasare
Department of Chemistry Govt. Science College, India
*Address all correspondence to: cgdevkate@gmail.com
1. Introduction
Indazole was first defined as a “pyrazole ring fused with the benzene ring” by the scientist Emil Fisher. It is broadly studied due to its remarkable chemical and biological properties. Indazole is from the azoles family containing carbon, hydrogen and nitrogen atoms. Indazole also called as benzpyrazole or isoindazolone which containing two nitrogen atoms. It is ten π-electron aromatic heterocyclic systems as a pyrazole molecule. The structure of indazole is given below in cylindrical bonds is as (Figure 1).
Figure 1.
Naturally accruing indazole nucleus.
Indazole derivatives are pharmacologically significant as they form the fundamental structure of numerous drug molecules, like Benzydamine used as anti-inflammatory agent and Granisetron, 5HT3 receptor antagonist for anti-emetic in cancer chemotherapy. Two nitrogen atoms in indazole can be able to be functionalized with high selectivity at different positions. Indazole show a range of biological activity such as anti-HIV, anti-cancer, anti-platelet, anti-inflammatory, serotonin 5-HT3 receptor antagonist and anti-tumouractivities [1, 2, 3, 4, 5, 6]. 3-Aminoindazoles which are valuable templates for medicinal chemistry. The scaffold is found in a huge number of compounds exhibiting a large number of biological activities including kinase inhibitors, HIV protease inhibitors, MCH receptor1 antagonists, CB1 receptor inhibitors and factor XIa inhibitors [7, 8, 9]. The 3-aminoindazoles have been able to mimic the adenine nucleus of ATP for the design of ATP-competitive receptor tyrosine kinase inhibitors with potent antitumor activities. Thus it is been potential valuable templates for pharmaceutical chemistry, hence effort has recently been taken to the synthesis of substituted indazole. Several method have been published for the synthesis of 3-aminoindazole the methods have several drawback is the use of costly reagents and catalyst, organic solvents, harsh conditions and thus have limited scope [10, 11, 12, 13]. In last few decades Chemist have attraction for Nitrogen containing heterocycle which possess potential antimicrobial property [14, 15, 16]. Indazole can be present in two forms which result from the displacement of proton among two nitrogen atoms, a method describe as proto tropic annular tautomerism. Without substituted indazole be present mostly as the 1H-tautomer based on the results from molecular studies.
The indazole ring contains two nitrogen atoms and thus annular tautomerism with concern to the location of the NH hydrogen atom. The variation in energy among tautomer’s the benzenoid type predominates in the gas phase solution. Solid state derivatives are generally found thermodynamically more constant than the analogous 2H forms, annular tautomerism of indazole benzenoid 1H-indazole tautomer and quinonoid 2H-indazole tautomer. Ortho-hydrazine benzoic acid on heating results in the formation of indazolone reported by Emil Fisher in 1800 (Figure 2) [17, 18, 19, 20].
Figure 2.
Naturally accruing indazole nucleus.
Biological importance of 3-aminoindazole Derivatives:- Indazoles are naturally occurring alkaloids like Nigellidine, Nigellicine and Nigeglanine. Nigellicinewas isolated from extensively spread plant Nigella sativa. Nigeglaninewas isolated from extracts of Nigella glandulifera. Merely few of the alkaloids studied upon isolation show the presence of indazole ring system. The first member of this alkaloid family Nigellicine [21] which is isolated in 1985 from the plant N. sativa an annual flowering plant, native to Southwest Asia. The seeds of this plant are used for thousands of years as a spice and for the treatment of a variety of diseases [22, 23, 24]. The structure of nigellicine has an intramolecular hydrogen bond among the carboxylate oxygen atom and the hydroxyl group. The structure of nigellicine is a pseudo cross conjugated heterocyclic mesomericbetaine, which means that it be able to be presented by dipolar canonical formula where both the positive and negative charge is delocalized in the structure [25].
Similarly other two alkaloids (Figure 3) Nigeglanine and Nigellidine are isolated from extracts of N. glandulifera and N. sativa. These two compounds be able to also be obtainable by their zwitterions formulae [26]. Indazole core is present in naturally occurring alkaloids and biologically active molecules. Nigellidine is a natural product containing an indazole nucleus, isolated from plant N. sativa and used in the treatment of a variety of diseases. Indazole and their derivatives are found to have a large range of activities. Previous findings on indazole derivatives are purposely known to be active as protein kinase inhibitors, cancer cell proliferative disorders, the methods 3-aminoindazole have several drawback is the use of costly reagents and catalyst, organic solvents, harsh conditions and thus have limited scope [27, 28].
Figure 3.
Naturally accruing indazole nucleus.
Stimulated from these observation and literature exploration revealed that no green and efficient, method is reported yet hence in the present work we are endeavored to synthesize 3-aminoindazole by using ultrasonic radiation and ceric ammonium nitrate (CAN) [Ce IV(NO3)6]2 as a catalyze reactions in organic synthesis because of many advantages such as good solubility in water, easily available, non-toxicity, simple work-up procedure, low cost, high reactivity and synthesized substituted-1H-indazol-3-amine derivative (3a-h) and screened for their antimicrobial activity [29, 30, 31, 32, 33, 34].
Chemicals used for the synthesis were of AR grade of Merck, S.D. Fine and Aldrich. The reactions were examined by E. Merck TLC aluminum sheet silica gel60F254 and visualizing the spot in UV Cabinet and iodine chamber. The melting points were note down in open capillary in paraffin bath and are uncorrected. 1H NMR spectra are logged on a Bruker AM 400 instrument (400 MHz) using tetramethylsilane (TMS) as an internal reference and DMSO-d6 as solvent. Chemical Shifts are specified in parts per million (ppm). Positive-ion Electro Spray Ionization (ESI) mass spectra were acquired with a Waters Micromass Q–TOF Micro, Mass Spectrophotometer. IR spectra were recorded on a Shimadzu IR Spectrophotometer (KBr, υmax in cm−1). The compounds are purified by using column chromatography on silica gel (60–120 mesh). Elemental (CHN) examination was done using Thermo Scientific (Flash-2000), the compounds were investigated for carbon, hydrogen and nitrogen and the results found are in good agreement with the calculated values.
The optimization of the reaction is done using different solvents and also solvent free condition was applied and the reaction carried out under ultrasound irradiation. When the reaction was performed without solvent the yield obtained was in trace amount. When different solvent like acetonitrile, toluene and ethanol it the yield was less and the time taken for completion of reaction was more. But using (CAN) (10 mol %) EtOH-H2O (2:2) (entry 9) at 50–60°C for 35 min. we got good yield in less time and thus the reaction was optimized. The results were summarized in (Table 1).
Entry
CAN mol (%)
Solvent
Time (min)
Yield (%)
1
—
—
80
5
2
5
MeCN
60
40
3
10
MeCN
60
58
4
5
Toluene
70
53
5
10
Toluene
70
60
6
5
EtOH
60
68
7
10
EtOH
60
76
8
5
EtOH-H2O (2:2)
35
80
9
10
EtOH-H2O (2:2)
35
93
10
15
EtOH-H2O (2:2)
35
86
Table 1.
Optimizing of the reaction conditions for 5-bromo-1-methyl-1H-indazol-3-amine (3c).
General Procedure for the synthesis 3-aminoindazole (3a-h):- A mixture of benzonitrile (1a-h) (1.0 mmol), hydrazine (2a-h) (1.2 mmol) and (CAN) (10 mol) in solvent EtOH-H2O (2:2) were taken in single neck round bottom flask and the flask containing reaction mixture was kept in the ultrasonic bath and was irradiated at 50-60°C for about 30–40 min. (the progress of reaction was monitored by TLC at different interval) separately as indicated in (Table 2). After the reaction was completed the reaction mass was poured on crushed ice. The obtained solid was filtered, washed with water and dried. The crude compound was crystallized using DMF-Ethanol. Their structure was confirmed by 1H NMR, physical data, mass, IR and elemental analysis.
Table 2.
CAN catalyze synthesis of 3-aminoindazole under ultrasound irradiation (3a-3 h).
Elemental Anal.Calcd. For C7H6FN3; calculated: C, 55.63; H, 4.00; N, 27.80 Found: C, 55.67; H, 3.98; N, 27.40.
3.2 Physico-chemical characterization
Benzonitrile (1a-h) is reacted with hydrazine (2a-h) in presence of catalyst ceric (IV) ammonium nitrate (CAN) in solvent EtOH-H2O by using ultrasonic irradiation which undergoes cyclocondensation reaction to give substituted 3-aminoindazole (3a-h). The physical constants like melting point and solubility were determined for all the intermediate and final products. At every stage the reaction is monitored with TLC. Newly synthesized compound have been characterized on the basis of spectral data and elemental analysis such as FT-IR, 1H NMR, 13CNMR and mass spectra and they also screened for antimicrobial activities.
The IR spectrum of 3c showed strong band absorption bands at 3424 cm−1 due to -NH- stretch in amine while bands at 1541 cm−1 is observed due to C=N stretch in Indazolyl and absorption band at 556 cm−1 showsC-Br aromatic stretching and stretch at 1344 cm−1 was observed for C-N str group confirms the cyclisation to form 5-bromo-1-methyl-1H-indazol-3-amine3c.1H NMR of 3c revealed a singlet signal at 3.65 ppm, at aliphatic region owing to three protons of -CH3 group attached to aromatic ring, one more singlet at δ 5.47 ppm confirm protons of –NH2- group, Remaining 1H NMR signal is present at aromatic region as expected. C13 NMR also supported data singlet signal at δ34.55, ppm revealed one aliphatic carbon, of -CH3 attached to indazole ring. ESI-MS Mass spectra also confirm the molecular ion at (m/z) value at 225[M + 1]+, and further supported by elemental analysis data found to be in good agreement with the molecular formula of C8H8BrN3.
Potent antibacterial/inhibition profile of 3-amino indazole (at different concentration) by agar disc-diffusion method: - The entire novel synthesized heterocyclic compounds 3a-h was screened for their in-vitro antimicrobial activity using disc-diffusion method. Their activity was compared with well-known commercial antibiotic Chloramphenicol. Antibacterial activity was determined by using Mueller Hinton Agar obtained from Hi media Ltd., Mumbai. Petri plates were prepared by pouring 10 mL of Mueller Hinton Agar for bacteria containing microbial culture was allowed to solidify. Test solutions were prepared with known weight of compound in DMSO and half diluted suitably to give the resultant concentration of 31-1000 μg/mL. Whatmann no.1 sterile filter paper discs (6 mm) were impregnated with solution and allowed to dry at room temperature. The discs were then applied and the plates were incubated at 37°C for 24 h (bacteria) and the inhibition zone (Figure 6) was measured as diameter in four directions and expressed as mean. The results of the antimicrobial screening are illustrated in the Tables 3 and 4. From the results it is clear that the compounds tested showed variable toxicity against different bacteria.
Zone of Inhibition (mm)
Compd. Code
Gram + ve Gram –ve
S. aureus
P.vulgaris
Conc. (μg/mL)
Conc. (μg/mL)
1000
500
250
125
63.5
31
1000
500
250
125
63.5
31
3a
21
22
21
20
17
13
27
24
21
18
17
10
3b
23
21
20
18
16
18
25
22
19
16
14
09
3c
25
21
19
20
16
15
28
23
21
17
15
11
3d
23
22
21
19
18
15
27
24
20
18
17
12
3e
19
20
16
15
13
14
21
19
15
14
13
09
3f
24
23
21
20
17
16
25
23
21
19
15
08
3 g
23
20
18
17
16
13
23
22
21
16
14
10
3 h
20
18
16
15
13
11
26
21
17
15
12
09
DMSO
—
—
—
—
—
—
—
—
—
—
—
—
Std. Drug Chloramphenicol
25
22
20
19
17
15
26
24
23
21
17
15
Table 3.
Antibacterial profile of 3-aminoindazole derivative (3a-h) .
Zone of Inhibition (mm)
Compd. Code
Gram –ve
E. coli
S.typhi
Conc. (μg/mL)
Conc. (μg/mL)
1000
500
250
125
63.5
31
1000
500
250
125
63.5
31
3a
26
24
22
21
16
12
16
15
12
11
10
09
3b
24
21
19
18
17
16
16
14
10
09
06
07
3c
25
24
20
17
16
15
17
16
11
10
09
08
3d
26
23
21
20
17
11
14
10
08
08
07
09
3e
23
22
20
18
14
12
16
14
12
11
09
07
3f
25
24
22
20
18
15
17
16
11
10
09
08
3 g
21
20
17
16
14
11
15
13
11
10
08
07
3 h
22
21
20
18
16
13
14
12
10
08
06
05
DMSO
—
—
—
—
—
—
—
—
—
—
—
—
Std. Drug Chloramphenicol
26
24
23
21
17
14
17
15
12
11
09
08
Table 4.
Antibacterial profile of 3-aminoindazole derivative (3a-h).
3.3 Mechanism of inhibition/prohibition
Gram-negative bacteria habitually owe low susceptibility as outer membrane of their cell wall not gets blocked/penetrated by drugs easily and factors like amount of peptidoglycan, receptors, and lipids availability, nature of cross-linking, autolytic enzymes activity greatly influence the bio-activity, permeation, and incorporation of the antibacterial drugs. There are three behaviors in which antibacterial drugs have thus far beenshown to exert their definite actions upon bacteria: 1) by interfering with the synthesis of the relatively rigid cell wall which Maintains the structural integrity of the bacterial cell (2) by destructivethe elusive membrane, which encompasses the bacterial cytoplasm and assists as an essential osmotic barricade to the free diffusion of severalmetabolites and (3) by blocking cytoplasmic metabolic reactions which are involved in critical synthetic processes within the cell. Consequences of bioassay indicated that compound (Figure 4 and 5) 3a, 3c, 3d, 3f showed excellent activity against S. aureus and P.vulgaris and E.coli. Remaining compounds exhibited reasonable activity against selected bacterial strains.
Figure 4.
Antimicrobial activity of compound 3a-h against Gram - bacteria S. aureus and P. vulgaris.
Figure 5.
Antimicrobial activity of compound 3a-h against Gram - bacteria E. coli and S. typhi.
In summary, in the present chapter we have described an efficient simple and reproducible method afforded various amino indazole derivatives (3a-h) in excellent yields, and without formation of undesirable side products. The synthetic protocol has been outlined in general reaction. At every stage the reaction was monitored with TLC. The physical constants like melting point and solubility were determined for all the intermediate and final products. Newly synthesized compound has been characterized on the basis of spectral data and elemental analysis such as FT-IR, 1HNMR, 13C NMR and mass spectra this chapter focused on helping futuristic researchers, clinicians, and academicians involved in synthesizing and corresponding biological screening of innate activity of certain novel amino indazole heterocycleswe have described here novel series of Indazole (3a-h) derivative. The presented series of compounds were synthesized in decent yields. The structure and purity of newly synthesized compounds were established by spectroscopic investigation and chemical examination. Antibacterial screening of synthesized substituted indazole (3a-h) derivatives exhibited a potent bactericidal. Thus, it could be powerfully stimulates major advances in remarkable significant chemotherapeutics in medicine, biology and pharmacy. Overall these indazole disturb macromolecules like cytoplasmic membrane covering cytoplasm which acts selective barrier to control internal composition of cell. Amino indazole derivative particularly interrupted such functional roles of cytoplasmic membrane and ionic outflow that resulted cell destruction/death. Synthesized potent bioactive substituted indazole derivatives may open new possibilities in the successful treatment of several diseases due to promising antibacterial profile. So, ample scope exists in further research of this heterocycle especially innate selectivity of these compounds needs to carry out their chemotherapy as potent antibacterial aims to target cell membrane of range of Gram-negative bacteria as to derive novel drugs ofInventive era. Among the synthesized compounds most of the compounds exhibited good to moderate activity against selected strains S. aureus, P. vulgaris and E. coli while poor activity was evaluated for S. typhi (Figure 5). This variation in toxicity it may attribute due to union ofdifferent substituent attached to the core 3-aminoindazole which may enhances the biological activities of parent nucleus.
The authors are gratified to, The Director, SAIF, Punjab University, and Chandigarh for providing, FTIR, CHN analysis, 1HNMR, Mass Spectra, 13C NMR. Authors are also thankful the Principal, Government Science College, Gadchiroli, for his support and cooperation and also pleased to Dr. Syed Abrar Ahmed and Dr. Mandar Paingankar, for there key assistance.
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Written By
Chandrashekhar Devkate, Satish Kola, Mohammad Idrees, Naqui J. Siddiqui and Roshan D. Nasare
Submitted: 11 September 2020Reviewed: 21 December 2020Published: 12 May 2021
Open access peer-reviewed chapter
