**Abstract**

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 <sup>1</sup> H 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.

**Keywords:** indazol, ceric (IV) ammonium nitrate catalyst, ultrasound irradiation, ecofriendly media, antimicrobial screening

#### **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**).

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 [1–6]. 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

**Figure 1.** *Naturally accruing indazole nucleus.*

receptor1 antagonists, CB1 receptor inhibitors and factor XIa inhibitors [7–9]. 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 [10–13]. In last few decades Chemist have attraction for Nitrogen containing heterocycle which possess potential antimicrobial property [14–16]. 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**) [17–20].

**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 [22–24]. 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].

disorders, the methods 3-aminoindazole have several drawback is the use of costly reagents and catalyst, organic solvents, harsh conditions and thus have limited

*Eco-Friendly, Green Approach for Synthesis of Bio-Active Novel 3-Aminoindazole Derivatives*

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 antimi-

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

scope [27, 28].

**Figure 3.**

**77**

**Figure 2.**

*Naturally accruing indazole nucleus.*

*DOI: http://dx.doi.org/10.5772/intechopen.95565*

*Naturally accruing indazole nucleus.*

crobial activity [29–34].

**2. Material and methods**

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

*Eco-Friendly, Green Approach for Synthesis of Bio-Active Novel 3-Aminoindazole Derivatives DOI: http://dx.doi.org/10.5772/intechopen.95565*

**Figure 2.** *Naturally accruing indazole nucleus.*

receptor1 antagonists, CB1 receptor inhibitors and factor XIa inhibitors [7–9]. 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 [10–13]. In last few decades Chemist have attraction for Nitrogen containing heterocycle which possess potential antimicrobial property [14–16]. 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

**Biological importance of 3-aminoindazole Derivatives:-** Indazoles are natu-

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 [22–24]. 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

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

rally occurring alkaloids like Nigellidine, Nigellicine and Nigeglanine.

negative charge is delocalized in the structure [25].

(**Figure 2**) [17–20].

**76**

**Figure 1.**

*Naturally accruing indazole nucleus.*

*Green Computing Technologies and Computing Industry in 2021*

**Figure 3.** *Naturally accruing indazole nucleus.*

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].

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 [29–34].
