A Mini-Review 5-Amino-N-Substituted Pyrazoles as Building Blocks for Bioactive Molecules

In this review a five-membered heterocyclic ring having two adjacent nitrogen atoms known as Pyrazole, we have framed 5-amino-N-substituted pyrazoles in particular focusing on its substantial role as a building block and starting materials for producing enormous heterocyclic skeletons. The exis-tence of this moiety in larger compounds renders them to expose medicinal, pharmacological and biological therapeutic activities. Enormous drugs con-tain 5-amino-N-substituted pyrazoles such as celecoxib anti-inflammatory, antipsychotic, anti-obesity, analgesic, and antidepressant. We reported various routes of synthesis and the use of these compounds.

pyrazole derivatives and highlights their behavior toward electrophilic and nucleophilic reagents, to which their highly active biological and pharmaceutical characteristics are due.

Behaviour of 5-Amino-1-Substituted Pyrazoles towards Electrophilic and Nucleophilic Reagents
Treatment of most 5-amino-1-substituted pyrazoles with electrophilic or nucleophilic reagents led to direct formation of imidazole pyrazoles, which are candidates for considerably highly bioactive systems.
Similarly, the cyclocondensation between aromatic aldehyde, 5-aminopyrazole 11 and isocyanide in acetonitrile with 4-toluene sulfonic acid as a catalyst at conditions and eco-friendly general procedures as shown in Scheme 17 [25].
Around 24 examples of spiro-heterocyclic compounds were synthesised following this simple one-pot protocol, as illustrated in Scheme 18.
In a related synthesis of spiro-heterocyclic compounds which seems to be an improvement over the earlier procedure and is more region-selective, MCRs Scheme 12. Cycloaddition reactions of compound 23 [20].   [26].
The structure-activity relationship (SAR) of amino-pyrazoles 54 as shown in Figure 1 has been approved as showing effective inhibition of p38a MAP kinase with very good cellular potency, which makes it an effective drug candidate for control of inflammatory disorders [27]. The use of 5-amino-pyrazole moiety led to the synthesis of designed scaffolds which produced potent selective p38α inhibiting drugs. The traditional procedure was used to prepare 5-amino-pyrazoles through condensation reaction of hydrazine 55 along with ethyl (ethoxymethylene) cyanoacetate 2 in ethyl alcohol in the presence of a base such as trimethylamine (Scheme 20). Hydrolysis to carboxylic acid before coupling with aniline using either HATU coupling or converting the acid carboxylic group to acid chloride and thereafter coupling it with aniline derivative 58 afforded good yields of the target compound 59 [27].
In addition, 5-amino-pyrazo derivatives were used in the synthesis of pyrazolo [3,4-d]pyrimidines in 244 examples [30]. Condensation of 5-heterylaminopyrazoles 64 with some carbonyl compounds in the presence of AcOH or Me3SiCl successfully produced pyrazolo [3,4-d]dihydropyrimidines 65 in good yields (Scheme 22). The best proposed mechanism explaining that reaction includes two steps: first, the reaction of 5-aminopyrazoles 62 with 2-halogenazines or azoles 63 in NaH/THF conditions, followed by ring closure with carbonyl compounds in Me3SiCl or AcOH medium.

Importance and Applications
Since the 1960s, the pyrazole moiety has been known to exhibit anticancer activity;  Scheme 21. One-pot diazotization reaction carried out on 5-amino-1H-pyrazole-4carbonitriles 60 to synthesize pyrazolo [3,4-d] [1,2,3]triazin-4-ones 61 [28].  it has also been shown to be an antitumor agent in Phase I studies. However, it was confirmed to be too toxic for human use, even in doses as low as 0.15 mmol/kg/day [31]. Researchers are keen to harness the powerful anticancer activity of pyrazoles without the toxic side effects, and synthesis of a variety of pyrazole derivatives are key to this pursuit [32]. Various derivatives have been tested, among them 1-thiocarbamoylpyrazole, 1-carboxamidopyrazole, which failed to show non-toxicity to humans, although it showed a remarkable anticancer clinical effect [33]. Compounds such as 5-amino-1-cyanoacetyl-3-(p-chlorophenyl)-pyrazole have been tested toward three human tumour cell lines: breast adenocarcinoma (MCF-7), non-small cell lung cancer (NCI-H460), and CNS cancer (SF-268), and it has shown potent inhibition in growth of human tumour cell lines as well [34]. Pyrazole nucleosides and condensed pyrazole nucleosides possess various biological activities which make them powerful drug candidates, and these have been tested toward various diseases caused by DNA viruses [35].

Conclusion
In summary, various routes exist for synthesis of 5-amino-N-substituted pyrazoles, which exhibit important chemical behavior towards electrophilic and nucleophilic reagents. Their tendency toward heterocyclisation reactions leads to the direct formation of imidazopyrazoles, which exhibit a variety of significant biological activities. The usefulness of 5-amino-N-substituted pyrazole molecules in the effort to obtain new heterocyclic compounds that have more accessible biocidal effects and enhancements is governed by substituent position and type.

Conflicts of Interest
The author declares no conflicts of interest regarding the publication of this paper.