Design, Synthesis, Chemistry and Biological Evaluation of Some Polyfunctional Heterocyclic Nitrogen Systems—Overview

The synthesis, preparation, chemical reactivities and biological activity of simple heterocyclic and heteropolycyclic nitrogen systems as small units as functional pyrazoles, pyridine and pyrimidine, and the related fused systems are reviewed. Among the various possible routes to the formation, isomeric structures have been cited because of patented reaching advanced phases of clinical trials, from 2000 to 2020.


Synthesis and Chemical Reactivities of a Polyfunctional Pyrazole [Edaravone Drug] as Base Unties
Edaravone drug and their analogs synthesized from the fusion of arylhydrazine with ethyl acetoacetate (Scheme 1) [11] [12].
Also, the interaction between compounds 4 and 5 with primary aromatic amines in refluxing DMF afforded N-aryl-N-pyrazolopyrimidine amines 10 and 11 respectively (Scheme 4), while when using piperazine as the secondary amine in boiling EtOH, produced N, N-di hetero arylpiperazines 12 and 13 respectively (Scheme 5) [4].
All the compounds obtained evaluated as antifungal agents, where the activity International Journal of Organic Chemistry   in the order 12 > 10a > 10b > 4 > 6 > 8. Only compound 12 exhibits a highly affect a cellobiose activity produced by Aspergillus Nodulins Fungi at 1000 and 100 µg/ml as biodynamic agent [15]. The hydrazino-groups when bonded to heterocyclic nitrogen systems, improve that possible activity to formation various heteropolycyclic systems characterized with biological, pharmacological and medicinal properties [16] [17] [18]. Thus, hydrazinolysis of compound 5 by refluxing with hydrazine hydrate in EtOH, yielded the corresponding hydrazine derivative 14 [19]. Ring closure On the other hand, the interaction between compound 5 with dithioic formic acid hydrazide in refluxing DMF led to the direct formation of compound 17 (Scheme 8) [20].
It is known that hydrazo and azo aromatic compounds exhibit an important in dust rate ant attention due to its application in the industrial chemistry and agriculture fields [21] [22]. Thus, the interaction between compound 5 and 14 (1:1 by moles) in refluxing isopropyl alcohol, the hydrazo-compound 21, which upon simple oxidation by warming with sulfur-in dry C 6 H 6 , yielded the azo-compound 22 (Scheme 9) [20].
It is an interest that interaction between compound 25 as polynuclophilic agents with π-e acceptors bearing a carbon triple group as unsaturated carbonitriles (A) and/or (B) in polar solvent as EtOH/piperidine as catalyst led to the direct formation of polyfunctional hetero polycyclic systems 28 and 29 respectively (Scheme 12) [23].
Recently, reported that [25]- [30], the introduction of fluorine atoms to heterocyclic nitrogen systems often improves then physical, chemical and biological properties
All the obtained compounds evaluated as antimicrobial agents (some Bacteria and fungi); were the compounds exhibit good to moderate activities in the order of 54, 47, 45 as bactericidal and the compounds 46, 50, 58 exhibit a fungicidal activity [33].  [44], and uses to obtaining various fused polyheterocyclic nitrogen systems 69 -73 as antimicrobial agents (Schemes 28-30) [44]. All the compounds obtained evaluated as antimicrobial agents, were the highly active compounds in the order 73 > 72 towards Bacillus bacterial S.L towards candida a. (fungi strain) [44].
The formation of compound 67 may be as shown in Figure 3.
Also, the chemistry of compound 83 was studied by treatment with polyfunctional reagents, because of their biological evaluation (Scheme 36 and Scheme 37) [66].

Attitudes of the Next New Work
Based upon these observations, the next work tends to synthesize some more new fused heteropolycyclic nitrogen systems containing polyfunctional groups because of their biocidal effects.