Synthetic of Some New Fluorine Compounds Bearing 1,2,4-Triazine Moieties and the Related Hetero-Polycyclic Nitrogen Systems as Pharmacological Probes-Overview

This overview summarizes recent advanced literature surveys on the synthesis of fluorine substituted 1,2,4-triazine containing various functional groups and/or the related hetero-polycyclic nitrogen systems have been reported. In addition, physical, chemical, and medicinal properties have been evaluated. The presence of fluorinated atoms often improves these properties with an increasing electronegativity. It, also, enhances the stability of formed carbanion and it improves the hydrophobic effects which have good biological activities. Graph Abstract Some important anti-HIV-1 and anticancer agent N N N NHR F


Graph Abstract
Some important anti-HIV-1 and anticancer agent
Most of the studies addressing synthesis and chemistry of fluorinated hetero-cyclic have been related to drug discovery research [9] [10]. It is interesting that replacing hydrogen and other functional groups with fluorine atoms can have a dramatic effect on the modulation of electronic, lipophilic, and steric parameters, all of which can critically influence both the pharmacodynamic and pharmacokinetic properties of drugs. Based upon these results, the present overview reports an important route of fluorine compounds substituted 1,2,4-triazine with the study of chemical reactivities and evaluation of the effects on the vital biological process.
The possible mechanism for the formation of compound 7 is in shown in Figure 1. Also, the structure of 7 deduced from mass fragmentation pattern is reported Figure 2.
The structure of compound 13 was deduced using the mass fragmentation pattern ( Figure 3) [6].
On other hand, fully fluorinated thiobarbituric acids bearing 1,2,4-triazine moieties 19 obtained from the interaction between compound 3 with 9 in ref-   The CDK2 inhibitory activity of the compounds 3-9 evaluated in comparison with olomoucine as standard according the reported method [14], where the highly inhibitor effects increase in the order 11 > 13 > 16 > 17 > 3. The compound 16 exhibit a good effect toward the tumor cells damage as the olomoucine. Also, the in vitro antitumor testing of the highly active compounds evaluated according the reported method [15] under different concentration. A sulforhodamine B (SRB) protein assay was used to estimate cell viability or growth by determining GI 50 , TGI, and LIC 50 . Compound 11 showed the anticancer activity against non-small cell lung, renal, and breast cancer cell, while compound 13 exhibit anti-cancer of type leukemia and breast cancer cell, compound 16 showed anti-cancer activity against non-small cell lung cancer, finally, compound 17 exhibit anti-cancer of type breast cancer [6].
Formal structure of compound 23 deduced from spectral measurements. Mass spectrometric study were recorded a molecular ion peak that the base peak Figure 4 [16].

Reactivity
The mass fragmentation pattern of compounds 21 and 26 give us a good indication about their stability Figure 5 and Figure        The obtained compounds 21-32 evaluated both in vitro and in vivo of antifungal activity by inhibition of fungal mycelial growth of Alternaria alterata, helimen thosporium sativum and Fusarium moniliform according the reported methods [21] [22] [23], where the compounds 23, 29 and 30 exhibit a high fungal toxicity activity. Prevention of blue mold development indicate the action of these compounds on the decay control on rind discs, were only the compounds 21 and 23 gave a good control at concentration at 500 mg/cm −1 against Alternaria alterata. The best germination (80% -90%) was achieved by treating the seeds with a solution containing 1000 mg/ml of the compound 23 followed by 29 under the same concentration (59% -70% germination) [16]. Similarly, the design, synthesis and molluscicidal activity of new phosphorus compounds bearing fluorine substituted 1,2,4-triazolo [5,1-c] [1,2,4]triazine derivative reported by Abdel-Rahman et al. [24].

Reactivity
Phosphorylation shown in (Figure 8). Also, mass spectroscopy study of compound 44, were shown the molecular ion peak at low % with a base peak at m/z 198 (100%) attributes C 12 H 12 N 3 + as Figure 9 [25].       Figure 10. Compound 48 also obtained [25] directly from refluxing 38 with thiosemicarbazide in acetic acid (Scheme 17). Formation of compound 48 from 38 may be tack's place via the addition reaction between an amino-group of 38 and highly positive Carbone atom of CS 2 followed by hydrazinolysis 47 and finally cyclocondensation via carbonyl group as shown in Figure 10.
The former structure of 64 deduced from the correct elemental analysis and spectral measurements. The mass fragmentation pattern of 64 gives us a good indication about that stability Figure 13       The herbicidal [28] Anti-microbial (Anti-vitiligo) [18]    The introduction of fluorine atoms to 1,2,4-triazine derivatives often enhance and improve those properties, especially the medicinal and pharmacological field [1] [31]- [36]. Recently, the high resistance of microbes towards most drugs and antibiotics, is driving an urgent need for the synthesis of new highly bioactive systems in view of control on these resistant [37] [38] [39]. Thus, all synthesized fluorine compounds 56-69 evaluated as anti-inflammatory agents by using the standard indomethacin drug as standards, according the reported method [30], the activities were ranked as 65 > 56 > 64 > > 58 > 67 > 60. Both the compounds 56 and 65 which contains a fluorine atom and an amino-group at the end of presence systems form a type of bio-conjugated systems. Also, a higher activity of compound 64 may be the formation of type combination between the thiazolidine-4-ones, and fluorine, chlorine bonded the terminal of systems [30].

Conclusion
A series of various fluorine compounds substituted with 1,2,4-triazine moieties have been developed by various routes. The results of these targets were characterized physically, chemically, or both, together with evaluations of the pharmacological activities. The introduction of fluorine atoms to heterocyclic nitrogen systems mostly enhances and improves the physical, chemical, and biological properties. In view of the fluorinated 1,2,4-triazine derivatives obtained, most have potentially beneficial applications for our life to treat various diseases such as anti-inflammatory, antimicrobial, or anti-HIV1 agents, or as cyclin dependent kinase inhibitors for tumor cell damage of DNA moiety. Hopefully, the present overview contributes an explanation of how new fluorine compounds bearing 1,2,4-triazine moieties and the related hetero-polycyclic nitrogen systems are formed and used.