Fatty Acids in Heterocyclic Synthesis : Part XIX Synthesis of Some Isoxazole , Pyrazole , Pyrimidine and Pyridine and Their Surface , Anticancer and Antioxidant Activities

Acryloylphenylstearamide (2) was utilized as a starting material for synthesis the titled compounds via one-pot synthesis. Compound (2) was reacted with hydroxylamine hydrochloride in pyridine and produced isooxazole (3), and with thiosemicarbazide in pyridine and/or hydrazine-hydrate in ethanol afforded pyrazoles (4), and (5), while the reaction of (2) with urea and/ or thiourea in an alcoholic solution of sodium ethoxide gave pyrimidinone (6) and pyrimidinedione (7). Also, reaction of (2) with acetylacetone and/or ethyl acetoacetate in acetic acid andammonium acetateafforded Pyridine derivatives (8), and (9) respectively. Addition of different amounts of propylene oxide (3, 5, 7 moles) to the synthesized compounds produced nonionic surfactants (2-9a-c). The physiochemical and surface active properties of the prepared surfactant as surface and interfacial tension, cloud point, wetting time, emulsion stability, foam height, CMC, resistance to hydrolysis and their biodegradability were investigated. Also, the surface parameters as effectiveness (πCMC), efficiency (PC20), maximum surface excess (Γmax) and (Amin) were evaluated.


Introduction
The anticancer activity of the synthesized compounds were reported, and it was found that pyrazoles 4 and 5 are highlyeffect against examined human tumor cells.Also, the antioxidant activity of those compounds was reported.
In the recent year a great effort of the researcher is interested in cancer, as it is one of the leading causes of death.Search for novel and selective anticancer agents has attracted considerable attention because of the problem associated with currently available anticancer drug as an unfavorable side effect such reduced bioactivity.

Result and Discussion
Herein, we report the synthesis of some new isoxazole, pyrazole, pyrimidine and pyridine with potential anticancer activity, which having surface active properties.Isoxazoles are unique in their chemical behavior and have attracted biological and pharmacological properties [9][10][11][12][13].
The structure of compound (3) was confirmed on the bases of IR, Mass, 1 H-NMR spectroscopic analysis as well as elemental analytical data.IR showed υNH at 3342 cm -1 , υC=O 1675cm -1 , 1 HNMR showed δ12.0 (s, 1H, exchangeable NH) besides, the aliphatic chain and aromatic protons.The fragmentation ofMass spectrum supported the proposed structure c.f. "figure 1".Pyrazole derivatives were designed and synthesized as potential protein kinase inhibitions [14][15][16].In the view to develop a specific antitumor therapies, Aminopyrazoles emerged as a powerful pharmacophore scaffold and they have been extensively used to design various kinase inhibitor.Large-scale research aimed for developing specific synthetic routes to these compounds.Thiourea and acyl group are used for their ability to form hydrogen bonds with the kinase.Also the thioamide is an isoester of amide and has the advantage of being a better hydrogen bond donor and sulfur is superior donor for π-π* interaction such bond being very importantin the ligand-kinase interaction.

Antioxidant Activity
Ascorbic acid was taken as standard.The ability of the synthesized compounds to prevent oxidation in rat brain and kidney homogenates and their antioxidant activity were evaluated using 2, 2'-and-bis (3-ethylbenzothiazoline-6sulphonic acid) (ABTS) inhibition.From the table 2, compounds, 5, and 4 were showed the most two effective compounds potent antioxidant activities than the other compounds.

Hydroxylation (Propoxylation)
Following Morgos procedure [22], 0.5 wt% KOH solution containing 0.01 mol of the synthesized compound was stirred and heated to 70°C while passing a slow stream of nitrogen through the system to flush out oxygen.The nitrogen stream was stopped and propylene oxide (3, 5 and 7 mole) was added dropwise with continuous stirring and heating under an efficient reflux system to retain the propylene oxide.The reaction was conducted at different intervals of time ranging from 1/2-1h.The apparatus was then filled with nitrogen and cooled.The reaction vessel was weighed.The amount of reacted propylene oxide and the average degree of propoxylation were determined from the increment in the mass of the reaction mixture [23].The selected average Pyrazole, Pyrimidine and Pyridine and Their Surface, Anticancer and Antioxidant Activities numbers of moles, n, are 3, 5 and 7.

Surface Active Properties of Surfactants
Surface and Interfacial Tensions Surface and interfacial tension measurements on 2 (a-c) -9 (a-c) were carried out according to Findlay [24] with aKrüss tensiometer [25] (Krüss GmbH, Hamburg, Instrument Nr.K6) for different concentrations of the synthesized surfactants (0.05-10-6 mol/L), using a platinum-iridium ring at constant temperature (25 ± 1°C).Paraffin oil was used for the interfacial tension measurements.The tensiometer was calibrated using the method described in ASTM Designation: D1331-01 [26].

Cloud Point
The cloud point is a measure of the inverse solubility of a nonionic surface active agent.In a temperature-controlled bath, a 1-wt% solution of the tested compound was gradually heated until the clear or nearly clear solution became definitely turbid [27].The temperature was then recorded and the solution was allowed to cool down until it became clear again.The process was repeated to check the reproducibility of the recorded temperature.
Wetting Time Wetting time was measured by immersing a cotton skein (1 g) in a 0.1 wt% solution of the prepared surfactants in distilled water at 25°C according to the Draves technique [28].The sinking time was measured in seconds.
Foaming Properties Foam height was measured by the Ross-Miles method [29].In this procedure a given surfactant solution was allowed to fall from a set height into the same surfactant solution in a volumetric cylinder, hence creating foam.The height of the foam was visually assessed.

Emulsion Stability
The emulsifying property of the prepared surfactants was determined as follows: In a 100-ml graduated stoppered tube; an aqueous solution of the surfactant (10 ml, 20 mmol) was mixed with light paraffin oil (6 ml).The mixture was shaken vigorously by magnetic stirring [Thermo scientific Cimarec TM stirring hot plate, model no: sp131320-30, estimated stirring speed (1, 100 rpm)] for 2 min at 25°C.The tube was placed upright and the separation of the formed emulsion was observed.The time taken for the separation of (9 ml) of the aqueous layer indicates the emulsion stability of the surfactant [30].

Critical Micelle Concentration (CMC) Measurements
The critical micelle concentration (CMC) is the minimum concentration at which surfactants molecules begin to form micelles [31].CMC values were obtained through a conventional plot of the surface tension versus the logarithm of the concentration of surfactant.The CMC concentration corresponds to the point where the surfactant first shows the lowest surface tension, and after which the surface tension remains nearly constant.
The effectiveness of a certain surfactant π CMC is expressed in terms of the decrease in the surface tension that is induced by this surfactant at the critical micelle concentration [32].It is calculated from the difference between the surface tension of pure water (γ 0 ) and the surface tension of the surfactant solution at the critical micelle concentration (γ CMC ).

Efficiency
The efficiency of a surfactant (PC 20 ) is defined by the values of the negative logarithm of the bulk concentration necessary to reduce surface tension by 20 mN/m [33].It can be calculated by the following equation, Eq. ( 2).
The values of the maximum surface excess Γmax expressed in mol/cm2 were calculated from surface or interfacial data by the use of Gibbs equation [34] Eq. (3).
Where δγ surface pressure in mN/m.C surfactant concentration.(δγ /δlogC) T is the slope of a plot of surface tension versus concentration curves below CMC at a constant temperature.
Minimum Surface Area (A min ) Knowing Γmax, it is easy to calculate the effective area occupied by each surfactant molecule adsorbed at the air/water interface at surface saturation [35,36].The average area A min (in Ǻ 2/mol) is given by Eq. (4).

Resistance to Hydrolysis
The resistance of a certain surfactant towards acid and base hydrolysis was established by measuring the surface tension of that surfactant in acidic and alkaline media.Thus, the surface tension of a 0.1% solution of the surfactant in 5% sulfuric acid or in 1% sodium hydroxide was measured at room temperature after boiling for 30 and 60 min.
Biodegradability of the Synthesized Surfactants.The biodegradation tests of the synthesized nonionic surfactants were performed according to the River Water Die-Away method [37].The river water for testing was sampled from the River Nile.In this test, a stirred solution containing the tested surfactant (1, 000 ppm) was incubated at 25°C.Samples were withdrawn daily, filtered using Whatman filter paper and the surface tension was measured using a Du-Nouy tensiometer (Kruss type K6).The process was repeated for 7 days.The biodegradation percentage D% was calculated in terms of the measured surface tension according toEq.(5).D = [(γ t −γ 0 ) / (γ bt −γ 0 )]× 100 (5) Where γ t surface tension at time t.γ 0 surface tension at time zero (initial surface tension).γ bt surface tension of the blank experiment at time t.

Conclusion
Some new synthesized compounds can be used as anticancer, antioxidant especially compounds 4 and 5 and also can be used in industrial uses such as a wetting agent in textile manufacture.

Figure 8 .
Figure 8. Dose-response effect of the synthesized compound.

Table 1 .
Cytotoxic activity of some compounds against human tumor cell.

Table 2 .
Antioxidant activity of the synthesized compounds.

Table 3 .
Physicochemical properties of the synthesized surfactants.

Table 4 .
Surface properties of some synthesized surfactants.
a Number of propylene oxide units

Table 5 .
Biodegradability of the synthesized surfactants.

Table 6 .
Resistance of the synthesized surfactants towards acidic and alkaline hydrolysis.