Synthesis and evaluation of α-hydroxy fatty acid-derived heterocyclic compounds with potential industrial interest

La reacción de cloruro de 2-hidroxiheptadecanoilo (2) con ácido antranílico produjo 2-(1-hidroxiheptadecil)-4H-3,1benzoxazin-4-ona (3) que fue usada como material de partida en la síntesis de compuestos heterocíclicos condensados y no condensados por reacción con nucleófilos nitrogenados (hidracina y formamida). La reacción de los productos sintetizados con distintas cantidades de óxido de propileno dio un grupo nuevo de compuestos no iónicos con una función doble como antibacterianos y agentes tensioactivos que pueden servir en la manufactura de medicamentos, cosméticos, pesticidas, o como productos antibacterianos y/o antifúngicos. Se determinaron las propiedades tensioactivas así como la capacidad antimicrobiana y la biodegrabilidad de los compuestos sintetizados.


Synthesis and evaluation of α-hydroxy fatty acid-derived heterocyclic compounds with potential industrial interest
Por, A. M. F. Eissa and R. El-Sayed Chemistry Department, Faculty of Science, Benha University, Egypt.ref_at@hotmail.comactivities such as antipyretic (El-Sayed, 2005;Amin, 1998), anti-inflammatory (Amin et al., 1998), antimitotic, anticancer agents (Aly, 2003).They also have good storage stability in detergents (Mohamed et al., 2003).This led us to synthesize 2-(1hydroxyheptadecyl)-4H-3,1-benzoxazin-4-one (3) and several quinazoline derivatives which may have pharmaceutical and industrial applications.This encouraged us to synthesize a novel group of nonionic surface active agents containing these nuclei.These compounds have a double function as antimicrobial and as surface active agents which may serve in the manufacturing of drugs, cosmetics, pesticides or as antibacterial and/or antifungal agents.The surface properties such as surface and interfacial tension, cloud point, foaming height, wetting time, and emulsification power were determined.Their biodegradability and antimicrobial properties were also screened.

MATERIALS AND METHODS
The melting points reported are uncorrected.IR spectra in KBr were measured on a Pye-Uncam SP-1000 infrared spectrophotometer on a KBr disk or nujol.The 1 H NMR spectra were obtained on a Varian EM-390-60 MHz spectrometer in DMSO as the solvent.Tetramethylsilane TMS served as an internal reference and chemical shifts are expressed as δ (ppm).UV spectra were registered with a Perkin-Elmer 550 S UV-Vis spectrophotometer using absolute ethanol as solvent.Mass spectra were recorded on a GC/MS Finning-MAT.Microanalyses were performed by the Micro analytical Unit at Cairo University.All the compounds gave satisfactory elemental analyses.Thin layer chromatography (TLC) was carried out on silica gel (MN-Kieselgel G., 0.2 mm thickness) and the plates were scanned under 254 nm ultraviolet light.Antimicrobial and antifungal activity tests were carried out by the microbiology Lab., Faculty of Science, Benha University, Egypt.

Conversion of the prepared compounds (3-15) to nonionic surfactants (16a-c -28a-c)
They are prepared by the addition of n moles of propylene oxide (n = 5, 10, 15) to one mol of a suitable product using KOH as catalyst.A complete description of the procedure is given in Morgos (1983).The reaction conditions are given in Table I.The amount of propylene oxide which reacted and the average degree of propenoxylation were determined through the increment in mass of the reaction mixture and also, by 1 HNMR protons.These products were confirmed by spectroscopic methods.The addition of propylene oxide gave a mixture of propenoxylated products whose structures were shown through IR and 1 HNMR.IR spectra to be two broad bands at 1100 and 950 cm -1 .The characteristic for νC-O-C ether linkage of polypropenoxy chain and 1 HNMR spectra showed the protons of propenoxy group at δ 3.2-3.7 (m, CH 2 CH(CH 3 )-O)-.

Cloud point
Cloud point was determined by gradually heating a surfactant solution (1.0 wt %) in a temperature controlled bath, and recording the temperature at which the clear, or nearly clear solutions become definitely turbid.The reproducibility of this temperature was checked by cooling the solutions until they became clear again (Wiel et al., 1963)

Wetting time
Wetting time was determined by immersing a sample of cotton fabric in a 1.0 wt % aqueous solution of surfactants (Draves et al., 1931) A. M. F. EISSA AND R. EL-SAYED

Foaming properties
Foaming properties were measured according to El-Sukkary et al (1987).In this procedure a 25 ml solution (1.0 wt %) was shaken vigorously for 10 seconds in a 100 ml graduated cylinder with glass stopper at 25 o C. The solution was allowed to stand for 30 seconds, and then, the foam height was measured.

Emulsification stability
Emulsification stability was prepared from 10 ml of a 20 mmol aqueous solution of surfactant and 5 ml of toluene at 40 o C. Emulsion stability was determined as the time it took 9 ml of an aqueous layer to separate from the emulsion once shaking had stopped.(Takeshi, 1970).

Biodegradability
Biodegradability was evaluated by surface tension measurements which were taken each day, on each sample during the degradation test.Biodegradation (Eter et al., 1974) percent (D) for each sample was calculated using the following equation: D = [(γ t -γ o ) / (γ bt -γ o )] x 100, where γ t = surface tension at time t, γ o = surface tension at zero time, γ bt = surface tension of blank experiment at time t (without sample).

Biological activity
The antimicrobial activities of the synthetized surfactants were determined in vitro using the hole plate and filter paper disc method (Rosen, 1989).Compounds were dissolved in 10% acetone at different concentrations (125, 250, 500 µg/ml).Agar plates were inoculated uniformly from a fresh broth culture of Gram +ve, Gram -ve bacteria and fungi.The disks were incubated at 28 o C for 24 h, and the formed inhibition zones were measured in mm.

Conversion of the prepared compounds (3-15) to nonionic surfactants (16a-c -28a-c)
The structure of a surface active agent requires a hydrophilic component.This is accomplished through the condensation of alkylene oxide at any active terminal group.Thus, the addition of propylene oxide gave mixtures of propenoxylated products whose structures were confirmed by IR and 1HNMR spectroscopy.

Surface active properties
The study of the surface active properties of the oxypropylated compounds was done in an aqueous solution (1wt %, pH = 7) at 25 o C. The results are listed in Table II.

Surface and interfacial tensions
The surface and interfacial tensions of the prepared compounds are shown in Table II.It can be observed that the new nonionic surfactants have pronounced surface activity.In general, the surface and interfacial tensions increase with an increase in the molecular weight of the hydrophobic moiety (Eissa et al., 2003).The data given in Table II shows that the values of surface and interfacial tensions increased with the increase in the number of propylene oxide units added to the molecule.

Cloud point
A very important factor in making the most efficient use of nonionic surfactants in an aqueous system is an understanding of the property called cloud point.The data (Table II) show that the cloud point SYNTHESIS AND EVALUATION OF α-HYDROXY FATTY ACID-DERIVED HETEROCYCLIC COMPOUNDS WITH POTENTIAL INDUSTRIAL...

Biodegradability
The trend of degradation in river die-away tests was followed by surface tension measurements.The results are given in Table III.The rate of degradation of these compounds depends on the size of the molecule; a bulky molecule diffuses through the cell membrane, and its degradation is more difficult.This means that molecules with a low proportion of propylene oxide are more degradable than those containing a higher proportion.

Biological activity
As show in Table IV most of the synthesized surfactants have remarkable antimicrobial activity towards the selected bacteria and fungi.The presence of heterocyclic moiety in the prepared nonionic surfactant molecule revealed an increase in biological activity.It is therefore clear that these surfactants were effective and inhibited the growth of all the microorganisms tested.

CONCLUSION
It can be concluded that all the prepared nonionic surfactants have good emulsifying properties in non edible media as insecticides and pesticides.A; Antimicrobial activity of tested compounds; the width of the zone of inhibition indicates the potency of antimicrobial activity, (-) no antimicrobial activity, (+) week activity with diameter equal to (0.5-0.7cm), (++) moderate activity with the diameter zone equal to (1.0-1.2cm),(+++) marked activity with the diameter zone equal to (1.6-1.8cm).MIC; Minimum inhibition concentration in µg/ml.
Scheme I a) Error was: surface and interfacial tensions = ± 0.1 dynes/cm; cloud point = ± 1 o C; foam height = ± 2 mm; wetting time = ± 1 sec; emulsion = ± 1 min b) n in the number of propylene oxide added to the chosen compound SYNTHESIS AND EVALUATION OF α-HYDROXY FATTY ACID-DERIVED HETEROCYCLIC COMPOUNDS WITH POTENTIAL INDUSTRIAL...