Synthesis and Antimicrobial Activity of New Schiff Base Compounds Containing 2-Hydroxy-4-pentadecylbenzaldehyde Moiety

Various novel Schiff base compounds have been synthesized by reaction of 2-hydroxy-4-pentadecylbenzaldehyde with substituted benzothiophene-2-carboxylic acid hydrazide and different substituted aromatic or heterocyclic amines in the presence of acetic acid in ethanol. The structures of all these compounds were confirmed by elemental analysis, IR, H-NMR, C-NMR, and mass spectral data and have been screened for antibacterial and antifungal activity.


Introduction
Compounds with the structure of -C=N-(azomethine group) are known as Schiff bases, which are usually synthesized by condensation of primary amines and active carbonyl groups.Schiff bases are an important class of compounds in the medicinal and the pharmaceutical field, including antibacterial [1,2], antifungal [3,4], and antitumor activity [5,6].Heterocyclic-containing Schiff bases can show dramatically increased biological activities.As evident from literature [7], it was noted that a lot of research has been carried out on Schiff bases, but no work has been done on this particular type of Schiff base.Aromatic Schiff bases possessing long alkyl chains have received overwhelming attention due to their possibility to show mesomorphic properties such as smectic and nematic phases [8][9][10][11].In this paper, we report the synthesis of a novel Schiff base from substituted benzothiophene-2-carboxylic acid hydrazide, various aromatic and heterocyclic amines with 2-hydroxy-4pentadecylbenzaldehyde as a moiety.We also report the results of biological screening for possible antibacterial and antifungal activity of the resulting derivatives and we discuss the relationship of molecular structure and the bioactivity (Table 1).
Cardanol is a phenolic compound with a C 15 aliphatic chain in the meta position, obtained from cashew nut shell liquid (CNSL).The structure and composition of cardanol is  given in Figure 2. It is a mixture of saturated and unsaturated (mono-, di-, and tri-) compounds.
Compounds 5a and 6a were obtained separately in good yield by refluxing compound 2 with an equimolar amount of compounds 5 and 6 in the presence of acetic acid in ethanol for 5 h.The configuration at the imine unit was not investigated; compounds 5a and 6a are arbitrarily shown in Z configuration in Scheme 3.
2-Hydroxy-4-pentadecylbenzaldehyde 2 was treated with aromatic amines to get new cardanol aldehyde derivative of Schiff base compounds.These new Schiff bases were fully characterized by elemental analysis, IR, MS, 1 H, and 13 C-NMR data.

Antimicrobial Evaluation
The cup plate method using Hi-Media agar medium was employed to study the antibacterial activity of the synthesized compounds against Gram-positive bacteria, Staphylococcus aureus, and Gram-negative bacteria, Escherichia coli.Preparation of nutrient broth, subculture, base layer medium, agar medium, and peptone water was carried out according to a standard procedure [14].Streptomycin was used as a reference drug and dimethylformamide as a control.The zone of inhibition produced by each compound was measured in mm.The evaluated compounds have shown low to moderate activities as compared to standard drug against the bacteria.The antifungal activities of the synthesized compounds were evaluated against two different fungi, that is, Candida albicans and Chrysosporium pannical, by the filter paper disc technique [15].

Experimental
All chemicals were analytical grade, purchased from commercial suppliers, and used as received without further purification.Melting points were determined in open capillaries and are uncorrected.FT-IR spectra were recorded on a Nicolet Fourier Transform IR spectrophotometer Impact 410 (Nicolet Instrument Technologies, Inc. WI, USA). 1 H-NMR and 13 C-NMR spectra were obtained in DMSO- 6 at 400 MHz for 1 H nuclei and 100 MHz for 13 C nuclei (Bruker Company, Germany).All chemical shifts are expressed in ppm relative to tetramethylsilane (TMS) as the internal standard.Mass spectra were obtained using matrix-assisted laser desorption ionization mass spectrometry (MALDI-TOF) by using dithranol as a matrix.Elemental analysis (C, H, N, and S) was performed on a Perkin Elmer 2400 analyzer.The purity of compounds was checked by TLC on silica gel and further purification was performed using column chromatography (silica gel, 60-120 mesh).

Synthesis of Compound 2 Was
Prepared according to Literature Procedure.See [12].

Synthesis of Compounds 3a-d
Was Also Prepared according to Literature Procedure.See [13].

Synthesis of 5-Pentadecyl-2-((thiazol-2-ylimino)methyl) phenol (6a)
. Cardanol aldehyde 2 (3.32 g, 0.01 mol) in ethanol (15 mL) and 2-aminothiazole (1.00 g, 0.01 mol) in the presence of glacial acetic acid (1 mL) were refluxed for 6 h.The reaction mixture was allowed to cool down to room temperature and poured onto ice cooled water with constant stirring.The resulting precipitate was filtered, washed with water, dried, and purified through column chromatography to get pure compound 6a as light yellowish solid. Yield

Synthesis of 2-((4-(Dimethylamino)phenylimino)methyl)-5-pentadecylphenol (7a).
To a stirred solution of compound 2 (3.32 g, 0.01 mol) and N,N-dimethylbenzene-1,4-diamine 6 Advances in Chemistry (1.36 g, 0.01 mol) in ethanol (20 mL), glacial acetic acid (1 mL) was added.The mixture was refluxed for 4 h.After the completion of the reaction (TLC-monitoring) the reaction mixture was cooled down to room temperature and then added to crushed ice.The precipitate was filtered, washed with water, dried, and purified through column chromatography by using n-hexane and ethyl acetate (50 : 50) as an eluent to afford pure compound 7a. Yield

Synthesis of 2-((4-Nitronaphthalen-1-ylimino)methyl)-5pentadecylphenol (8a).
A mixture of compound 2 (3.32 g, 0.01 mol) and 4-nitronaphthalen-1-amine (1.88 g, 0.01 mol) in ethanol (20 mL) and few drops of glacial acetic acid was refluxed for 5 h.After the completion of the reaction (TLC-monitoring), the reaction mixture was cooled down to room temperature and then poured into ice cold water.The precipitate was filtered, dried, and recrystallized from methanol to give pure product 8a as light yellowish solid.

General Procedure for Synthesis of New Schiff 's Base (9a-g).
A mixture of 2-hydroxy-4-pentadecylbenzaldehyde 2 (0.01 mol) and various aromatic amines (0.01 mol) in the presence of glacial acetic acid (1 mL) in ethanol (30 mL) was refluxed for 5 h.The completion of the reaction was monitored by TLC.The reaction mixture was allowed to cool down to room temperature and then poured into crushed ice.The precipitate was filtered, dried, and recrystallized from absolute ethanol.The resulting solid was further purified by column chromatography [silica, n-hexane/ethyl acetate (90 : 10)] to get pure compounds 9a-g (Scheme 4).

Conclusion
In conclusion, a new series of 6-substitued-3-chloro-N  -(2hydroxy-4-pentadecylbenzylidene)benzothiophene-2-carbohydrazide derivatives were synthesized, fully characterized, and evaluated for their antibacterial and antifungal activities.The newly synthesized compounds exhibited low to moderate antibacterial activity against S. aureus and B. subtilis andsignificant antifungal activity against C. albicans and C. pannical.It can beconcluded that these classes of compounds certainly hold great promise towards good active leads in medicinal chemistry.A further study to acquire more information concerning pharmacological activity is in progress.

Table 1 :
Antibacterial and antifungal activity of the tested compounds.