Synthesis of Some Novel Compounds of Saccharinyl Acetic Acid Containing Nucleus and Evaluation of Their Biological Activities as Antimicrobial

A new series of Compounds of Saccharinyl Acetic acid Containing nucleus have been prepared via an improved synthetic procedure. Where saccharinyl moiety have been introduced to 4-benzylidine-2-methyl-1,3-oxazole-5-one in position 2 , compound (3) which has been reacted with nitrogen neucleophiles as hydrazine hydrate , phenyl haydrazine, aniline, p-toludine, m,p-aminobezoic acid to get compounds from (4-6). Also the reaction of compound (3) witharomatic substrate in presence of anhydrous AlCl3 (Friedel – Crafts reaction) afforded acetamide derivative (7) via the elimination of arylidine group. Moreover saccharinyl acetic acid hydrazide (8) was refluxed in acetic anhydride to give benzisothiazole derivative (9), which reacted with carbon nuleophiles (Grignard reagent) to afford compound (10). But when compound (9) reacted with PCl5/POCl3 it gave compound (11) which reacted with urea and thiourea to give compound (12(a, and b)). Also the condensation of compound (9) with aromatic aldehyde gave compound (13). Structures of all synthesized compounds were elucidated from I.R., 1HNMR, mass-spectroscopy, and elemental analysis.

The reported pharmaceutical properties of saccharin and its derivatives [1][2][3][4] and in connection [5][6][7][8][9] with our ongoing interest to developing new synthetic strategies for construction of heterocyclic systems involving saccharin due to its significant biological 10- 12 and pharmacological activities.Also imidazole derivatives are of interest to medical chemists for many years because of their biological activities such as anticancer, anti tubercular, antibacterial, and antifungal activities [13][14][15][16][17][18][19][20][21][22] In view of the above facts we report in the present work the synthesis and antimicrobial activities of Saccharinylderivatives.

Chemistry
Melting points were determined in open capillaries using Gallen Kamp melting point apparatus and are uncorrected F.T.-IR spectra (KBr.disc) were recorded on a Perkin Elmer 1720 F.T. -IR spectrometer. 1H -NMR spectra were recorded on varin Gemini NMR spectrometer 300 MHz using TMS as internal standard.All reactions were monitored by TlC using aluminum silica gel plates 60 F 245. Elemental analysis and antimicrobial activity were carried out at micro-analytical center, faculty of science, cairo university, Egypt.Elemental analysis of all synthesized compounds is in agreement with the structure elucidated.

general procedure for the preparation of imidazolone derivatives ( 6a-d) From ( saccharinyl-N-acetamido ) cinnamide derivatives( 5a-d) by cyclization .
A solution of compounds 5a-d (10 m mole) in acetic anhydride (15ml) was boiled under reflux for 2h.The resulting solution was poured onto crushed ice , and the product that separated out was filtered off, washed with solution of sodium hydrogen carbonate followed by water and then dried.The products were recrystallized from a proper solvent.
The reaction mixture was decomposed with ice-cold hydrochloric acid.Then the ethereal layer was separated and dried over anhydrous Na 2 SO 4 .
To Mg metal (10m mole) in dry ether (40ml) an alkyl halide namely, ethyl iodide , methyl iodide or benzyl chloride (30m mole) in dry ether (20ml) was added dropwisely.The reaction mixture was refluxed and compound a (10m mole) in dry ether (40ml) added portion wise within 1h.

Formation of compounds ( 12 a and b)
A mixture of compound 11 ( 10m mole) was refluxed with urea and / or thio-urea ( 10 m mole ) in ( 40ml) sodium ethoxide for 3h, then cooled and poured into water.The solid that separated was dried and recrystallized from benzene -ethanol (1 :1) to give 12a and for 12b.A mixture of compound 9 (10m mole) and aromatic aldehyde (10m mole) namely Benz aldehyde , p-chloro-Benz aldehyde and anisaldehyde in (40 ml).

Antimicrobial Activity
The antimicrobial activity (in vitro) of some synthesized compounds was determined against some bacteria and fungi using tetracycline and amphotericin B as standard antimicrobial agents by using the agar diffusion method 28 , 29 .
The obtained zones of inhibition were presented in table 1, which indicated that most of the synthesized derivatives have moderate to good antimicrobial activities.