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A series of new cyclic imides (3,4-dimethyl maleimides) and (1,8-naphthalimides) substituted with 1,3,4-oxadiazole ring were prepared by following four different methods. The first one involved direct reaction of 5substituted–2 -amino-1,3,4oxadiazole with 3,4-dimethyl maleic anhydride under certain conditions while the second method involved reaction of 5-subsitiuted-2amino-1,3,4-oxadiazole with 1,8naphthalic anhydride in the presence of glacial acetic acid. The strategy used in performing the third method based on Gabrial synthesis involving treatment of 5substituted-2-amino-1,3,4-oxadiazoles with chloro acetyl chloride to afford 2-(2-chloro acetyl amino)-1,3,4-oxadiazoles which in turn were used subsequently in reaction with 1,8-naphthalimide producing three new N-(2-acetyl amino-5-substituted-1,3,4oxadiazole-2-yl )-1,8-naphthalimides. The strategy used in performing the fourth method based on Williamson reaction including reaction of the prepared 2-(2-chloro acetyl amino)-1,3,4oxadiazoles with N-( hydroxy phenyl )3,4dimethyl maleimides to afford nine new N-[2-oxyacetamido-5substituted 1,3,4-oxadiazole-2yl )phenyl]-3,4-dimethyl maleimides. Finally antibacterial activity of all the prepared new cyclic imides were evaluated against two types of bacteria and the results showed that most of the new imides posses high biological activity against these organisms. Introduction Cyclic imides are important family of organic compounds possess structural features which confer potential biological activity and pharmaceutical use [1,2] . Their molecules contain an imide ring with a general structure [-CO-N(R)-CO-], so that they are hydrophobic and neutral and can therefore cross biological membranes in vivo. A diversity of biological activities and pharmaceutical uses have been attributed to them, such as antibacterial, antifungal, anti nociceptive, anticonvulsant and antitumor [3] .On the other hand 1,3,4oxadiazoles belong to a group of heterocycles that have been attracting attention for last two decades due to their wide range of biological interactions [4,5] . Many of them exhibit antibacterial, anticonvulsant, anticancer activities and are used to fight infections involving AIDS [6-8] . They are also applied in agriculture as herbicides, fungicides or insecticides [9,10] . Keeping these above facts in view it was thought worthwhile to synthesize new compounds by incorporating cyclic imide and 1,3,4-oxadiazole ring in a single molecular framework. The resulted new molecules were expected to possess biological activity since they were built from two biologically active components. Experimental All chemicals employed were of analytical reagent grade and were used without further purification. FTIR spectra were recorded on SHIMADZU FTIR-8400 Fourier Transform Infrared Spectrophotometer using KBr discs. Melting points were determined in open capillaries on Thomas Hoover apparatus and were uncorrected. 1 HNMR and 13 CNMR spectra were recorded on Bruker spectro spin ultra shield magnets 300 MHz instrument, using DMSO– d6,CDCl3 as solvents and TMS as internal reference. Elemental analysis were preformed on Perkin Elmer 240 element analyzer. 1-Preparation of 2-amino -5-substituted 1,3,4-oxadiazoles [1-6] The titled compounds were prepared according to literature procedures [11] with minor modifications and the required semicarbazones were synthesized via direct reaction between aldehydes and hydrazine hydrate according to literatures [12] . Ahlam MaroufAl-Azzawi 16 Semicarbazone (0.01 mol) and sodium acetate (0.02 mol ) were dissolved in (3040 mL ) of glacial acetic acid in a suitable round bottomed flask equipped with a dropping funnel for the addition of bromine.Bromine (0.7 mL in 5 mL glacial acetic acid) was added drop wise with stirring and cooling. Stirring was continued for 1 hr. then the resulted solution was poured on crushed ice with vigorous stirring. The resulting solid was filtered, washed thoroughly with water,dried and recrystallized from ethanol. Physical properties and FTIR spectral data of compounds [1-6] are listed in Table (1). 2-Preparation of N -(5-substituted -1,3,4oxadiazole-2-yl)-3,4dimethyl maleimides [7-12] The titled imides were prepared according to literatures [13] with some modifications: A solution of (0.01 mol) of 2amino-5substituted -1,3,4-oxadiazole in (25 mL) of diethyl ether was added drop wise to a solution of (0.01 mol) of 3,4-dimethyl maleic anhydride dissolved in(25 mL) of diethyl ether with stirring and cooling.The resulted mixture was stirred for additional 2 hrs. at room temperature then was left over night. The obtained precipitate was filtered,washed with ether and dried then was purified by recrystallization from cyclohexane. Physical properties and FTIR spectral data of compounds [7-12]are listed in Table (2). 3-Preparation of N-(5-substituted-1,3,4oxadiazole-2-yl)-1,8-naphthalimides [13-18] A solution of (0.01mol) of 2-amino-5substituted 1,3,4-oxadiazole in (20 mL) chloroform was added drop wise to (0.01 mol) of 1,8-Naphthalic anhydride dissolved in (30 mL) of chloroform with stirring then (5mL) of glacial acetic acid was added and the mixture was refluxed for four hours [14] . The resulted mixture was cooled to room temperature before pouring into crushed ice with vigorous stirring. The obtained precipitate was filtered, washed thoroughly with water and dried then was purified by recrystallization from benzene. Table (3) lists physical properties and FTIR spectral data of the prepared imides [13-18]. 4Preparation of 5-substituted -2-(2-chloro acetyl amino ) -1,3,4oxadiazoles[19-21] Chloro acetyl amino oxadiazoles were prepared by following literature procedures [15] . A mixture of 2amino-5-substituted -1,3,4oxadiazole (0.02 mol) and chloro acetyl chloride ( 0.02 mol ) in chloroform (50 mL ) was refluxed in the presence of K2CO3 (0.02mol) for eight hours. Excess of solvent was removed in vacuo and the residue was stirred with water before filtration. The obtained precipitate was washed with 5 % NaHCO3 solution then with water and dried then was purified by recrystallization from acetone. Physical properties and FTIR spectral data of compounds [19-21] are listed in Table (4). 5-Preparation of N-(2acetyl amino-5substituted-1,3,4oxadiazole –2yl )1,8naphthalimides [22-24] Synthesis of the titled imides were performed via the following two steps: 5-1-Preparation of 1,8Naphthalimide potassium salt Naphthalimide (0.01 mol) was dissolved in (25mL )of absolute ethanol then was heated in a water bath. The resulted clear solution was added to alcoholic potassium hydroxide solution with stirring and cooling then the obtained precipitate was filtered and dried [16] . 5-2Preparation of compounds [22-24] (0.01 mol) of the prepared 1,8naphthalimide potassium salt was added gradually with stirring to (0.01 mol) of compound [19], [20] or [21] dissolved in (30 mL) of absolute alcohol [17] . The resulted mixture was refluxed for eight hours with continuous stirring then was cooled to room temperature.The obtained precipitate was filtered, washed with 5 % NaHCO3 solution then with water and dried. Purification of the product was preformed by recrystallization from n-hexane. Physical properties and FTIR spectral data of compounds[22-24]are listed in Table (5). 6-Preparation of N-[4-(2-oxyacetamido-5substituted-1,3,4-oxadiazole–2-yl)phenyl] 3,4dimethyl maleimides[25-27] (0.015 mol) of 4-(hydroxy phenyl)-3,4dimethyl maleimide was dissolved in (15 mL ) Journal of Al-Nahrain University Vol.14 (1), March, 2011, pp.15-29 Science 17 of 10 % solution of sodium hydroxide. To the resulted clear solution (0.015mol) of compound [19], [20] or [21] dissolved in (20 m L) of acetone was added gradually with stirring. The resulting mixture was refluxed for three hours then cooled to room temperature before pouring into (50 mL) of cold water with vigorous stirring. Dilute HCl solution was added drop wise with stirring and cooling until neutralization then the formed precipitate was filtered, washed with water several times, dried and finally recrystallized from cyclohexane. Physical properties and FTIR spectral data of compounds [25-27] are listed in Table (6). 7-Preparation of N [3-(2-oxyacetamido-5substituted-1,3,4-oxadiazole–2-yl)phenyl] -3,4-dimethyl maleimides[28-30] The titled compounds were synthesized via reaction of equimolar amounts of 3-(hydroxy phenyl)-3,4-dimethyl maleimide and compound [19], [20] or [21] following the same procedure used in th preparation of compounds [ 25 – 27 ]. Physical properties and FTIR spectral data of compounds [28-30] are listed in Table (6). 8-Preparation of N-[2-(2-oxyacetamido-5substituted-1,3,4-oxadiazole–2-yl) phenyl] -3,4dimethyl maleimides[31-33] The titled compounds were prepared by following the same procedure used in the synthesis of compounds [25-27] except using of 2-(hydroxy phenyl) -3,4dimethyl maleimide instead of 4-(hydroxy phenyl )-3,4dimethyl maleimide. Physical properties and FTIR spectral data of compounds[31-33]are listed in Table(6). 9-Biological study The cup plate method using nutrient agar medium was employed in studying the antibacterial activity of the prepared imides against two types of bacteria, staphylococcus aureous (Gram positive)and E scherichia coli (Gram negative) respectively. DMF was used as sample solution and sample size for all the compounds was fixed at (0.1mL). Using a sterilized cork borer cups were scooped out of agar medium contained in a Petri dish which was previously inoculated with the microorganisms. The test compound solution (0.1 mL) was added in the cups and the Petri dishes where subsequently incubated a 37 0 C for 48 hours.Zones of inhibition produced by each compound was measured in mm and the results are listed in Tables (10) and (11). Results and Discussion Since both cyclic imides and 1,3,4oxadiazoles are very important organic compounds having wide spectrum of biological activities [18,19] the target of the present

maǧallaẗ ǧāmiʻaẗ al-nahrayn. al-ʻulūm/journal of al-nahrain university. science

Synthesis, Characterization and Evaluation of Antibacterial Activity of Several New 3,4-Dimethyl Maleimides and 1,8-Naphthalimides Containing 1,3,4-Oxadiazole Ring