SYNTHESIS, CHARACTERIZATION, AND STUDY THE BIOLOGICAL ACTIVITY OF SOME SCHIFF'S BASES, AND 1,3 - OXAZEPINE COMPOUNDS DERIVED FROM SULFAMETHOXAZOLE DRUG

This study including synthesis of some new Schiff bases compounds [1 ‐ 6] from the reaction of Sulfamethoxazole drug with some aromatic aldehydes in classical Schiff base method then treatment Schiff bases with succinic anhydride to get oxazepines rings [7-11]These derivatives were characterized by melting point,FT ‐ IR, 1 H NMR and mass spectra. Some of synthesized compounds were evaluated in vitro for their antibacterial activities against three kinds of pathogenic strains Staphylococcus aureus , Escherichia coli and Pseudomonas aeruginosa by agar diffusion disk method, and against the fungal species ( Candida ). The results showed that some of these derivatives have good antibacterial activities compared to biological activity of parent drug.

4-Amino-N-5-methyl-3-isoxazolylbenzenesulfonamide is the common name of Sulfamethoxazole, but N1-5-Methyl-3-isoxazolyl sulfanilamide, is the IUPAC name( Figure  1).This drug was considered by previous working groups ( Lyon, 1980;Lyon, 1987).Sulfamethoxazole is an antibiotic that has been used since the 1990s to treat various general injuries in humans and different species. There wasmore usein the treatment of acute infections of the urinary tract. AlsoSulfamethoxazole is used against gonorrhea, meningitis, respiratory infections and prevention of poor meningococcal meningitis. Given the relatively unfavorable, pattern of tissue delivery, antibacterial medication that is widely used to treat various systemic infections worldwide with trimethoprim or pyrimethamine. With methoprim, the mixture is used mainly to treat the device's inflammation. Sulfamethoxazole of chloroquineresistant plasmodium falciparum malaria (Lyon,1980;Gennaro, 1995; Elggellal& Alshadly, 2014).
Researches on complexes of sulfamethoxazole have a lot of physiological and pharmacological due to complexes of sulfa drugs have been discovered to be more bacteriostatic than the medication themselves (  A heterocyclic compound consisting of an oxygen atom at site 1 and a nitrogen atom at position 3 in addition to five carbon atoms is 1,3-Oxazepinecompound. In 1965, the oxazepine derivative was introduced use to relieve psychoneurosis symptoms marked by anxiety and stress(Kuluod& Hamid, 2013). Oxazepine derivatives has been shown to display a broad range of biological activites, including antibacterial, antifungal, hypnotic relaxant, muscle inflammatory and antiepileptic activities (Taha, 2017

MATERIALS AND METHODE Materials and measurements of physical
Both reactants and solvents used in this study were reagent grade and are available from companies such as Sigma-Aldrich, BDH and Fluka. Sulfamethoxazole was obtained from Samara, Iraq.
Melting points have been registered and are uncorrected using a hot stage Gallen Kamp melting point apparatus. SHIMADZU model FT-IR-8400S was used to receive the FT-IR spectrum. On the BRUKER model Ultra shield 300MHz spectrophotometer . 1 H-NMR spectra were obtained in the DMSO-d6 solution with the TMS as the internal standard. Mass spectra were recorded using Mass Spectrometer, Agilent Technology (HP) at Tehran University, Central Lab, Iran.

Common technique of preparing of Schiff bases (1-6)
For 6-8 hrs, a mixture of Sulfamethoxazole (0.0039 mole,1 g), and various aromatic aldehydes (0.0039mol) in absolute ethanol (15 mL) and 3 drops of glacial acetic acidwere refluxed(Jassim & Ali, 2018; Abdullah et al., 2013).The mixture was cooled and the solid was purified after the end of the reaction, checked with TLC ethanol: benzene (1:1),then recrystallized from ethanol and collected by filtration, as shown in (Scheme 1) (Table 1) describes the physical properties of these compounds.

RESULTS AND DISCUSSION
The Schiff's bases compounds of sulfamethoxazole (1-6) were synthesized in good percentage from the reaction ofSulfamethoxazole with different aromatic aldehydes in absolute ethanol as a solvent. These compounds have been synthesized according to the steps described in (Scheme 1).
The 1 H-NMR spectra of compounds (7and10) showed the signal at 2.26and2.29ppm due to proton of (CH 3 ) group,and signal at 2.06-2.79ppm due to the protons of oxazepine ring (CH 2 ), while the other signals are listed in as shown in (Figures 9 and 10).
The compound 1 mass spectrum (Figure 11), shows the molecular ion at m/z = 387.4,an d the compound 3 mass spectrum, (Figure 12), shows the molecular ion at m/z = 420.28.

BIOLOGICAL ACTIVITY Anti-bacterial activity
Three forms of pathogenic strains(S. aureus,E.coliand P. aeruginosawere used to test the antimicrobial activity of the synthesized compounds(2,4,7,10and11) using the agar diffusion process.Appropriate spaced separate holes were created by Muelle Hinton agar (6mm in diameter) appropriate spaced separate holes were filled with 0. 1mLconcentration of prepared compounds that dissolve in DMSO before spreading the bacteria on agar.These plateswere incubated for 24 hr at 37 o C,the bacteria growth inhibitionzone around the holeobser vedand measured in millimeter of diameter (Entesar& Enaam, 2017; Saleh& Ali, 2020). Results and clarification are given in (Table 6).

CONCLUSION
The results indicate that the synthesized compounds (2, 4,7,10 and 11) have a microbial activity against the tested organisms up to 3.2mg/ disk.Thesederivatives showed higheffect against S. aureusand moderately activity againstE.coliand P.aeruginosa.the fungal species, Candida albicans showed higher sensitivity toward the compounds 6 and 8 more than compound 7 .