SYNTHESIS AND STUDY OF SOME BIOCHEMICAL EFFECTS OF SOME NEW QUINOXALINE DERIVATIVES

SUMMARY AND CONCLUSIONThe thesis comprises the following:a- Organic synthesis of some new quinoxaline derivatives.b- Study of biochemical effect of some synthetic compounds.a. The organic synthesis:The project aimed to synthesis some new quinoxaline. Thus the reaction of 4-Methylphenylene-diamine 1 with -dicarbonyls namely benzil, p-dichlorobenzil, tetraketones, 9,10-phenanthrenequinone and acenaphthenequinone resulted in cyclocondensation affordinScheme 1The compound 1 was reacted with arylidene pyruvic acid and with aroyl pyruvate to produce quinoxalines 4a-c and 7a-c respectively (Scheme 2).Scheme 2Hydrazinolysis of compounds 7a-c using hydrazine hydrate yielded 1,2-dihydropyridazino[3,4-b]quinoxaline 14a-c respectively (Scheme 3).14a-cScheme 3Upon reacting quinoxalines 7a-c with P2S5 in dry pyridine afforded thienoquinoxaline 16a-c (Scheme 4).16a-ca; Ar = C6H5b; Ar = C6H4Cl(p)c; Ar = C6H4CH3(p)Scheme 4Chlorolysis of quinoxaline derivatives 7a-c using POCl3 afforded the corresponding dichloroquinoxaline derivatives 17a-c respectively.7a-c 17a-ca; Ar = C6H5b; Ar = C6H4Cl(p)c; Ar = C6H4CH3(p)Refluxing 2-chloroquinoxalines 17a-c with ethoxide yielded 2-ethoxyquinoxalines 20a-c.17a-c 20a-ca; Ar = C6H5b; Ar = C6H4Cl(p)c; Ar = C6H4CH3(p)Chloroquinoxalines 17a-c were reacted with arylamines namely; aniline and/or anthranilic acid to give arylaminoquinoxalines 21a-f.17a-c 21a-fAr Ar\a; C6H5 C6H5b; C6H4Cl(p) C6H5c; C6H4CH3(p) C6H5d; C6H5 C6H4COOH(o)e; C6H4Cl(o) C6H4COOH(o)f; C6H4CH3(p) C6H4COOH(o)When compounds 21d-f were allowed to react with POCl3 afforded quinazolinoquinoxalines 24a-c.21d-f 24a-ca; Ar = C6H5b; Ar = C6H4Cl (p)c; Ar = C6H4CH3 (p)The synthesis of semicarbazides 27a-c were achieved by the reaction of 17a-c with semicarbazide.17a-c 27a-ca; Ar = C6H5b; Ar = C6H4Cl (p)c; Ar = C6H4CH3 (p)Compounds 17a-c were reacted with sodium azide at room temp. yielded the corresponding azido derivatives 28a-c while under heating 17a-c tetrazoloquinoxaline derivatives 29a-c were obtained (Scheme 5).29a-cScheme 5b. The biochemical effect:In the toxicity studies, it was found that the tested compounds 4b and 4c were considered to be non lethal to the dose 200 mg/kg. The most effective doses for the inhibition of Ehrlich carcinoma cell EAC growth for 4b and 4c were found 100 mg/kg. TreatmenDetermination of some biochemical parameters in serum and liver of tumor bearing mice after injection single and repeated doses of the tested compounds 4b and 4c were found as follows:In serum:1. Glucose :The tested compound 4b showed high a significant decrease (-41%) for the single dose and insignificant increase (+11.04%) for the repeated doses. The tested compound 4c showed high a significant decrease (-54%) for the single dose and insignificant decrea2. Total protein :The tested compound 4b showed insignificant increase (+5.7%) for the single dose and insignificant increase (+6.7%) for the repeated doses. The tested compound 4c showed significant increase (+15.4%) for the single dose and insignificant decrease (-6.7%) 3. Albumin:The tested compound 4b showed insignificant increase (+1.8%) for the single dose and insignificant increase (+1.5%) for the repeated doses. The tested compound 4c showed insignificant increase (+1.2%) for the single dose and insignificant decrease (-11.9%4. Urea:The tested compound 4b showed high significant increase (+107.8%) for the single dose and high significant increase (+46.96%) for the repeated doses. The tested compound 4c showed high significant increase (+55.4%) for the single dose and high significant5. Creatinine:The tested compound 4b showed significant increase (+33.8%) for the single dose and high significant increase (+166%) for the repeated doses. The tested compound 4c showed insignificant increase ( +52.2% ) for the single dose and high significant increase6. Total bililrubin:The tested compound 4b showed significant decrease (-14%) for the single dose and significant increase (+8.8%) for the repeated doses. The tested compound 4c showed significant increase (+23.3%) for the single dose and significant increase ( +35% ) for th7. Cholesterol:The tested compound 4b showed high significant decrease (-20.7%) for the single dose and insignificant increase (+14.1%) for the repeated doses. The tested compound 4c showed high significant increase ( -22.56% ) for the single dose and significant increa8. Triglyceride:The tested compound 4b showed insignificant increase ( +25.9% ) for the single dose and high significant increase ( +94.8% ) for the repeated doses. The tested compound 4c showed significant increase ( +30.9% ) for the single dose and high significant inc9. AST and ALT :The tested compound 4b showed insignificant increase of AST and ALT (+0.2% and +1.15%) for the single dose respectively and insignificant increase (+4.1%) of AST and high significant increase (+22.36%) of ALT for the repeated doses. The tested compound 4cIn liver:1. Glycogen:The tested compound 4b showed insignificant decrease (-9.5%) for the single dose and insignificant increase (+5.3%) for the repeated doses.The tested compound 4c showed insignificant increase (+23.8%) for the single dose and insignificant increase (+29.5%) for the repeated doses.2.Total lipid :The tested compound 4b showed significant decrease (-20.03% and -24.6%) for the single dose and repeated doses respectively. The tested compound 4c showed high significant decrease (-42.4% and -32.9%) for the single dose and the repeated doses respectivel3. AST:The tested compound 4b showed insignificant increase (+3.12%) for the single dose and insignificant decrease (-3.72%) for the repeated doses.The tested compound 4c showed insignificant decrease (-3.13% and -2.16% ) for the single dose and the repeated doses respectively.4. ALT :The tested compound 4b showed insignificant decrease (-3.4% and -6.5%) for the single dose and the repeated doses respectively.The tested compound 4c showed insignificant decrease (-5.65%) for the single dose and significant decrease (-8.7%) for the repea5. Alkaline phosphatase:The tested compound 4b showed significant increase (+68.8%) for the single dose and high significant increase (+28%) for the repeated doses.The tested compound 4c showed high significant increase (+168% and +90.9%) for the single dose and the repeated doses respectively.From the previous results some of biochemical parameters of the tested compounds 4b and 4c were safe and showed insignificant alteration.In conclusion, our data indicate that the tested compounds 4b and 4c exert antitumor activity so, we recommend to use their components as antitumor agents specially the tested compound 4c.