الفهرس 
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Abstract
This thesis comprises four main chapters. Introduction,discussion, biological activity of a number of the prepared compounds, and experimental part.
The first chapter is the introduction which involves general literature review for the newly synthetic methods for 1,3,4-oxadiazole derivatives.
The second chapter is devoted in detailed discussion of the results obtained throughout the work by the candidate; in which D-glucose reacted with 3-oxobutanoate (ethyl acetoacetate), to afford ethyl 5-(1`,2`,3`,4`-tetrahydroxybutyl)-2-methylfuran-3-carboxylate (327).
Treatment of compound 327 with hydrazine hydrate afforded the corresponding hydrazide 5-(1`,2`,3`,4`-tetrahydroxybutyl)-2-methylfuran-3-carbohydrazide (328), which on condensation with a number of pyridinecarboxaldehydes, namely, 2-pyridinecarboxaldehyde, 3-pyridinecarboxaldehyde and 4-pyridinecarboxaldehyde, furnished the corresponding hydrazone derivatives; 2-methyl-N’-[(pyridin-2-yl)methylene]-5-(1`,2`,3`,4`-tetrahydroxybutyl)furan-3-carbohydrazide (329), 2-methyl-N’-[(pyridin-3-yl)methylene]-5-(1`,2`,3`,4`-tetrahydroxybutyl)furan-3-carbohydrazide (330), 2-methyl-N’-[(pyridin-4-yl)methylene]-5-(1`,2`,3`,4`-tetrahydroxybutyl)furan-3-carbohydrazide (331),respectively.
Acetylation of these compounds 329-331 with a mixture of acetic anhydride and pyridine, afforded the corresponding O-acetyl derivatives; 1`-[5-methyl-4-((2-(pyridin-2-yl)methylene)hydrazinecarbonyl)furan-2-yl]butane-1`,2`,3`,4`-tetrayl tetraacetate (332), 1`-[5-methyl-4-((2-(pyridin-3-yl)methylene)hydrazinecarbonyl)furan-2-yl]butane-1`,2`,3`,4`-tetrayl tetraacetate (333), 1`-[5-methyl-4-((2-(pyridin-4-yl)methylene)hydrazinecarbonyl)furan-2-yl]butane-1`,2`,3`,4`-tetrayl tetraacetate (334), respectively.
Oxidative cyclization of 333 and 334 with iodine, yellow mercuric oxide and magnesium oxide, resulted in 1,3,4-oxadiazole derivatives: 1`-[5-methyl-4-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)furan-2-yl]butane-1`,2`,3`,4`-tetrayl tetraacetate (335) and1`-[5-methyl-4-(5-(pyridin-4-yl)-1,3,4-oxadiazol-2-yl)furan-2-yl]butane-1`,2`,3`,4`-tetrayl tetraacetate (336), respectively.
Deacetylation of 1,3,4-oxadiazole 336 in methanolic-ammonia, afforded the corresponding de-O-acetylated compound: 1`-[5-methyl-4-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)furan-2-yl]butane-1`,2`,3`,4`-tetrol (337) and 1`-[5-methyl-4-(5-(pyridin-4-yl)-1,3,4-oxadiazol-2-yl)furan-2-yl]butane-1`,2`,3`,4`-tetrol (338).
On the other hand, periodate oxidation of the prepared acyclic C-nucleosidehydrazones 329-331 gave the corresponding formyl derivatives; 5-formyl-2-methyl-N’-[(pyridin-2-yl)methylene]furan-3-carbohydrazide (339), 5-formyl-2-methyl-N’-[(pyridin-3-yl)methylene]furan-3-carbohydrazide (340), and 5-formyl-2-methyl-N’-[(pyridin-4-yl)methylene]furan-3-carbohydrazide (341).
Furthermore, reduction of the prepared aldehydes 339-341 using sodium borohydride, resulted in the corresponding hydroxymethyl derivatives; 5-(hydroxymethyl)-2-methyl-N’-[(pyridin-2-yl)methylene]furan-3-carbohydrazide342, 5-(hydroxymethyl)-2-methyl-N’
[(pyridin-3-yl)methylene]furan-3-carbohydrazide 343, and 5-(hydroxymethyl)-2-methyl-N’-[(pyridin-4-yl)methylene]furan-3-carbohydrazide 344.
Acetylation of 343 and 344 gave the corresponding mono O-acetyl [5-methyl-4-(2-((pyridin-3-yl)methylene)hydrazinecarbonyl)furan-2-yl]methyl acetate (345) and [5-methyl-4-(2-((pyridin-4-yl)methylene)hydrazinecarbonyl)furan-2-yl]methyl acetate (346), respectively.
Similarly, oxidative cyclization of these mono O-acetyl hydrazones 345 and 346, resulted in 1,3,4-oxadiazole derivatives: [5-methyl-4-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)furan-2-yl]methyl acetate (347) and [5-methyl-4-(5-(pyridin-4-yl)-1,3,4-oxadiazol-2-yl)furan-2-yl]methyl acetate (348), respectively.
Deacetylation of 1,3,4-oxadiazoles 347 and 348 with methanolic-ammonia, afforded the corresponding de-O-acetylated derivatives: [5-methyl-4-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)furan-2-yl]methanol (349) and [5-methyl-4-(5-(pyridin-4-yl)-1,3,4-oxadiazol-2-yl)furan-2-yl]methanol (350), respectively.
In addition, dehydrative cyclization of the acyclic C-nucleoside compound 327 with acetic acid (10%) afforded the corresponding cyclic C-nucleoside as two isomers; the isomeric D-ribo-anhydro 351 (with inversion of configuration) as the major isomer, and that having D-arabino 352 configuration (with retention of configuration) as the minor isomer.
Treatment of the prepared anhydro derivative with hydrazine hydrate, afforded the corresponding D-ribo-anhydrohydrazide compound 5-(3’,4’-dihydroxytetrahydrofuran-2’-yl)-2-methylfuran-3-carbohydrazide (353), which on condensation with two pyridinecarboxaldehydes, namely; 3-pyridinecarboxaldehyde and 4-pyridinecarboxaldehyde, yielded the corresponding D-ribohydrazone derivatives; 5-(3’,4’-dihydroxytetrahydrofuran-2’-yl)-2-methyl-N`-[(pyridin-3-yl)methylene]furan-3-carbohydrazide (354) and 5-(3’,4’-dihydroxytetrahydrofuran-2’-yl)-2-methyl-N`-[(pyridin-4-yl)methylene]furan-3-carbohydrazide (355).
Acetylation of these anhydro-cyclic C-nucleoside 354 and 355, afforded the corresponding O-acetyl derivatives: 2`-[5-methyl-4-(2-((pyridin-3-yl)methylene)hydrazinecarbonyl)furan-2-yl]tetrahydrofuran-3`,4`-diyl diacetate (356) and 2`-[5-methyl-4-(2-((pyridin-4-yl)methylene)hydrazinecarbonyl)furan-2-yl]tetrahydrofuran-3`,4`-diyl diacetate (357), respectively, which on oxidative cyclization furnished the corresponding 1,3,4-oxadiazoles: 2`-[5-methyl-4-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)furan-2-yl]tetrahydrofuran-3`,4`-diyl diacetate (358) and 2`-[5-methyl-4-(5-(pyridin-4-yl)-1,3,4-oxadiazol-2-yl)furan-2-yl]tetrahydrofuran-3`,4`-diyl diacetate (359), respectively.
Deacetylation of 1,3,4-oxadiazoles 358 and 359 with methanolic-ammonia, afforded the corresponding de-O-acetylated derivatives: 2`-[5-methyl-4-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)furan-2-yl]tetrahydrofuran-3`,4`-diol (360) and 2`-[5-methyl-4-(5-(pyridin-4-yl)-1,3,4-oxadiazol-2-yl)furan-2-yl]tetrahydrofuran-3`,4`-diol (361).
Condensation of aldehydes 340 and 341 with thiosemicarbazide gave 2-((5-methyl-4-(2-((pyridin-3-yl)methylene)hydrazinecarbonylfuran-2-yl)methylene)hydrazinecarbothioamide
(362) and 2-((5-methyl-4-(2-((pyridin-4-yl)methylene)hydrazinecarbonylfuran-2-yl)methylene)hydrazinecarbothioamide (363), respectively.
Condensation of aldehydes 339-341 with a number of aroylhydrazine derivatives afforded the corresponding hydrazones: 5-((2-benzoylhydrazono)methyl)-2-methyl-N`-((pyridin-2-yl)methylene)furan-3-carbohydrazide (364), 5-((2-benzoylhydrazono)methyl)-2-methyl-N`-((pyridin-3-yl)methylene)furan-3-carbohydrazide (365), 5-((2-benzoylhydrazono)methyl)-2-methyl-N`-((pyridin-4-yl)methylene)furan-3-carbohydrazide (366), 5-((2-(4-methoxybenzoylhydrazono)methyl)-2-methyl-N`-((pyridin-3-yl)methylene)furan-3-carbohydrazide (367), 5-((2-(4-methoxybenzoylhydrazono)methyl)-2-methyl-N`-((pyridin-4-yl)methylene)furan-3-carbohydrazide (368), 5-((2-(4-chlorobenzoylhydrazono)methyl)-2-methyl-N`-((pyridin-2-yl)methylene)furan-3-carbohydrazide (369), 5-((2-(4-chlorobenzoylhydrazono)methyl)-2-methyl-N`-((pyridin-3-yl)methylene)furan-3-carbohydrazide (370), 5-((2-(4-chlorobenzoylhydrazono)methyl)-2-methyl-N`-((pyridin-4-yl)methylene)furan-3-carbohydrazide (371), 2-methyl-5-((2-(4-methylbenzoylhydrazono)methyl)-N`-((pyridin-2-yl)methylene)furan-3-carbohydrazide (372), 2-methyl-5-((2-(4-methylbenzoylhydrazono)methyl)-N`-((pyridin-3-yl)methylene)furan-3-carbohydrazide (373). 2-methyl-5-((2-(4-methylbenzoylhydrazono)methyl)-N`-((pyridine-4-yl)methylene)furan-3-carbohydrazide (374), 2-methyl-5-((2-(4-nitrobenzoylhydrazono)methyl)-N`-((pyridin-2-yl)methylene)furan-3-carbohydrazide (375), 2-methyl-5-((2-(4-nitrobenzoylhydrazono)methyl)-N`-((pyridin-3-yl)methylene)furan-3-carbohydrazide (376), 2-methyl-5-((2-(4-nitrobenzoylhydrazono)methyl)-N`-((pyridin-4-yl)methylene)furan-3-carbohydrazide (377).
On an alternative scheme, periodate oxidation of compound 327 afforded the corresponding formyl derivative: ethyl 5-formyl-2-methylfuran-3-carboxylate (378), which on treatment with aroylhydrazine derivatives gave the corresponding hydrazones: ethyl 5-((2-benzoylhydrazono)methyl)-2-methylfuran-3-carboxylate (379), ethyl 5-((2-(4-methoxybenzoyl)hydrazono)methyl)-2-methylfuran-3-carboxylate (380), ethyl 2-methyl-5-((2-(4-methylbenzoyl)hydrazono)methyl)furan-3-carboxylate (381), respectively.
Oxidative cyclization of these hydrazones 379-381, furnished the corresponding 1,3,4-oxadiazole derivatives; ethyl 2-methyl-5-(5-phenyl-1,3,4-oxadiazol-2-yl)furan-3-carboxylate (382), ethyl 5-(5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl)-2-methylfuran-3-carboxylate (383) and ethyl 2-methyl-5-(5-(p-tolyl)-1,3,4-oxadiazol-2-yl)furan-3-carboxylate (384), respectively.
Boiling of the derivatives 382-384 with hydrazine hydrate afforded the corresponding hydrazide derivatives: 2-methyl-5-(5-phenyl-1,3,4-oxadiazol-2-yl)furan-3-carbohydrazide (385), 5-(5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl)-2-methylfuran-3-carbohydrazide (386), 2-methyl-5-(5-(p-tolyl)-1,3,4-oxadiazol-2-yl)furan-3-carbohydrazide (387), respectively.
In addition, condensation of hydrazide derivatives 385-387 with 3-pyridinecarboxaldehyde and 4-pyridinecarboxaldehyde afforded the corresponding hydrazones: 2-methyl-5-(5-phenyl-1,3,4-oxadiazol-2-yl)-N`-((pyridin-3-yl)methylene)furan-3-carbohydrazide (388), 2-methyl-5-(5-phenyl-1,3,4-oxadiazol-2-yl)-N`-((pyridin-4-yl)methylene)furan-3-carbohydrazide (389), 5-(5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl)-2-methyl-N`-((pyridin-3-yl)methylene)furan-3-carbohydrazide (390), 5-(5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl)-2-methyl-N`-((pyridin-4-yl)methylene)furan-3-carbohydrazide (391), 2-methyl-N`-((pyridin-3-yl)methylene)-5-(5-(p-
tolyl)-1,3,4-oxadiazol-2-yl)furan-3-carbohydrazide (392), 2-methyl-N`-((pyridin-4-yl)methylene)-5-(5-(p-tolyl)-1,3,4-oxadiazol-2-yl)furan-3-carbohydrazide (393), respectively.
Oxidative cyclization of hydrazones 388-391, furnished the corresponding 1,3,4-oxadiazole derivatives; 2-(5-methyl-4-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)furan-2-yl)-5-phenyl-1,3,4- oxadiazole (394), 2-(5-methyl-4-(5-(pyridin-4-yl)-1,3,4-oxadiazol-2-yl)furan-2-yl)-5-phenyl-1,3,4- oxadiazole (395), 2-(4-methoxyphenyl)-5-(5-methyl-4-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)furan-2-yl)-1,3,4-oxadiazole (396) and2-(4-methoxyphenyl)-5-(5-methyl-4-(5-(pyridin-4-yl)-1,3,4-oxadiazol-2-yl)furan-2-yl)-1,3,4-oxadiazole (397), respectively.
The structure of the prepared compounds was ascertained from spectral data; infrared, 1H-NMR, 13C-NMR, 2D-NMR, and mass spectra.
The third chapter: showed the antioxidant effect and antimicrobial activity of number of the prepared compounds using two species of fungi and four species of bacteria showed that there have a remarkable growth inhibition of the examined microorganisms with different values depending on the structure of the prepared compounds and microorganism type.
On the other hand, the antiproliferative activity of the selected five compounds were tested against HCT-cell line, MCF-7cell line and HepG2 cell line which showed a remarkable activities.
The fourth chapter: include the experimental work carried out by candidate.
The result was illustrated by (53) tables, (92) figures. The thesis is ended by (222) references.