الفهرس 
Acknowledgment
Antifungal activity of griseofulvin and its analoguesOnly 14 pages are availabe for public view
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Abstract
The present study is concerning with the design and synthesis of some new griseofulvin derivatives and biological evaluation of their antifungal and anticancer activities. The thesis combines four main sections: introduction, scope of investigation, results and discussion and experimental section addition to references and summary. Introduction: contains some griseofulvin analogues and their biological activities and examples of drugs used in treatment of cancer via inhibition of mitosis. This section discusses problem of low water solubility of griseofulvin and its effect on the oral absorption and the reported methods for improvement of griseofulvin water solubility. Scope of investigation: this section presents the scientific basis of the search based on what was previously introduced in the introduction section of the therapeutic properties of griseofulvin derivatives and the problem of irregular oral absorption of griseofulvin from the gastrointestinal tract resulting from its low water solubility. So the thesis targeted preparation of some new griseofulvin derivatives to improve its antifungal or anticancer activity as well as to improve the solubility in water so as to improve absorption from the gastrointestinal tract. Results and discussion: this section combines five parts: Part I: the chemistry part, which includes an explanation of the various methods used in the preparation of intermediate and final compounds and confirmation of their chemical structures using IR, FT-IR, 1H-NMR, 13C-NMR and elemental analyses. In this thesis we reported synthesis of eight new final compounds 5-12 in addition to three reported intermediates 2-4. Chemical nomenclatures of these compounds are as follows: • (2S,6’R)-7-Chloro-4,6-dimethoxy-6’-methyl-3H-spiro[benzofuran-2,1’-cyclohexane]-2’,3,4’-trione (2) * • (2S,6’R)-2’-Benzyloxy-7-chloro-4,6-dimethoxy-6’-methyl-3Hspiro[benzofuran-2,1’-cyclohex[2]en]-3,4’-dione (3) * • (E/Z)-(2S,6’R)-2’-Benzyloxy-7-chloro-4’-(hydroxyimino)-4,6-dimethoxy-6’- methyl-3H-spiro[benzofuran-2,1’-cyclohex[2]en]-3-one (4) * • 2-((E/Z)-([(2S,6’R)-2’-Benzyloxy-7-chloro-4,6-dimethoxy-6’-methyl-3-oxo3H-spiro[benzofuran-2,1’-cyclohex[2]en]-4’-ylidene]amino)oxy)acetic acid (5). • (E/Z)- 2-((2S,6’R)-7-Chloro-2’,4,6-trimethoxy-6’-methyl-3-oxo-3Hspiro[benzo-furan-2,1’-cyclohex[2]en]-4’-ylidene)hydrazine-1-carboxamide (6). • 2-((2S,6’R)-7-Chloro-2’,4,6-trimethoxy-6’-methyl-3-oxo-3Hspiro[benzofuran-2,1’-cyclohex[2]en]-4’-ylidene)hydrazine-1- carboximidamide (7). • 3-[((2S,6’R)-7-Chloro-2’,4,6-trimethoxy-6’-methyl-3-oxo-3Hspiro(benzofuran-2,1’-cyclohex[2]en)-4’-ylidene)amino]propanoic acid (8). • (E/Z)-N’-(( 2S,6’R)-7-Chloro-2’,4,6-trimethoxy-6’-methyl-3-oxo-3H spiro [benzofuran-2,1’-cyclohex [2]en]-4’-ylidene)isonicotinic acid hydrazide (9). • 2-[(2S,6′R)-2’-Benzyloxy-7-chloro-4,6-dimethoxy-6’-methyl-3-oxo-3Hspiro[ benzofuran-2,1’-cyclohex[2]en]-4’-ylidene]hydrazine-1-carboxamide (10). • 2-[(2S,6′R)-2’-Benzyloxay-7-chloro-4,6-dimethoxy-6’-methyl-3-oxo-3Hspiro [benzofuran-2,1’-cyclohex[2]en]-4’-ylidene]hydrazine-1- carboximidamide (11). • 3-[((2S,6’R)-2’-Benzyloxy-7-chloro-4,6-dimethoxy-6’-methyl-3-oxo-3Hspiro [benzofuran-2,1’-cyclohex[2]en]-4’-ylidene)amino] propanoic acid (12). * Previously synthesized compounds. Part II: the biology part, this part reviews the results of the various biological studies that have been conducted on the synthesized compounds and divided into two parts: Evaluation of antifungal activity: Antifungal activity of compounds 5-12 was evaluated using eight different fungal strains, using griseofulvin and clotrimazole as reference drugs. The results showed that some of the prepared compounds have strong antifungal activity and experienced comparable or better activity than griseofulvin. Evaluation of anticancer activity: Anticancer activity of compounds 8 and 12 was evaluated according to the protocol of National Cancer Institute, NCI, USA, against a panel consisting of 60 human cancer cell lines, derived from nine cancer cell types (Leukemia, Non small cell lung cancer, Colon cancer, Central nervous system cancer, Melanoma, Ovarian cancer, Renal cancer, Prostate cancer and Breast cancer). The tested compounds 8 and 12 showed variable activities against the different cell lines. Moreover, compounds 5-7 and 9-11 were tested for anticancer activity against breast MCF-7 and colorectal HCT116 cell lines and the obtained results were compared to that of griseofulvin and 2’-benzyloxygriseofulvin (3). Compounds 10 and 11 showed higher activity than griseofulvin and compound 3 against MCF-7 and HCT116 cell lines. Part III: the study of molecular modeling. Molecular modeling (docking) study was performed using MOE software (V. 2016.08) for in silico evaluation of the binding characters of the synthesized compounds 5-7 and 9-11 in comparison to griseofulvin, compound 3 and taxol. The docking study revealed a significant effect of the added moieties on the binding of the tested compounds to the tubulin active site. Part IV: the study of physicochemical properties. The effects of the structural modification on the physicochemical and ADME-Tox properties of the synthesized compounds were also in silico studied and revealed that the modification increased the predicted water solubility and oral absorption of the target compounds 5-12. Part V: the study of solubility in water. Water solubility of the synthesized derivatives 5-12 at pH 1.2 and 6.8 buffer solutions was determined and compared to that of griseofulvin and compound 3. All investigated compounds revealed higher solubility values than griseofulvin and compound 3. Compounds 7, 9 and 11 had the highest solubility values at pH 1.2 buffer solution, while compounds 5, 8 and 12 revealed the highest solubility at pH 6.8 buffer solution. Expermintal: this section outlined the detailed explanations of different experiments used, this section includes four sections: Chemistry section described the different procedures used for synthesis of the synthesized compounds 2-12. This section also presented all detailed spectroscopic and analytical data of the synthesized compounds. Biology section outlined the different fungal strains used for evaluation of the antifungal activity of the synthesized compounds 5-12, as well as the methods used for evaluation of the anticancer activity of synthesized compounds 5-12. Molecular docking section described the methodology and software used for molecular docking of the target compounds 5-7 and 9-11. Physicochemical properties calculations and solubility measurement section includes the website used for calculation of physicochemical properties, and also contains the methods used for measurement of water solubility of the target compounds 5-12.