The Crystal Structure Of Fluconazole Drug Research

Fluconazole is a wide–spectrum triazole antifungal agent, which can strongly and continuely inhibit the synthesis of fungi sterol. It is commonly used in the treatment of localized candidiasis, systemic candidiasis, cryptococcal meningitis because of its broad spectrum, effective antifungal activity, especially for deep suppression, and it can through the distinctive features of the blood–brain barrier. It is the first selection of deep antifungal drugs.From the coordination chemistry’s point of view, fluconazole drug is an ideal ligand. It contains five potential coordination atoms, and it has higher symmetry and strong coordination ability: N atom from triazole 4–even can bridge the metal and in 2–even can chelate with the metal. Fluconazole drug potential coordination geometry lay a good foundation for synthesis of crystals.Therefore, in this work, we present 13 new crystals of fluconazole with different structures, which were synthesized by using six kinds of metal salts, and introdecing succinic acid, fumaric acid, molonic acid, 5–hydroxy isophthalic acid as the second ligands at the same time. All compounds were structurally characterized by X–ray single–crystal diffraction together with X–ray powder diffraction, infrared spectroscopy and thermogracimetric analysis, element analysis. The crystals show different structural characteristics which affected by coordination tendency of metal cation, reaction conditions, anionic and so on. We summarize the new crystals of fluconazole drug law of coordination, structure characteristic and the factor of influencing the fluconazole coordination polymer structure. It is of great importance for further design and synthesis.This thesis mainly is divided into two parts. The first part studies the synthesis of fluconazole hydrate, testing the solubility in various solvents and it has good solubility in general organic solvents, but poorly soluble in water, carbon tetrachloride, hexane, diethyl ether, petroleum ether. We use a variety of methods to its crystal structure has carried on the preparation, and characterization.The second part synthetizes 13 new crystals with using fluconazole drug as raw materials. The coordination polymers 1, 2, 6 are using Cu(NO3)2, CuCl2 to introduce Cu(II) ion and crystallizing in the polar monoclinic space group P21/c. In compounds 1 and 2, the hydroxyl oxygen and N atom from triazole 2–even chelate with the metal Cu(II) ion forming 0d structure. In compound 6, fluconazoles bridge metal ions to form one-dimensional chain structure and then via the O–H···Cl hydrogen bonds built into two–dimensional. In compounds 3 to 5 have been synthesized using CuCl2 and succinic acid. 3 and 4 crystallize in polar triclinic space group P–1, and 5 belong to monoclinic space group P21/c. In compound 3, the succinic acid as a terminal ligand, bridge Cu(II) ions to form dinuclear copper unit. One of the structural unit in 4, fluconazoles bridge metal ions to form 1d chain structure and the 1d chain generates a 2d on the basis of hydrogen bonds. The other structural unit exhibits a 1d chain via the aromatic stacking which filling in between two–dimensional layer to generate a 3d network structure on the basis of hydrogen bonds. In compound 5, the fluconazole ligand bridging to metal ions to from a 40–menberd macrocyclic fragment, it exhibits a 2d network by macrocyclic fragment mediastinal arraged alternately, and the succinic acid bridging the 2d network to form a double–layer structure and then constructed 3d network through hydrogen bonds. Compounds 7–10 were synthesized by using Cu(NO3)2, and introducing fumaric acid, malonic acid, 5–hydroxy isophthalic acid as the second ligands at the same time. 7 and 10 crystallize in polar triclinic space group P–1, and 8–9 belong to monoclinic space group P21/c. Among them, 7–9 exhibit a 2d structure, and the fumaric acid and molonic acid are as terminal ligands in compound 8 and 9. When hydrogen bonding interaction in 8 and 9 can be taken into topological considerations, the 3d supramolecular architecture of them could be topologically described with the Schl?fli symbol(4·82)(4·85), and the connectivity of 7 can be simplified as a(3,3,5)–connected 3d network and overall Schl?fli symbol can be described as a(4·6·8)(4·64·84·10)(63). Compound 10 is one-dimensional chain structure. Compound 11–13 represent the 1d chain and crystallizing in the polar triclinic space group P–1.We tentatively researched and the results indicated that complexes 7–9 had nearly ineffective cytotoxic activity onto A549 cell line. The mechanism remains to be further studies and determined.