Study On The Synthesis,Antifungal Activity And Structure-Activity Relationship Of 4-Fluorophenyl-1,5-Benzothiazepines Derivatives

1,5-benzothiazepine is a kind of important heterocycle compounds and has high biological activities and drug activities. Some benzothiazepine derivatives have become a drug in the treatment of cardiovascular diseases and used for clinical purposes. The deepening research found that 1,5-benzothiazepine derivatives have anticancer, fight ulcer,antispasmodic and affect blood circulation. At the same time, the antibacterial and bactericidal activity has attracted much attention.Our group found that 2-ethoxycarbonyl-4-phenyl-1,5-benzothiazepine and the fluorinated phenyl on C-4, 2-methoxycarbonyl/ethoxycarbonyl-1,5-benzothiazepine have strong inhibition for cryptococcus neoformans. It has great significance to find a new mechanism of action and special antibacterial function of miscellaneous drugs. On the basis of reservation of the structural feature of two-benzothiazepine mentioned above, the thesis design and synthesize the 4-difluorophenyl/trifluorophenyl/phenylcyclohexane trifluoromethyl substituted new benzothiazepine derivatives containing fluorine. The evaluation of the antifungal activity of these new compounds revealed that four difluorinated phenyl substituted benzothiazepine generally have good antibacterial activity, and the number and location of F, as well as the changes in the structure in benzene rings which on C-4 of seven-membered ring have little influence on activity of C. Neoformans. On the other hand,study the highly sensitive compounds structure-activity relationship, by removing the seven-membered ring ester group on two, reduction of mixed carbon and nitrogen of double bond, replace the S on the seven-membered ring atom synthesis such as four series1,5-benzothiazepine derivatives Through the active suppression test to the C. neoformans,discussed the molecular structure of the structure unit and the biological activity of contact.The thesis consists of two parts. The first part is the synthesis of4-difluorophenyl/trifluorophenyl/phenylcyclohexane trifluoromethyl substituted1,5-benzothiazepine derivatives and the evaluation of antifungal activity of these new compounds. The second part is the structure-activity relationship study of1,5-benzothiazepine derivatives with high activity on four aspects..The specific research work:1. Different F substituted acetophenone and glyoxylic acid and methanol/ethanol were used as raw materials, to synthesize α,β-unsaturated ketones by aldol condensation,esterification and eliminate reaction. α,β-unsaturated ketones with 2-amino thiophenol again after by Michael addition, intramolecular dehydration reaction, to synthesize a series of1,5-benzothiazepine. the structures of these new compounds are determined by IR, 1H-NMR,13C-NMR, HRMS, and according to the crystal structure, it was further confirmed that the compound structure is consistent with the designed compounds.2. The antifungal activities of those compounds were screened using the disk diffusion method against C. albicans and C. Neoformans. The results showed that the part of compound3a~3f especially of fungi C. Neoformans has high sensitivity, showed strong inhibition.Furthermore, with a concentration gradient test and the minimum bacteriostasis and minimum bactericidal test, the results showed that with fewer dose per piece, its bacteriostatic activity is diminished. The results revealed that the MIC and MFC values for the above compounds were much lower than those of fluconazole and the MIC80 was close.3. Study the highly sensitive compounds 3a~3f structure-activity relationship. Therefore,there are four series compounds synthesized which includes getting rid of seven-membered ring ester group on C-2, reduction of mixed carbon and nitrogen of double bond, replace the S on the seven-membered ring atom for the synthesis of O, N atoms. The antifungal activities of those compounds were screened and found that poor synthetic compounds bacteriostatic activity even disappear, the above results show that the molecules of the 1,5-benzothiazepine ester group on C-2, carbon and nitrogen double bond structure unit, and S atoms is necessary groups of this kind of compounds with antibacterial activity.