Design, Synthesis, And Antibacterial (Antifungal) Activities Of Imidazoles Derivatives

There are two parts in my dissertation:Part 1, design, synthesis, and antibacterial (antifungal) activities of 2-imidazolyl-2,4-diene ketone derivatives. The cure of infectious diseases becomes more and more difficult due to the emergence of new type pathogenic fungi and the frequent development of resistance to the existing drugs used in clinical in recent years. So there is an urgent need for the discovery of new compounds with antifungal activities. Compound 14 (MIC= 2～16 μg/mL) containing an imidazole moiety and a 2,4-dienone motif with significant activity toward several fungi was discovered in our screening. Then, a total of 25 derivatives of this compound were designed, synthesized and their inhibitory activities against eight kinds of selected clinical isolates were evaluated through in vitro assays. Among them,9 (27-29、32、34、37、40-41、44) compounds exhibited strong antifungal activities (0.25 μg/mL ≦ MIC≦ 64 μ.g/mL) against at least four kinds of test fungi,3 compounds (29、40、41) showed strong antifungal activities (0.25μg/mL≦ MIC≦ 64 ug/mL) against all test fungi. The antifungal activities of compounds 29 and 40 were more potent than that of the lead compound, and even these two compounds exhibited potent antifungal activities toward the fluconazole-resistant isolate C. albicans 64110 (MIC= 8 μg/mL). In addition, they had significant inhibitory effects toward two Gram-positive bacteria (MIC= 4～8 ug/mL). The results of antifungal activity studies in vivo indicated that compound 29 showed good therapeutic effect to the fluconazole-resistant isolate C. albicans 64110 (ED50= 2.693 mg/kg/day). All of these results fully explained that the compound 29 developed by this paper exhibited strong, broad-spectrum inhibitory effects toward Candida spp. Based on the results of antifungal activity in vivo, the structure-activity relationship of 2-imidazolbasely-2,4-diene ketone derivatives was summarized, which provided a structural basis and design ideas for the development of new, broad-spectrum and anti-resistant fungi drug in the future.Part 2, design, synthesis, and antibacterial activities of 2-imidazolyl-1,4-diene-3-ketone derivatives. Bacterial infection is a kind of quite prevalent diseases. A large number of antibiotics and synthetic drugs and so on are avalible in clinic. These drugs have been playing a vital role in the treatment of infectious diseases. However, despite increased awareness and improved treatment strategies, the frequent development of resistance to the antibacterial drugs used in clinical settings contributes to the the death of millions of people. Therefor there is a pressing need for the discovery of new compounds with antibacterial activities. Two compounds 68-69 were discovered previously in our group, which exhibited good inhibitory effects on Staphylococcus aureus UA1758 and Staphylococcus epidermidis UF843 (MIC 8-32 μg/mL). A new structural framework 70 was obtained by combining 68 and 69. Then, a total of 30 derivatives (72-101) of this compound were designed, synthesized and their antibacterial activities toward two kinds of selected clinical isolates were evaluated through in vitro antibacterial activity assays. There were half of compounds exhibited strong antibacterial activities (1 μg/mL≦ MIC≦ 32 μg/mL) against at least one kind of test strains. Among them,9 compounds (74、76、82、84、86-89、92) showed strong inhibitory activities (1 μg/mL ≦ MIC≦16 μg/mL) against both of the test strains; the antibacterial activities of five compounds (76、86、88-89、90) were more potent than that of the lead compounds 68-69. The inhibitory activities of nine compounds (74、76、82、84、86-88、92) against five kinds of Gram-negative isolates which were collected from clinic were evaluated. But all the compounds were invalid (MIC> 128μg/mL). It is indicated that the compounds developed by this paper can selectively inhibit Gram-positive bacteria. Based on the results of antibacterial activity in vitro, the structure-activity relationship of 2-imidazolbasely-1,4-diene-3-ketone derivatives was summarized, which provided a good lead compound structure for the development of new and anti-Gram-positive bacteria drug candidates in the future.