Synthesis And Antimicrobial Activity Of Novel Bis-Azole Derivatives

Research and development of azole antimicrobial agents have become one of hot area in medicinal chemistry. Based on the current investigative situation of azole agents, a series of novel bis-imidazole and bis-benzimidazole compounds as antibacterial and antifungal agents were designed, synthesized and evaluated for antimicrobial activities of these novel compounds in vitro in this thesis.Novel bis-azole compounds were divided into two parts: alkyl and aralkyl bis-imidazoliums and tertiary amine-type bis-imidazoles. Alkyl and aralkyl ones were prepared from commercial imidazole. The intermediate imidazole sodium, which was obtained by treatment of imidazole with NaH, reacted with halobenyl chloride to afford the mono-imidazoles (21a ~ 21c), and the laters reacted with a series of alkyl and aralkyl dibromides to yield the target bis-imidazolium compounds (22a ~ 22b). The tertiary amine-type bis-imidazoles were synthesized from substituted benzyl chloride as starting material. The reaction of halobenzyl chlorides with diethanolamine gave the diols (23a ~ 23d), then were brominated with PBr3 to afford the dibromides (24a ~ 24d), after that reacted with imidazole to yield the target bis-imidazole compounds (25a ~ 25d).Novel bis-benzimidazoles compounds could be prepared by two synthetic routes. One is to use benzimidazole as starting material, first to prepare benzimidazole sodium, and then react with substituted benzyl chloride to synthesize the mono-benzimidazole intermediates (26a ~ 26c), after that react with a series of alkyl and aralkyl dibromides to afford the target bis-benimidazolium compounds (27a ~ 27k). Another synthetic route is that benzimidazole first reacted with dibromide to prepare bis-benimidazole compounds (28a ~ 28b), then quaternized with substituted benzyl chloride to yield the target bis-benimidazoliums (27l ~ 27m).All the synthesized compounds were confirmed by IR, MS, 1H and/or 13C NMR spectra.The preliminary antimicrobial activities against 2 fungi (Aspergilus fumigatus,Candida albicans) and 5 bacteria (Bacilus proteus,Escherichia coli,Pseudomonas aeruginosa,Bacillus subtilis,Staphylococcus aureus) showed most of synthesized compounds among tested bis-azoles and their intermediates exhibit significant antibacterial activity. Compounds 22a, 27c, 27e, 27f, 27k, 27l and 27m) gave better activity against some bacteria than two reference drugs chloramphenicol and nofloxacin; all compounds showed less antifungal activities than the drug fluconazole in clinic. Among all compounds, bis-benzimidazole compound 27k showed best antimicrobial activities both fungi and bacteria.Bis-azoliums displayed better antibacterial activity than bis-azoles, and bis-benzimidazoles is better than bis-imidazoles for biological activity, possible reason is that benzimidaozle has one aromatic benzene ring, could help to interact between synthesized compounds and fungi or bacteria.Orth-chloro, meta-chloro and para-chloro benzyl group can help to strengthen antibacterial activities, 2,4-difluoro and 3,4-dichloro derivatives gave better activities , but the difference is very small.In this thesis, 35 compounds were synthesized, including 16 intermediates, 6 bis-imidazoles and 13 bis-benzimidazoles, all bis-azole compounds are new compounds.