Synthesis, Antimicrobial And Antitumor Activities Of Azole-based Piperazine Derivatives

Piperazine derivatives were extensively investigated and used as drugs in the field of medicinal sciences, and actively investigated in antibacterial, antifungal and anti-cancer aspects. Azole rings including triazole, imidazole and benzimidazole ones were important pharmacophores in drug design, and many outstanding achievements in their derivatives as antibacterial, antifungal and anti-cancer agents have been obtained. Based on the recent advances in the research and development of piperazine derivatives, in this thesis, azole-based piperazine derivatives and 1,2,3-triazole linked piperazine derivatives have been designed and synthesized, and were investigated in vitro for their antimicrobial and antitumor activities. Some reaction conditions and structure-activity relationships were also discussed. The main contents are as follows:A series of azole-based piperazine derivatives were prepared from the commercially available (4-chlorophenyl)(phenyl)methanone as starting materials through multisteps. The key chloride intermediates cholroethyl piperazine 46, cholropropyl piperazine 47 and chloracetyl piperazine 48 were obtained by the reduction of compound 42 with sodium borohydride, chlorination with sulfurous dichloride, N-1 aralkylation of piperazine and its N-4 chloracetylation or alkylation. The reactions of 46-48 with respectively triazole, benzotriazole, imidazole or benzimidazole to afford the target compounds 49-54.The novel 1,2,3-triazole piperazine derivatives 63-68 were synthesized by the reaction of azides 61 and 62 with corresponding terminal alkyne compounds 56-60. The azides 61 and 62 were prepared by the reaction of chloride 47 and 48 with sodium azide, and the alkyne compounds 56-60 were obtained by the reaction of propargyl bromide with azoles, phenol, sulfanilamide or enorxacin separately in the presence of K2CO3. The N-alkylation of chloracetyl piperazine 48 with sulfanilamide or enorxacin afforded the corresponding sulfanilamide piperazine 69 and enorxacin derivative 71.All the new synthesized compounds were confirmed by IR,1H NMR and MS spectra.Their preliminary antimicrobial assays showed that most compounds exhibited moderate to good antibacterial and antifungal activities, especially compounds 48,52b and 52e gave remarkable and broad-spectrum antimicrobial efficacy with MIC values ranging from 3.1 to 25μg/mL. These compounds were also effective against methicillin-resistant Staphylococcus aureus, comparable to that of standard drug chloramphenicol against this bacterium. These compounds are promising for further research and development as antimicrobial agents.The structure-activity relationships showed that the heterocyclic moiety had noticeable effect on the antibacterial activities. The imidazolyl or 2-phenyl imidazolyl residues should have the synergistic effect on biological activities, and their derivatives 52b and 52e were most potent antimicrobial agents among azole-containing piperazine derivatives 49-54. Compared to the compounds 49-54,1,2,3-triazole-bridged piperazine derivatives 63-68 showed poor antimicrobial activity. The replacement of azole rings with diverse phenols resulted in the decrease or complete loss of their activity. The introduction of sulfanilamide or enorxacin also led to the decrease in their antimicrobial activity. These facts suggested that the azoles were important functional moieties for their antimicrobial activity. Besides, spirocyclopiperazinium salts displayed moderate antibacterial and antifungal activities. Their activities increase proportionately as the length of the carbon chain increases up to 5 atoms, beyond which antibacterial activity decreases dramatically.The antitumor activity showed that nineteen synthesized piperazine derivatives exhitibed inhibitory activity against PC-3 cell to some extent, and 1,2,3-triazole linked piperazine derivatives 63-68 showed weaker antitumor activity than azole containing piperazine derivatives 49-54. The structure-activity relationships also showed that the heterocyclic moiety had noticeable effect on the antibacterial activities. Compounds 49 and 53a with the benzimidazole nucleus were found to be the most effective in vitro, both of them could inhibit more than 70% growth of the PC-3 at the concentration of 100μM, which was deserved to further development. However, replacement of benzimidazole with imidazole or triazole ring would resule in the decrease of their antitumor activity.In this work, fifty compouds were successfully synthesized. Among these prepared compounds, thirty-three compounds were new including fourteen azole based piperazine derivatives, thirteen 1,2,3-triazole linked piperazine derivatives, one sulfanilamide piperazine, one enorxacin derivative and two azide intermediates, two terminal alkyne compounds..