Synthesis Of Novel Imidazole Compounds And Their Relational Antimicrobial Study

Imidazole ring is an important and highly polar five-membered aromatic heterocycle. The researches and developments of imidazole-based compounds have been being quite active field due to their wide potential applications as medicinal drugs, agrochemicals and so on. Especially, the applications of imidazole derivatives in medicinal chemistry have achieved great progress. Furthermore, the electron-rich nitrogen heterocycle could not only readily accept or donate proton but also easily form diverse weak interactions. These special structural characteristics of imidazole ring are beneficial for its derivatives to readily bind with a variety of enzymes and receptors in biological systems, thereby exhibiting broad bioactivities. The imidazole ring should be vital to the physiological action for important biological activities since it is prevalently present in naturally occurring products and a range of bioactive substances. These specific physiological properties and unusually important roles in vital processes have been attracting special interest in imidazole-based medicinal chemistry. The presence of imidazole ring may be favorable for improving water solubility to some extent and has been extensively used to design and develop various bioactive molecules. Quinolones are an important kind of topoisomerase-targeting synthetic antibacterial agents. However, the increasingly worrisome resistance caused by the prevalently clinical use led to limited therapeutic efficacy in clinic. Therefore, the pursuit of structurally novel drugs with more efficiency, less toxicity and less resistance remains to be a highly challenging topic in medicinal chemistry. Based on the current situation in the researches of quinolone and imidazole in recent years, a series of novel quinolone imidazoles were designed and synthesized. These novel compounds were evaluated for their antimicrobial activity, and structure-activity relationships were also discussed and summarized. Cytotoxicity and ionization constants(p Ka values) of some highly active target compounds were evaluated to predict their pharmacokinetics behaviors. The interaction between active target molecules and human serum albumin and the preliminary antibacterial mechanism were also discussed. The main work was summarized as follows:(1) Preparation of novel quinolone imdazoles: Commercially available quinolones were N-alkylated by 2-(chloromethyl)oxirane to yield quinolones II-2a–c, subsequently the epoxy ring was opened by various substituted imidazoles and benzimidazoles in acetonitrile using potassium carbonate as base to produce target compounds II-3a–j,II-6a–j,II-7a–b,II-8a–e,II-9a–e and II-10.(2) Preparation of novel quinolone-based metronidazole derivatives: The intermediates 4-substituted derivatives of 2- methyl-5-nitroimidazole were first prepared from cyclic amino and 2- methyl-5-nitroimidazole. The following ring opened reaction by quinolones N-alkylated intermediates III-2a–c in acetonitrile with potassium carbonate as base to afford the target quinolone metronidazole derivatives III-3a–i.(3) Preparation of novel quinolone azolylthioethers: The N-alkylation of commercially available quinolones with 2-(chloromethyl)oxirane produced intermediates IV-2a–c. Commercially convenient azoles in acetonitrile were reacted with compounds IV-2a–c respectively at 75 oC in the presence of potassium carbonate as base to produce the target quinolone azoles IV-3a–c, IV-4a–f and IV-5a–f. The intermediates IV-7a–b were prepared by the reaction of thiosemicarbazide with halobenzyl halides IV-6a–b via a multi-component procedure without isolation of intermediates when dissolved in ethanol in the absence of base.(4) Preparation of novel quinolone benzimidazoles:(i) Commercially available quinolone V-1a reacted with formamide at 70 oC gave N-formyl quinolone V-2. Quinolones V-1a–b were esterified to afford the corresponding esters V-3a–b, and further treated with formamide to give N-formyl intermediates V-4a–b in high yields. The following cyclization in 1,4-dioxane with anhydrous copper sulfate accessed the target quinolone benzimidazoles V-6a–b;(ii) The intermediates haloalkyl benzimidazoles V-8a–f, V-10a–h and V-12a–g were prepared from o-phenylene diamines and halogen-substituted carboxylic acids. These prepared benzimidazole halides respectively were further coupled with the piperazine in quinolones V-1a–b to smoothly produce the target benzimidazole-quinolone hybrids V-13–16;(iii) Quinolone hybrids V-17a–b were conveniently prepared via Mannich reaction starting from quinolones V-1a–b and paraformaldehyde. Shiffbase-linked hybrids V-18a–b were smoothly obtained by condensation reaction of N- formyl quinolone esters V-4a–b with 2-aminobenzimidazole.(5) The newly synthesized compounds were characterized by 1H NMR, 13 C NMR, IR, MS and HRMS spectra.(6) The prepared intermediates and target compounds were evaluated for their in vitro antimicrobial activities. The biological assays indicated that some synthesized compounds could significantly inhibit the growth of tested microorganisms and some of them displayed equipotent or superior efficacies to the current clinical drugs. Notably, quinolone imdazolyl ethanol II-8b displayed comparable or even better antimicrobial activities in contrast with the reference drugs.(7) The interactions of compound II-8b, Cu2+ ion and MRSA DNA revealed that compound II-8b could intercalate into DNA through copper ion bridge to form a steady II-8b–Cu2+–DNA ternary complex which might further block DNA replication to exert the powerful bioactivities. Study of compound II-8b with human serum albumin indicated that compound II-8b could be effectively stored and carried by human serum albumin.(8) The ability of quinolone-based metronidazole III-3i to permeabilize the bacterial cell membrane was studied and revealed that tested compound was efficient in permeabilizing the membranes of both Gram-positive(MRSA) and Gram-negative(B. proteus) bacteria. Cell cytotoxic study suggested that the compound III-3i did not show cytotoxicity to human HEK 293, mouse MEFs and C2C12 cell lines.(9) Bioactive assay manifested that most of the azolylthioether quinolones exhibited good antimicrobial activities. Especially, imidazolylthioether quinolone IV-4e displayed remarkable anti-MRSA and anti-P. aeruginosa efficacies with low MIC values of 0.25 μg/m L, even superior to reference drugs. They induced bacterial resistance more slowly than clinical drugs. Molecular docking study indicated strong binding interactions of compound IV-4e with topoisomerase IV–DNA complex, which correlated with the inhibitory effect.(10) The investigations of quinolone benzimidazole V-15 m revealed that this compound was membrane active and did no t trigger the development of resista nce in bacteria. It not only inhibited the formation of biofilms but also disrupted the established Staphylococcus aureus and Escherichia coli biofilms. It was able to inhibit the relaxation activity of E. coli topoisomerase IV. Moreover, this compound also showed low toxicity against mammalian cells.One hundred and fifty-eight compounds were successfully synthesized in this thesis. One hundred and twelve compounds were new, including thirty three quinolone imdazolyl ethanols, twelve quinolone-based metronidazole derivatives, fifteen quinolone azolylthioethers, fifty two quinolone benzimidazoles.