Design And Synthesis Of Novel1,2,4-triazole Quinoline Derivatives And Their Antimicrobial Activities And Supramolecular Chemistry

Quinoline ring is an important nitrogen-containing aromatic heterocyclic backbone. This unique structural feature endows quinoline derivatives to possess extensive potential applications in medicinal and supramolecular chemistry. Quinoline is a popular scaffold which is used to construct various bioactive agents, artificial ion receptors and molecular probes. In recent years,1,2,4-triazole analogues have been also frequently employed in drug developments especially as antimicrobial candidate compounds. Based on the current researches in quinoline derivatives, herein, a series of novel1,2,4-triazole quinoline carboxylic acids and1,2,4-triazole quinoline Schiff base compounds were designed and effectively synthesized, and the suitable condition for the synthesis of some target compounds was explored. All the newly synthesized compounds were evaluated for their antibacterial and antifungal activities in vitro and the preliminary structure-activity relationships were discussed. In addition, the supramolecular interactions of title compounds with metal ions and Bovine Serum Albumin (BSA) were also investigated. The main work was summarized as follows:(1) Synthesis of1,2,4-triazole quinoline carboxylic acids:The key intermediates1,2,4-triazole quinoline-4-carboxylic acids54a-g were prepared by multistep reactions including Friedel-Crafts, N-aralkylation and cyclization reactions starting from the commercially available materials substituted-benzene, chloroacetyl chloride,1,2,4-triazole and isatin, and then the chlorination of compounds54a-g with excessive thionyl chloride produced the acyl chloride intermediates. The subsequent reactions of acyl chloride55with heterocyclic amines including morpholine, piperazine, piperidine and pyrrolidine afforded the target compounds56a-d and59a-f respectively; with fatty amines (ethanolamine and diethanolamine) gave title compounds57a-d; with sulfonamide afforded1,2,4-triazole quinoline sulfonamide derivatives60a-f; the treatment of compound56b with hydrochloric acid afforded its corresponding hydrochloride58.(2) Synthesis of1,2,4-triazole quinoline Schiff bases:1,2,4-Triazole quinoline-4-carboxylic acid54g was transformed into the corresponding acyl chloride55g via chlorination reaction. The intermediate55g reacted with hydrazine hydrate (80%) in EtOH afford the acid hydrazide61with satisfactory yields. The following condensation reactions of compound61with various aldehydes including substituted benzaldehydes and aromatic heterocyclic aldehydes produced1,2,4-triazole quinoline Schiff bases62a-q and63a-b.(3) The suitable condition for the preparation of1,2,4-triazole quinoline-4-carboxylic acids54a-g was explored. The pH values of the reaction system exhibited great effect on the yields of the title compounds54a-g by influencing the quaternization of1,2,4-triazole moiety, and the weak acid solution (pH=3) was more favorable for the formation and precipitation of the desired compounds.(4) All these new1,2,4-triazole quinolines were characterized by IR,1H NMR and MS spectra, some of them were confirmed by13C NMR and HRMS spectra.(5) The in vitro antibacterial and antifungal evaluations indicated that most target compounds exhibited moderate to excellent antibacterial and antifungal activities, and some of them showed equipotent or superior activities in comparison with current clinical drugs. Especially,1,2,4-triazole quinoline carboxylic acids bearing2,4-difluorophenyl moiety gave better antibacterial potence than other analogues. It was noteworthy that1,2,4-triazole-derived quinoline hydrochloride58was able to effectively inhibit the growth of all test bacteria except for B. subtilis at concentration of4to32μg/mL.1,2,4-Triazole quinoline compounds57b with diethanolamine moiety and hydrochloride58showed effective antifungal efficacy with MIC values in the range of8-32μg/mL. The antibacterial results showed that1,2,4-triazole quinoline Schiff bases62e-g,62h-j and62k-n containing the electron-withdrawing character moieties like cyano, nitro groups and halogen atoms respectively displayed much better antibacterial activities than those of other compounds. Noticeably, compound62k gave the best anti-MRSA and anti-E. coli efficacies with MIC values of16and4μg/mL, which were greatly superior to Chloromycin (MIC=32and16μg/mL, respectively).(6) The preliminary structure-activity relationships manifested that the type of substituents in benzene ring played an important role in the antimicrobial activity. The bioactivity results revealed that2,4-difluorophenyl group was more favorable for their bioactivities than other halophenyl moieties. Furthermore, Schiff base moiety should be specially helpful for biological activity. The introduction of electron-withdrawing character moieties like cyano, nitro groups and halogen atoms could improve the antimicrobial efficacy of title compounds.(7) The supramolecular recognition of1,2,4-triazole quinoline compounds54g and62k to a series of metal cations were investigated by UV-Vis spectroscopy. It was found that compounds54g and62k could interact with Cu2+ion and construct1:1inclusion complexes. The binding constants Ks (L/mol) and gibbs free energy changes AG0(kJ/mol) were calculated. The specific interaction of1,2,4-triazole quinoline Schiff base62k with BSA (Bovine Serum Albumin) was evaluated by fluorescence spectrophotometer. The experimental results demonstrated that they can form ground-state supramolecular complexes; the drive forces of this process mainly came from the hydrogen bonds interactions and van der Waals. The combination of compound62k with BSA was favorable for the storage and transmission in blood and the targeting function of the compound in vivo. The good property of compound62k made it worthy to be further investigated as potential antimicrobial agent.In summary, forty seven compounds were successfully synthesized in this thesis and all the compounds were new including seven1,2,4-triazole quinoline-4-carboxylic acids, nineteen1,2,4-triazole quinoline amides, one1,2,4-triazole quinoline hydrochloride, one1,2,4-triazole quinoline hydrazide and nineteen1,2,4-triazole quinoline Schiff bases.