Design And Synthesis Of Novel Benzotriazoles And Their Antimicrobial Evaluation

Benzotriazole and its derivatives are an important type of aromatic poly-nitrogen heterocyclic compounds, which have been widely applied in medicinal chemistry and possess large developing value. As a bioisoster of important pharmacophores such triazole, imidazole and benzimidazole, benzotriazole could form various noncovalent bonds including hydrogen bonds, coordination bonds and π-π stacking interactions, regulate the lipid-water partition coefficient of medicinal agent, and improve their physico-chemical property as well as pharmacokinetic property, then improve the bioactivities of drugs. In comparison with triazole, benzotriazole has a larger conjugated system, the unique structure makes it more readily bind with different enzymes and receptors in organism, thus exhibiting a broad range of biological and pharmacological activities including anticancer, antifungal and antibaciterial activity and so on. Therefore, benzotriazole has been widely used to construct drugs molecules. On the basis of current domestic and internationl research status of benzotriazole compounds in the antimicrobial field, this thesis designed and synthesized novel series of benzotriazole fluconazole analogs derivatives and benzotriazole quinoline analogs, and evaluated their antimicrobial activities. The main contents were summarized as follows:The novel benzotriazole fluconazole analogues were synthesized via a series of reactions from commercially available substituted benzenes. The chemical structures of all the newly synthesized compounds were characterized through 1H NMR, 13C NMR, IR and MS spectra. The in vitro bioactive assay suggested that most of the newly synthesized compounds possessed comparable antifungal and antibacterial activities to the reference drugs or even better antifungal and antibacterial activities than the reference drugs toward the test strains. Halobenzyl tertiary amine tetrazole derivatives exerted relatively better activities in inhibiting the growth of tested strains in comparison with alkyl compounds. Among them, compound 501 displayed good antibacterial activity against MRSA with MIC value of 4 μg/mL, which was 2-fold more potent than Chloromycin, and it aslo displayed 3-fold stronger antifungal activity (MIC=4 μg/mL) than Fluconazole (MIC=16 μg/mL) against Beer yeast. The obtained antimicrobial results also revealed that benzotriazolyl oxirane displayed stronger antimicrobial activity and broader antimicrobial spectrum than benzotriazolyl ethanone. Futhermore, the interaction of compound 501 with calf thymus DNA displayed that compound 501 could effectively intercalate into DNA to form a compound 501-DNA complex that might futher block DNA replication and thereby exert good antibacterial and antifungal activities. Molecular docking experiments suggested that compound 501 projected into base-pairs of DNA hexamer duplex, forming two hydrogen bonds with guanopterin of DNA. The theoretical calculations were in accordance with the experimental results.The novel series of benzotriazole bromoethylamino quinoline derivatives as Fluconazole analogues were synthesized from commercially available substituted phenylamines. The chemical structures of newly synthesized compounds were characterized by 1H NMR,13C NMR, and MS spectra. The single crystal of compound 54d was obtained by solvent evaporation method at room temperature. Its crystal structure was determined by Brucker SMART diffractometer to confirm the spatial structure of this compound. Bioactive assay suggested that most of the intermediate and target compounds could effectively inhibit the tested strains. Particularly, compound 55d exhibited better antibacterial activity (MIC=4 μg/mL) against MRSA in comparison with Chloromycin (MIC=16μg/mL) and Norfloxacin (MIC=8 μg/mL). In addition, compound 55c showed comparable antifungal acitivity (MIC=16 μg/mL) to the reference drug Fluconazole against Beer yeast. The preliminary structure-activity relationships showed that the introduction of halogen group and benzotriazole enhanced the antimicrobial activities of compounds to some extent. However, the incorporation of hydroxyl group could not improve the biological activity. The interaction between the most bioactive compound 55d with DNA was explored by the UV-vis absorption spectroscopic method. The results suggested that compound 55d could intercalate into DNA to form 55d-DNA complex, which might further block DNA replication to exert its antimicrobial activities.