Design And Synthesis Of Novel Benzimidazoles And Evaluation For Their Antimicrobial Activities

Benzimidazoles as important aromatic fused heterocycles containing a phenyl ring and an imidazole ring, possess larger conjugated system and stronger electron transport abilities than those of benzene and imidazole, which led to its extensive applications in chemical and medicinal fields. Recently, antimicrobial resistance, including antibiotic resistance, has become a threat to health of human beings. The development of novel antimicrobial agents which were different from that of well known classes of antimicrobial drugs, may be served as an excellent strategy to overcome antimicrobial resistance. A large number of researches indicated highly active benzimidazole molecules may inhibit microbial DNA transcription, replication or hinder its important metabolites, thus exerting powerful antimicrobial activities by affecting the normal life cycles of microorganisms. Especially, the latest research revealed that novel benzimidazole derivatives could inhibit cell division. Therefore, the modification of benzimidazole ring to design and synthesize novel structural bioactive molecules has aroused great attention. Based on the current investigation and development in benzimidazole derivatives, a series of novel benzimidazole derivatives were designed and synthesized. The structures of all the new compounds were characterized by modern spectra. Their antimicrobial activities were evaluated and the preliminary structure-relationships were also investigated. The interactions of highly active compounds with DNA were further investigated by fluorescence and UV-Vis spectroscopic methods. The mechanisms of antimicrobial action mechanisms were proposed. The main contents were summarized as follows:(1) A novel series of benzimidazole derived naphthalimide triazoles and the corresponding triazoliums have been successfully synthesized and characterized by 1H NMR,13C NMR,1H-1H COSY, IR and HRMS spectra. All the new compounds were screened for their antimicrobial activities in vitro by two-fold serial dilution. 2-Chlorobenzyl triazolium Ⅱ-8g and the compound Ⅱ-9b with octyl group exhibited the best antibacterial activities among all the tested compounds, especially against S. aureus with minimum inhibitory concentration of 2 μg/mL which was equipotent potency to Norfloxacin (MIC=2 μg/mL) and more active than Chloromycin (MIC=7 μg/mL). Triazoliums Ⅱ-8g and Ⅱ-8f bearing 3-fluorobenzyl moiety displayed the best antifungal activities (MIC=2 - 19 μg/mL) against all the tested fungal strains without being toxic to PC 12 cell line within concentration of 128 μg/mL. Further investigations via fluorescence and UV-vis spectroscopic methods revealed that the compound Ⅱ-8g could effectively intercalate into calf thymus DNA to form the Ⅱ-8g-DNA complex which could block DNA replication, exerting powerful antimicrobial activities.(2) A novel series of benzimidazole derived naphthalimide as artificial intercalators have been successfully synthesized for the first time via convenient and efficient synthetic procedures and characterized by 1H NMR,13C NMR, IR and HRMS spectra. All the new compounds were screened for their antimicrobial activities in vitro by two-fold serial dilution. The benzimidazole derived naphthalimide triazole hydrochloride salt Ⅲ-7e exhibited potent activities and broad antibacterial spectrum against the tested strains with MIC values ranging from 4 to 64 μg/mL except for B. proteus, especially against S. aureus with minimum inhibitory concentration of 4 μg/mL which was more active than Chloromycin (MIC= 8 μg/mL). Further investigations by fluorescence and UV-vis spectroscopic methods revealed that compound Ⅲ-7e as the artificial intercalator could effectively intercalate into S. aureus DNA to form the Ⅲ-7e-DNA complex which could block transcription and replication as well as DNA repair processes, and thus exerted their powerfully antimicrobial activities. Subsequent the molecular docking results showed that compound Ⅲ-7e and the residue ARG-144 and ARG-84 of the gyrase-DNA complex could form hydrogen bonds.