Synthesis And Properties Of Antimycobacterium Compounds Based On Benzimidazole

Benzimidazole compounds are promising azo-containing heterocyclic compounds in the field of medicinal chemistry.With the in-depth research of many researchers on benzimidazole compounds,many applications of them in organic synthesis and medicinal chemistry have been discovered.Benzimidazoles have good biological activities in the fields of anti-inflammatory,analgesic,antiviral infection and antifungal,and they can also be used in the treatment of tumor,hypertension,diabetes,HIV and other major diseases.Recent studies have found that benzimidazole derivatives have good effects against Mycobacterium tuberculosis.Based on above all,a series of new 1,2,5-trisubstituted benzimidazoles and pyrimidine-benzimidazoles containing cyano group,halogen,thiophene ring,piperazine ring and pyrimidine ring were designed and constructed according to the structure-activity relationship of the drug molecules,which were expected to exhibit excellent anti-Mycobacterium activity.The main research work is as follows.1.On the basis of previous research,15 kinds of 2,5-disubstituted benzimidazole were synthesized by employing substituted o-phenylenediamine and different aromatic aldehydes as raw materials under microwave-assisted condition.Furthermore,15 new 1,2,5-tri-substituted benzimidazole were prepared using K₂CO₃as an acid-binding agent under microwave irradiation on the basis of the optimized reaction conditions.The method had a wide range of substrate adaptability.The target products with a yield of 66-99%can be obtained within 15 min.Besides,the effects of different substituents on the yield of the target product were investigated,and the reaction mechanism was speculated.2.In this paper,on the basis of confirming the structures of 2-mercapto-4-hydroxy-6-methylpyrimidine,2,4-dihydroxy-6-methylpyrimidine,2-amino-4-hydroxy-6-methylpyrimidine and 5 kinds of 2-chloromethylbenzimidazole derivatives,the effects of heating method,material feeding ratio,acid binding agents and alcohol water ratio on the yield of 2-（（（5,6-di-substituted 1H-benzimidazol-2-group）methyl）thioate）-6-methylpyrimidine-4-ol were investigated by choosing the sulfur alkylation reaction of 2-mercapto-4-hydroxy-6-methylpyrimidine and 2-chloromethylbenzimidazole as the model reaction.The optimal synthesis condition was determined,and five designed target products were successfully synthesized.On this basis,the synthesis of 2,2’-(（（6-methyl pyridine-2,4-2）dual（oxygen））double（methylene）double（5,6-instead of 1H-benzene and imidazole）was explored.It can be seen that the nucleophilicity of sulfhydryl,hydroxyl and amino groups directly affected the smooth proceeding of alkylation reaction.3.On the basis of the characterization of the synthesized 1,2,5-tri-substituted benzimidazoles and pyrimidine-benzimidazoles by high resolution mass spectrometry（HRMS）,infrared spectroscopy（IR）,nuclear magnetic ¹H and ¹³C spectra,and crystal structure analysis,the antibacterial activity of the synthesized compounds against Mycobacterium smegmatis（highly homologous to Mycobacterium tuberculosis）was evaluated.In conclusion,the target product 1,2,5-trisubstituted benzimidazole was synthesized by an environmentally friendly method with short reaction time and high yield,which laid the foundation and provided basic data for the industrial production of it.Besides,the synthesized compounds exhibited good anti-Mycobacterium smegmatidis activity,which laid a foundation for the design of antituberculosis drugs based on benzimidazole.