Design And Synthesis Of Bedaquiline Analogs As Potent Inhibitors Of Drug-resistant TB

Tuberculosis is caused by mycobacterium tuberculosis, which is a common human disease predominantly affecting the developing world. Tuberculosis is often co-infected with human immunodeficiency virus( HIV). The emergence of muhidrug resistant( MDR) and extensively drug-resistant( XDR) tuberculosis has made the situation more serious. Therefore, there is an increasing demand for new anti-tuberculosis drugs to efectively control the disease, in which the bedaquiline analogs have good inhibitory activity in MDR-TB.The design idea of this paper is showed that a practical method for construction of substituted dibenzo[b,f]oxepin-one derivartives(the compound 3) from easily prepared substituted 1-[2-(2-Bromo-Phenoxy)-phenyl]-ethanone(the compound 1) by two steps dual Pd-catalyzed intramolecular α-arylation of ketone and Pd-catalyzed intermolecular α-arylation of ketone was established and the two steps can be achieved by one-pot reaction. The product obtained is transformed to conformation-immobilized bedaquiline analogues by acetamide anion attacting carbonyl and carbonyl reduction.This method has the characteristics of easily prepared materials, easy steps, excellent yields and high dioselectivities. Ten bedaquiline analogs obtained have been tested. The compound V4 exhibited efficient anti-TB activity. The compound V4 showed the most potent inhibitory activity(MIC=8 μg/ml for drug-resistant Mycobacteriun tuberculosis). These findings expanded the chemical diversity of drug-resistant Mycobacterium tuberculosis inhibitors.