One of the most significant breakthroughs in the battle against tuberculosis is the recent approval of the quinoline compound, TMC207, for the treatment of drug-resistant tuberculosis. To gain insight into the molecular determinants of the activity of TMC207 and to evaluate the scope of quinoline compounds as antitubercular agents, we synthesized a series of TMC207 derivatives and evaluated their anti-tubercular activity. Making the lateral chain of the drug rigid by linking it to an adjacent phenyl substituent resulted in a decrease in activity. In contrast, replacing a phenyl substituent of TMC207 with a quinoline moiety gave bisquinolines that demonstrated potent antitubercular activity in in vitro experiments, in ex vivo mouse bone marrow macrophage assays, and also in in vivo mouse model of the disease. These results provide new guiding principles for modifying the TMC207 scaffold for developing efficacious anti-tubercular drugs and set the stage for the development of bisquinolines as a promising new class of antitubercular agents.