Tuberculosis (TB) is presently regarded as one of the most dangerous infective diseases worldwide and one of the major AIDS-associated infections. To shorten the current treatment regimen, there is an urgent need to identify new anti-TB agents which are active against both replicating TB (R-TB) and nonreplicating TB (NRP-TB). Mefloquine, a well-known antimalarial drug was found to possess reasonable activity against NRP-TB, and accordingly, 30 new analogues were synthesized and evaluated for their anti-TB activity against Mycobacterium tuberculosis H(37)Rv. As the target of mefloquine in Mycobacterium tuberculosis remains unknown, we resorted to modifying mefloquine in a variety of chemically convenient ways, which led us in turn to the active hydrazone 10 a. Further modifications of 10 a led to compound 7 f, with an improved anti-TB activity/selectivity profile with both less cytotoxicity and less predicted CNS side effects compared with mefloquine. The clear structure-activity relationships (SARs) derived from this study should facilitate our ultimate goal of identifying improved anti-TB agents.