The antibacterial activities of a series of triazolyl oxazolidinones against Mycobacterium tuberculosis strain in vitro and in vivo in a mice model are presented. Most active compounds were noncytotoxic against VERO cells with acceptable selectivity indexes (SI) as measures of compound tolerability. Structure activity relationships (SARs) revealed that analogs with alkylcarbonyl (IC90: < 0.2 to 0.422？μg/mL) and arylcarbonyl (IC90: < 0.2 to 2.103？μg/mL) groups at the piperazine 4N-position-displayed potent antimycobacterium activities, comparable to the methanesulfonyl (IC90: < 0.2？μg/mL) analog, linezolid (IC90: < 0.2？μg/mL), and isoniazid (IC90: < 0.034？μg/mL). The furanylcarbonyl derivative also displayed potent activity, while the arylsulfonyl analogs were inactive. Of the triazolyl oxazolidinones, the morpholino (PH-27) derivative with medium bioavailability in plasma was most active in vivo, but relatively less efficacious than isoniazid. 1. Introduction Tuberculosis (TB) caused by Mycobacterium tuberculosis, a contagious and fatal disease, is considered a global epidemic and a major threat to public health. TB is becoming more prevalent in the world today than any other time in human history. It has been estimated that over a third of the world’s population is infected with the TB bacilli, with 9.4 million new cases and nearly 1.7 million deaths in 2009 [1, 2]. Most infected people harbor latent TB infection (LTBI), and people with HIV/AIDS and compromised immune system are more likely to develop the disease. TB continues to be a leading cause of death in HIV/AIDS patients, forming a lethal combination. A number of drugs, namely, isoniazid, rifampicin, ethambutol, and pyrazinamide are often administered over a prolonged period of time and may lead to the development of resistant strains due to patient-poor compliance among other factors. The development and spread of resistant M. tuberculosis, pose a vital challenge to the control of TB world-wide. In recent years, the emergence and spread of resistant M. tuberculosis strains has fuelled the TB epidemic by making it more difficult to treat. Multidrug-resistant (MDR) TB, which is resistant to the first line anti-TB agents, namely, isoniazid and rifampicin are increasing with >500,000/yr new cases of MDR-TB worldwide [3, 4]. Extensively drug-resistant (XDR) TB, resistant to first line anti-TB agents, namely, isoniazid, rifampicin, fluoroquinolones, and one of three injectable drugs, such as capreomycin, kanamycin, or amikacin is awfully difficult to treat and is considered a worldwide threat to TB
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