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This success has led to the development of potentially safer analogues of bedaquiline and a search for alternative classes of ATP synthase inhibitors. In particular, the spectacular success of the drug bedaquiline in treating multi-drug-resistant TB (MDR-TB) by inhibition of the mycobacterial enzyme ATP synthase has resulted in a largely curative regime (NIX-TB) for this disease, despite bedaquiline's side effect of hERG channel inhibition. These are aimed at a wide variety of mycobacterial targets, including the control of gene expression, inhibition of drug efflux pumps, and of proteins in the mycobacterial electron transport chain. The rise of drug-resistant tuberculosis (TB) in recent times has become a major global health problem, and this resurgence of such a major infectious disease has also provided an impetus for the development of new classes of drugs. Ultimately, we show that some of these THNAs possess reduced lipophilic properties, decreased hERG liability, faster mouse/human liver microsomal clearance rates and shorter plasma half-lives compared with bedaquiline, potentially addressing of the main concerns of persistence and phospholipidosis associated with bedaquiline. Design, synthesis and comprehensive structure-activity relationship studies for approximately 80 THNA analogues are described, with a small selection of compounds exhibiting potent (in some cases MIC 90 <1 μg/mL) in vitro M.tb growth inhibition taken forward to pharmacokinetic and off-target profiling studies. In this work, we report tetrahydronaphthalene amides (THNAs) as a new class of ATP synthase inhibitors that are effective in preventing the growth of Mycobacterium tuberculosis (M.tb) in culture. Bacterial ATP synthase inhibitors such as bedaquiline and next-generation analogues (such as TBAJ-876) have shown promising efficacy in patient populations and preclinical studies, respectively, suggesting that selective targeting of this enzyme presents a validated therapeutic strategy for the treatment of TB. Drug resistant tuberculsosis (TB) is global health crisis that demands novel treatment strategies.