Tuberculosis (TB) remains a major global health challenge, particularly with the increasing burden of multidrug-resistant (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB). BDQ a diarylquinoline antimycobacterial agent, has emerged as a key component of modern MDR-TB therapy due to its unique mechanism of inhibiting the F1Fo ATP synthase of Mycobacterium tuberculosis , leading to disruption of cellular energy metabolism and bacterial death. As part of the WHO-recommended all-oral treatment regimens, BDQ has demonstrated significant clinical efficacy against drug-resistant TB. This review highlights the synthesis, structure–activity relationship (SAR), mechanism of action, pharmacokinetics (PK), pharmacodynamics (PD), resistance mechanisms, and safety profile of BDQ. SAR studies emphasize the importance of the diarylquinoline scaffold in maintaining potent antimycobacterial activity through ATP synthase inhibition. BDQ also exhibits favourable pharmacokinetic properties, including extensive tissue distribution and a long half-life that supports once-daily dosing. Early concerns regarding cardiotoxicity associated with QT interval prolongation and hERG channel interactions prompted extensive medicinal chemistry efforts aimed at separating antimycobacterial efficacy from cardiotoxic liability, resulting in the development of next generation diarylquinoline analogues with improved safety profiles. Despite its clinical success, emerging resistance associated with atpE mutations, efflux mechanisms, and metabolic adaptation highlights the importance of continued research and optimized combination therapies.
Gawande et al. (Sun,) studied this question.