Next-Generation Benzimidazole Derivatives as Potent Inhibitors of Drug-Resistant Mycobacterium tuberculosis: A Review

Tuberculosis (TB) remains the leading cause of death from a single infectious agent, and drug-resistant Mycobacterium tuberculosis (Mtb) continues to threaten treatment success. The WHO Global Tuberculosis Report 2025 estimates 10.7 million new TB cases and 1.23 million deaths in 2024, including roughly 390,000 new cases of multidrug-/rifampicin-resistant TB (MDR/RR-TB). Bedaquiline, delamanid and pretomanid have transformed the management of resistant disease, yet resistance to bedaquiline, drug toxicity and drug-drug interactions underline the need for new chemotypes acting on new targets. The benzimidazole nucleus is a privileged scaffold in medicinal chemistry, and over the past decade benzimidazole derivatives have emerged as one of the more productive antitubercular chemotypes. This review critically summarises the evidence for the principal mycobacterial targets of benzimidazoles. The mycolic acid transporter MmpL3 is now the best-supported target, with three series (the EJMCh compounds, the HC2099/MSU-43085 series and the 2,5,6-trisubstituted benzimidazoles originally proposed as FtsZ inhibitors) showing evidence of MmpL3 engagement; for the third series, however, the reassignment from FtsZ rests on a single recent study that did not exclude additional targets and awaits direct biochemical and independent confirmation. The cytochrome bc1 complex (QcrB), through lansoprazole sulfide and 2-(benzylthio)benzimidazoles, and type II NADH dehydrogenase (NDH-2), through 2-aryl-benzimidazoles, provide energy-metabolism targets, while benzimidazole ureas illustrate ATP-site inhibition of DNA gyrase in other bacteria. We discuss structure-activity relationships using quantitative data from the primary literature, hybrid design strategies, pharmacokinetic and safety liabilities (including the short half-life and lack of chronic-model efficacy of MSU-43085), and the evaluation cascade needed to convert in vitro hits into clinical candidates. We conclude with priorities for resistance-informed, structure-guided development of benzimidazoles within combination regimens.