Scaffold Hopping in Tuberculosis Drug Discovery: Principles, Applications, and Case Studies

Tuberculosis (TB) imposes a major global health challenge, aggravated by the emergence of drug-resistant Mycobacterium tuberculosis (Mtb) strains. Scaffold hopping, a medicinal chemistry approach that modifies the molecular backbone of known bioactive compounds, has emerged as a promising tool in the development of novel drugs, including TB therapeutics. This perspective provides an insight into the application of scaffold hopping across varying degrees of structural modifications, highlighting successful case studies targeting key Mtb pathways, including energy metabolism, cell wall synthesis, proteasome function, and respiratory processes. Beyond traditional and in silico methods, scaffold hopping has spurred the discovery of compounds with improved pharmacological profiles, such as improved pharmacokinetics, enhanced efficacy, reduced toxicity, and resistance circumvention. The findings support scaffold hopping's potential to address the limitations of current anti-TB drugs as a versatile and innovative approach to accelerate TB drug discovery.