Antituberculosis agents: Beyond medicinal chemistry rules

Mycobacterial infections are among the most widespread infectious diseases worldwide. For instance, tuberculosis (TB) is one of the top 10 causes of death worldwide and it is the leading cause from a single infectious agent. Of particular concern is the growing number of drug-resistant mycobacterial strains, that requires therapy prolongation and the use of less effective and more toxic drugs. One of the challenges in the treatment of TB is represented by the peculiar structure of the mycobacterial cell wall, which represents an effective defense against external insults, since its poor accessibility. For these reasons, the treatment is based on the administration of a cocktail of antimycobacterial drugs that must be prolonged (6-month standard) promoting, in turn, the occurrence of resistance. The search for novel effective therapeutic regimens has led to a nourished TB pipeline that mostly includes new chemical entities characterized by high killing potency and innovative mechanism of action. Alongside, “non-antimicrobial” host- and pathogen-directed therapies are emerging as effective strategies to support the standard treatment. Analysis of the molecules in the pipeline demonstrates that antituberculosis agents, either antimicrobial or adjuvant, are rarely compliant with the most common medicinal chemistry rules and largely evade the boundaries of drug-likeness, resulting in a “stand-alone” pharmaceutical class. In this chapter, the structural characteristics of several molecules in the TB pipeline are critically reviewed, and useful suggestions for the design of the next-generation antituberculosis drugs, both antimicrobial and adjuvant, are provided.