Novel camphane-based anti-tuberculosis agents with nanomolar activity

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Microbiology

Background:

• Tuberculosis (TB) remains a significant global health threat.
• Drug-resistant strains of Mycobacterium tuberculosis necessitate the development of new therapeutic agents.

Purpose of the Study:

• To design and synthesize novel amidoalcohols and amidodiols based on the camphor scaffold.
• To evaluate the in vitro antimycobacterial activity of these new compounds against Mycobacterium tuberculosis.

Main Methods:

• Synthesis of camphor-based amidoalcohols and amidodiols.
• In vitro activity testing against Mycobacterium tuberculosis H37Rv and a multidrug-resistant (MDR) strain.
• Quantitative Structure-Activity Relationship (QSAR) modeling for lead optimization.

Main Results:

• Several novel compounds exhibited significantly enhanced antimycobacterial activity compared to ethambutol.
• Activity shifted from micromolar to nanomolar concentrations with minor structural modifications.
• QSAR analysis identified optimal structural features for nanomolar activity, including two hydrogen bond donors and up to three rings.

Conclusions:

• Camphane-based amides represent a promising new scaffold for developing antimycobacterial drugs.
• The study provides a foundation for further optimization of these compounds to combat tuberculosis.