Novel, Achiral 4‑Nitroimidazole Compounds with Potent Antitubercular Activity

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Drug Discovery

Background:

• Approved tuberculosis treatments delamanid and pretomanid are chiral, complicating synthesis and increasing toxicity.
• Chiral separation reduces synthetic accessibility and potentially impacts drug efficacy and safety profiles.

Purpose of the Study:

• To synthesize easily accessible achiral 4-nitroimidazole analogs.
• To evaluate the in vitro antitubercular activity and cytotoxicity of novel compounds.
• To identify compounds with improved efficacy and safety profiles compared to existing treatments.

Main Methods:

• Synthesis of a library of achiral 4-nitroimidazole derivatives.
• In vitro testing for antitubercular activity using MIC90 assays.
• In vitro assessment of cell toxicity.
• Evaluation of metabolic stability using human liver microsomes.

Main Results:

• Achiral 4-nitroimidazoles incorporating tetrazole moieties demonstrated potent antitubercular activity.
• Compounds 7e (0.24 μM) and 7q (0.92 μM) exhibited submicromolar MIC90 values.
• These lead compounds showed no significant cell toxicity and good metabolic stability.

Conclusions:

• Novel achiral 4-nitroimidazole-tetrazole hybrids are promising candidates for tuberculosis treatment.
• These compounds offer potential advantages in synthetic accessibility and safety.
• Further development of these compounds could lead to improved therapeutic options for drug-susceptible and drug-resistant tuberculosis.