1,2,3,4,8,9,10,11-octahydrobenzo[j]phenanthridine-7,12-diones as new leads against Mycobacterium tuberculosis

Area of Science:

• Medicinal Chemistry
• Microbiology
• Drug Discovery

Background:

• Tuberculosis (TB) remains a significant global health challenge, causing over 1.4 million deaths annually.
• The emergence of drug resistance and the HIV pandemic exacerbate the threat of TB.
• Novel therapeutic strategies, including companion drugs, are crucial for combating TB.

Purpose of the Study:

• To design and synthesize novel 2-aza-anthraquinone derivatives with antimycobacterial activity.
• To evaluate the in vitro efficacy of these compounds against Mycobacterium tuberculosis and other mycobacterial species.
• To assess the safety profile, including acute toxicity and genotoxicity, of the synthesized compounds.

Main Methods:

• Synthesis of various tetrahydro- and octahydrobenzo[j]phenanthridinediones.
• In vitro susceptibility testing against Mycobacterium tuberculosis, including multidrug-resistant strains.
• Evaluation of intracellular antimycobacterial activity.
• Assessment of acute toxicity and genotoxicity.

Main Results:

• The synthesized 2-aza-anthraquinone derivatives demonstrated high in vitro potency against Mycobacterium tuberculosis at submicromolar concentrations.
• Compounds were effective against clinically relevant mycobacterial species and susceptible to multidrug-resistant strains.
• The compounds effectively targeted intracellular replicating Mycobacterium tuberculosis.
• Genotoxicity studies indicated that these compounds could be dismissed, suggesting a favorable safety profile.

Conclusions:

• Tetrahydro- and octahydrobenzo[j]phenanthridinediones represent a promising scaffold for the development of new anti-TB drugs.
• The demonstrated antimycobacterial activity and favorable safety profile warrant further investigation for TB therapeutic applications.