Lead selection and characterization of antitubercular compounds using the Nested Chemical Library

Area of Science:

• Medicinal Chemistry
• Drug Discovery
• Microbiology

Background:

• Tuberculosis (TB) drug discovery is a global health priority, necessitating novel agents to combat multidrug resistance.
• Existing strategies include target-based approaches and phenotypic screens for antitubercular agents.

Purpose of the Study:

• To identify novel antitubercular compounds using an integrated screening strategy.
• To discover compounds with high efficacy and safety profiles against Mycobacterium tuberculosis.

Main Methods:

• Screening of over 17,000 compounds using both whole cell-based assays (Corynebacterium glutamicum, Mycobacterium tuberculosis) and target-based assays (protein kinases, PimA, topoisomerases).
• Evaluation of compound potency via minimal inhibitory concentrations (MIC) and assessment of mutagenicity and cytotoxicity.
• Lead optimization through medicinal chemistry strategies and confirmation in phenotypic assays.

Main Results:

• Target-based screening yielded potent enzyme inhibitors but lacked sufficient antimycobacterial activity.
• Whole cell-based screening identified several potent antitubercular hits with MICs < 10 microM.
• Identified hits were non-mutagenic, non-cytotoxic, represented diverse scaffolds, and some targets were elucidated.

Conclusions:

• An integrated screening approach successfully identified promising antitubercular lead compounds.
• Whole cell-based assays are effective for discovering novel antitubercular agents with favorable safety profiles.
• Further medicinal chemistry optimization led to potent, novel compounds for potential TB treatment.