Abstract
Mycobacterium tuberculosis (M. tb) is the pathogenic bacterium responsible for tuberculosis (TB). Despite the availability of a vaccine and numerous antibiotics, TB continues to be one of the leading causes of death worldwide and in 2023 contributed to 1.25 million deaths. TB has lengthy treatment options ranging from 3-9 months, typically consisting of a four-drug regimen with isoniazid, rifampicin, ethambutol, and pyrazinamide. More concerningly, drug-resistant (DR) M. tb strains have emerged due to poor treatment adherence, incorrect prescribing, and inadequate healthcare systems. Multidrug-resistant (MDR) TB is resistant to two of the most potent anti-TB drugs, isoniazid and rifampicin, making first-line treatment ineffective. This leaves patients with treatment options that are more toxic and less effective, highlighting the need for new anti-TB agents that are efficacious against drug-resistant strains and can shorten treatment timelines. Our lab has developed highly potent anti-TB agents comprising the indole-2-carboxamide and acetamide pharmacophores. These agents have excellent potency against a panel of mycobacterial pathogens, including M. tb, with minimum inhibitory concentration (MIC) values of 0.06 – 0.5 µg/mL, which is more potent than the first-line drug ethambutol (M. tb MIC = 1 µg/mL). Although these series have excellent antitubercular activity, they suffer from poor aqueous solubility. Our central hypothesis is that bioisosteric replacement of the indole or phenyl ring to sp3 saturated cycloaliphatics would increase aqueous solubility while maintaining high antitubercular activity. Two series of bicyclopentane and cubane analogs were synthesized and evaluated for antimycobacterial activity, aqueous solubility, and permeability. Several compounds demonstrated improved solubility relative to the parent series, and most compounds exhibited intermediate to high permeability. GEM053 emerged as the lead compound with the highest aqueous solubility (219.1 ± 35.8 µg/mL) and permeability (12.1 ± 0.45 × 10⁻⁶ cm/s) while retaining measurable antitubercular activity (MIC 50 µg/mL). Although potency was reduced relative to the parent lead compounds, the improved physicochemical profile supports continued optimization of sp³-rich bioisosteric replacements within this scaffold. This work establishes a foundation for future optimization aimed at balancing antimycobacterial potency with favorable developabilityproperties in anti-TB drug candidates.