5-Iodotubercidin: A Novel Anti-Tuberculosis Lead with Promising Antimicrobial Activity, Pharmacokinetics, and Safety Profile

Abstract Aims Tuberculosis (TB) remains a major global health threat, underscoring the urgent need for novel therapeutics. 5-Iodotubercidin (5-ITu), a purine-based protein kinase inhibitor, has not been previously evaluated for anti-tuberculosis (anti-TB) applications. Methods and Results This study presents the first comprehensive characterization of 5-ITu as a lead compound for TB treatment, focusing on its antimicrobial activity, pharmacokinetic (PK) properties and safety profile. 5-ITu exhibited notable antimicrobial activity against Mycobacterium tuberculosis (MTB) standard strain H37Rv and 25 multidrug-resistant (MDR) clinical isolates, with MIC values ranging from 0.23 to 0.9 µg mL−1, while showing MIC values >32 µg mL−1 against eight other bacterial strains. Checkerboard assays revealed synergy with multiple anti-TB drugs against clinical MDR isolates. The permeabilizing effect of 5-ITu on the bacterial inner membrane, along with the associated dissipation of membrane potential and reduction of intracellular ATP, was confirmed by membrane integrity and function assays. PK study in mice following oral administration of 10 mg kg−1 showed rapid absorption, high plasma exposure, and an atypical plateau during the elimination phase. Cytotoxicity assays and acute toxicity studies in mice revealed moderate toxicity of 5-ITu toward mammalian cells and rodents. Conclusions Despite its moderate toxicity, the promising anti-TB activity and favorable PK profile of 5-ITu support its potential as a lead compound for structural optimization in anti-TB drug development.