Novel antitubercular agents based on 2,4-disubstituted 5-(aryl-2-ylmethyl)-5H-pyrrolo[3,2-d]pyrimidines

Tuberculosis (TB), caused by Mycobacterium tuberculosis ( Mtb ), remains a global health challenge, especially with the rise of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains. Current treatment regimens are prolonged and associated with significant toxicity, underscoring the need for novel therapeutic agents. This study investigates a new series of 2,4-disubstituted 5-(aryl-2-ylmethyl)-5 H -pyrrolo[3,2- d ]pyrimidine derivatives as potential antitubercular agents. The most promising compound, 74 , exhibited potent anti-TB activity, including against MDR strains, with a MIC 99 of 2 µM. Structure-activity relationship studies identified critical substitutions at positions 2- and 4- of the core scaffold that enhanced antimycobacterial potency, while bulkier aromatic moieties at position 5- were preferred. Despite its high efficacy, 74 demonstrated significant cytotoxicity, inhibition of cytochrome P450 enzymes and cardiotoxicity through hERG channel inhibition, highlighting challenges in further development. Pharmacokinetic studies of 74 revealed favorable systemic exposure with a prolonged half-life, suggesting its potential for less frequent dosing. Nonetheless, in vitro assays demonstrated rapid metabolic turnover, likely due to high intrinsic clearance, and the compound's elevated logD values further indicate the need for structural modifications to improve both solubility and metabolic stability. Efforts to introduce more polar substituents at the 4-position led to a loss of anti-TB activity, emphasizing the complexity of balancing potency and safety. • Novel pyrrolopyrimidines show potent activity against M. tuberculosis strains. • Compound 74 exhibits MIC 99 of 2 µM against Mtb and MDR-TB strains. • Derivatives 74 and 75 show potent activity against Gram-positive bacteria. • Ames test confirms no mutagenic potential of lead compounds. • In vivo PK study reveals long half-life and sustained exposure for compound 74.