Early preclinical development of amino acid biosynthesis pathway inhibitor DRILS-1398 as a potential anti-TB drug.

The search for new anti-tubercular agents is vital for the fight against , particularly given the rise of drug-resistant strains. DRILS-1398, a pyrazolo[4,3-]pyrimidine derivative, was discovered as a potent inhibitor of chorismate mutase (-CM) with an IC = 3.0 ± 0.2 M ( = 3) and IC = 10 M. The compound demonstrated efficacy against multi-drug resistant strains (MIC = 4 μg/mL, ∼10.0 μM) and effective inhibition of intracellular in THP-1 macrophages. With favorable pharmacokinetics, moderate stability , and a promising safety profile, DRILS-1398 showed no toxicity at doses up to 500 mg/kg b.w./day when dosed orally daily once for 7 consecutive days in mice. Both DRILS-1398 and its formulation DRILS-1398(F) were successful in clearing infection from the lungs and spleen in murine models. These findings suggest DRILS-1398 as a promising lead candidate for developing a first-in-class anti-tubercular drug.