Scaffold Hopping Strategy toward New 4‑Aminoquinazolines Active Against Extracellular and Intracellular

A series of 4-aminoquinazolines was designed through a scaffold hopping approach inspired by pharmacophoric features of known antimycobacterial agents. The compounds were synthesized via a one-pot silylation-amination reaction under solvent-free conditions, affording the desired molecules in 70%-99% yields. Antimycobacterial evaluation using multiple strains and assay platforms revealed potent activity, with MIC values as low as 0.28 μM. Structure-activity relationship analysis identified the N-(3-phenylpropyl)-quinazolin-4-amine scaffold as a promising chemotype. Mechanistic studies indicated that the compounds do not act via QcrB inhibition, membrane disruption, ROS induction, or MmpL3 targeting. The most active derivatives displayed favorable selectivity indices, lacked broad-spectrum antibacterial activity, and demonstrated intracellular efficacy in a macrophage infection model. Despite low metabolic stability, the scaffold's potency, selectivity, and intracellular activity support its potential as a lead series. These findings suggest a novel, yet unidentified mechanism of action and provide a promising starting point for anti-TB drug campaigns.