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

TL;DR

Scientists designed new 4-aminoquinazoline compounds that effectively target tuberculosis bacteria both inside and outside cells, potentially offering a new treatment approach.

Contribution

A new scaffold hopping strategy led to potent 4-aminoquinazolines with intracellular activity and a novel mechanism against tuberculosis.

Findings

4-aminoquinazolines showed potent antimycobacterial activity with MIC values as low as 0.28 μM.

The N-(3-phenylpropyl)quinazolin-4-amine scaffold emerged as a promising chemotype with good selectivity and intracellular efficacy.

Mechanistic studies ruled out several known targets, suggesting a novel mechanism of action.

Abstract

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 Mycobacterium tuberculosis 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.

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