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

Area of Science:

• Medicinal Chemistry
• Drug Discovery
• Organic Synthesis

Background:

• Tuberculosis (TB) remains a significant global health challenge, necessitating the development of novel therapeutic agents.
• Existing anti-TB drugs face challenges including resistance and toxicity, driving the search for new drug classes.
• Scaffold hopping strategies offer a rational approach to designing novel chemical entities with potential therapeutic benefits.

Purpose of the Study:

• To design and synthesize a novel series of 4-aminoquinazolines inspired by known antimycobacterial pharmacophores.
• To evaluate the antimycobacterial activity and identify structure-activity relationships (SAR) within the synthesized compounds.
• To investigate the mechanism of action and assess the potential of these compounds as lead candidates for anti-TB drug development.

Main Methods:

• Scaffold hopping approach utilizing pharmacophoric features of existing antimycobacterial agents.
• One-pot silylation-amination reaction under solvent-free conditions for compound synthesis.
• Antimycobacterial evaluation against multiple strains using various assay platforms, including MIC determination.
• Mechanistic studies to elucidate the mode of action, excluding known targets and pathways.
• In vitro assessment of selectivity, metabolic stability, and intracellular efficacy in a macrophage model.

Main Results:

• Synthesis of 4-aminoquinazolines achieved in high yields (70%-99%).
• Potent antimycobacterial activity observed, with minimum inhibitory concentrations (MICs) as low as 0.28 μM.
• Structure-activity relationship (SAR) analysis identified the N-(3-phenylpropyl)-quinazolin-4-amine scaffold as a promising chemotype.
• Mechanistic studies ruled out inhibition of QcrB, membrane disruption, ROS induction, and MmpL3 targeting.
• The most active compounds exhibited favorable selectivity indices, lacked broad-spectrum activity, and showed intracellular efficacy.
• Low metabolic stability was noted for the most active derivatives.

Conclusions:

• The synthesized 4-aminoquinazolines represent a promising new chemotype for anti-TB drug discovery.
• The compounds exhibit potent antimycobacterial activity and favorable selectivity, with intracellular efficacy.
• The findings suggest a novel, yet unidentified mechanism of action against Mycobacterium tuberculosis.
• Despite limitations in metabolic stability, the identified scaffold provides a strong starting point for further optimization in anti-TB drug campaigns.