2. Academic Validation
  3. Scaffold Hopping Strategy toward New 4‑Aminoquinazolines Active Against Extracellular and Intracellular

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

  • ACS Med Chem Lett. 2025 Jun 30;16(7):1410-1419. doi: 10.1021/acsmedchemlett.5c00276.
Guilherme Arraché Gonçalves 1 2,  Alexia de Matos Czeczot 1,  Marcia Alberton Perelló 1,  Eric Greve 3,  Renee Allen 3,  Camili Zanella Zotti 1,  Laura Calle González 1 4,  Andresa Berger 1 4,  Josiane Delgado Paz 1,  Lídia Klatt Oliveira 1,  Sidnei Moura E Silva 5,  Cristiano Valim Bizarro 1 4,  Luiz Augusto Basso 1 2 4,  Tanya Parish 3 6,  Pablo Machado 1 2 4
Affiliations

Affiliations

  • 1 Instituto Nacional de Ciência e Tecnologia em Tuberculose, Centro de Pesquisas em Biologia Molecular e Funcional, Pontifícia Universidade Católica do Rio Grande do Sul, 90616-900 Porto Alegre, Rio Grande do Sul, Brazil.
  • 2 Programa de Pós-Graduação em Medicina e Ciências da Saúde, Pontifícia Universidade Católica do Rio Grande do Sul, 90616-900 Porto Alegre, Rio Grande do Sul, Brazil.
  • 3 Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, Washington 98101, United States of America.
  • 4 Programa de Pós-Graduação em Biologia Celular e Molecular, Pontifícia Universidade Católica do Rio Grande do Sul, 90616-900 Porto Alegre, Rio Grande do Sul, Brazil.
  • 5 Laboratório de Biotecnologia de Produtos Naturais e Sintéticos, Universidade de Caxias do Sul, 95070-560 Caxias do Sul, Rio Grande do Sul, Brazil.
  • 6 Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington 98109, United States of America.
PMID: 40666484 DOI: 10.1021/acsmedchemlett.5c00276
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 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.

Keywords

Drug design; Intracellular activity; Mycobacterium tuberculosis; Quinazolines; Structure−activity relationship.

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