4-aniloquinazolines are found in several anticancer drugs approved by the United States Food and Drug Administration (US FDA), and act primarily as receptor tyrosine kinase inhibitors (RTKs). Structure-activity relationship studies of 4-anilinoquinazolines targeting the epidermal growth factor receptor (EGFR) have demonstrated that the groups at the C6 and C7 positions play a fundamental role in solubility and activity of these compounds, since they are projected toward the solvent region. On the other hand, groups at the C3’ and C4’ positions are related to enhanced inhibitory activity and modulation within the allosteric pocket, respectively. Although 4-anilinoquinazolines act primarily as EGFR inhibitors, significant inhibitory activity against other receptors such as vascular endothelial growth factor receptor 2 (VEGFR2), human epidermal growth factor receptor-type 2 (HER2), several human carbonic anhydrase isoforms (hCA), and histone deacetylase 6 (HDAC6) has been reported. Herein, we present recent advances (2020-2025) in the design and synthesis of novel 4-anilinoquinazolines with anticancer activity, focusing especially on functionalization methodologies applied to this scaffold and how these modifications influence its inhibitory and antiproliferative activity against different receptors and cell lines, respectively. • 4-Anilinoquinazoline scaffolds play an important role as tyrosine kinase inhibitors. • Solubility and activity are affected by groups at the C6 and C7 positions of the quinazoline ring. • Groups at the C3’ and C4’ positions of the aniline moiety may increase inhibitory activity and modulate the allosteric pocket. • In order to synthesize more anticancer candidates, new functionalization methodologies are required.
Ferreira et al. (Sun,) studied this question.
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