Serendipitous Identification of Azine Anticancer Agents Using a Privileged Scaffold Morphing Strategy

Area of Science:

• Medicinal Chemistry
• Drug Discovery
• Organic Synthesis

Background:

• Privileged scaffolds are crucial in drug discovery for creating bioactive compound libraries.
• Scaffold decoration, morphing, and hopping are key techniques for chemical space exploration.
• Triazine compounds previously showed antiviral activity.

Purpose of the Study:

• To synthesize novel pyrimidine and pyridine derivatives via scaffold morphing.
• To evaluate the anticancer potential of these new azine compounds.
• To assess the in vitro ADME properties of the most promising derivatives.

Main Methods:

• Scaffold morphing of triazine compounds to create pyrimidine and pyridine derivatives.
• Anticancer activity screening against lymphoma, hepatocarcinoma, and colon epithelial carcinoma cell lines.
• In vitro ADME studies including passive permeability and metabolic stability.

Main Results:

• Five novel azine derivatives exhibited acceptable to good anticancer activity.
• The synthesized compounds demonstrated low cytotoxicity against healthy fibroblasts.
• The lead derivatives showed favorable passive permeability and resistance to metabolic degradation in vitro.

Conclusions:

• The scaffold morphing approach successfully generated potent anticancer agents.
• The novel pyrimidine and pyridine derivatives represent promising candidates for further anticancer drug development.
• Favorable in vitro ADME profiles suggest potential for in vivo efficacy.