Novel 3-Amino-2-methylquinazolinone NF-κB Inhibitors: Synthesis and Potential Anti-Inflammatory Function

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Immunology

Background:

• Persistent activation of the nuclear factor kappa B (NF-κB) pathway is implicated in chronic inflammatory diseases and cancer.
• Developing effective NF-κB inhibitors is crucial for preclinical research and therapeutic strategies.

Purpose of the Study:

• To synthesize novel quinazolinone derivatives using innovative methodologies.
• To evaluate the inhibitory potential of these compounds against the canonical NF-κB pathway.

Main Methods:

• Synthesis of quinazolinone compounds via a novel one-pot multi-component reaction.
• Inhibition assays using a transgenic HeLa reporter cell line to measure NF-κB activity.
• Assessment of pro-inflammatory cytokine (interleukin-6) production in macrophage cultures.
• Molecular docking analysis to predict compound-target interactions.

Main Results:

• Eighteen quinazolinone compounds were synthesized and tested for NF-κB inhibition.
• Compounds 5o and 10 demonstrated activity against NF-κB-dependent luciferase expression.
• Compound 5o significantly attenuated interleukin-6 production in macrophages.
• Molecular docking suggested compound 5o interacts with the p65/DNA complex.

Conclusions:

• Compound 5o is a promising candidate for inhibiting the canonical NF-κB pathway.
• The synthesized quinazolinones, particularly 5o, warrant further investigation in preclinical models of inflammatory diseases.