Synthesis and Evaluation of 1,2,3-Triazole-Linked Trifluoromethyl Quinazolinone Derivatives as Anticancer Agents: Docking Interaction Analysis

A series of novel triazole-linked trifluoromethyl quinazolinone derivatives were synthesized starting from 2-amino-6-(trifluoromethyl)benzonitrile. Its base hydrolysis afforded 2-amino-6-(trifluoromethyl)benzoic acid. The subsequent reaction of this product with phenyl isocyanate gave 2-hydroxy-3-phenyl-5-(trifluoromethyl)quinazolin-4(3H)-one, which was further reacted with 2-chloroacetamide under Smiles rearrangement conditions to obtain 2-amino-3-phenyl-5-(trifluoromethyl)quinazolin-4(3H)-one. The acylation of the latter with 2-bromoacetyl bromide led to 2-bromo-N-[4-oxo-3-phenyl-5-(trifluoromethyl)-3,4-dihydroquinazolin-2-yl]acetamide (5), whose subsequent reaction with sodium azide provided 2-azido-N-[4-oxo-3-phenyl-5-(trifluoromethyl)-3,4-dihydroquinazolin-2-yl]acetamide. The copper-catalyzed azide–alkyne cycloaddition (click) reaction of the resulting azide with a series of substituted arylpropargyl bromides gave the target 1,2,3-triazole-linked quinazolinone derivatives. All final compounds were evaluated for anticancer activity against four human cancer cell lines: HeLa (cervical carcinoma, CCL-2), COLO 205 (colon adenocarcinoma, CCL-222), HepG2 (hepatocellular carcinoma, HB-8065), and MCF-7 (breast adenocarcinoma, HTB-22). The products bearing the 4-(ortho-hydroxyphenyl) and 4-(ortho-fluorophenyl) substituents in the 1,2,3-triazole ring showed promising activity, and their potential docking interactions were analyzed.