Convergent synthesis and cytotoxicity of novel trifluoromethyl-substituted (1H-pyrazol-1-yl)(quinolin-4-yl) methanones

• A convergent synthesis of new trifluoromethylated (1H-pyrazol-1-yl)(quinolin-4-yl) methanones (16 examples), is presented.
• High regiosectective [3 + 2] cyclocondensation reactions are successful performed to obtain pyrazoles under green conditions.
• Significant cytotoxicity in human leukocytes only at high concentrations for (di-heteroaryl) methanones, is observed.
• Most of new (1H-pyrazol-1-yl)(quinolin-4-yl) methanones were in agreement with Lipinski’s rule of five.

A convergent synthesis of a series of 16 new polysubstituted (5-hydroxy-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl)(quinolin-4-yl)methanones, starting from isatin and alky(aryl/heteroaryl) ketones, is described. The diheteroaryl methanones were achieved at yields of up to 95% by a [3 + 2] cyclocondensation reaction involving 4-alkyl(aryl/heteroaryl)-4-methoxy-1,1,1-trifluorobut-3-en-2-ones (by two-step reaction) and 2-alkyl(aryl/heteroaryl)-4-carbohydrazides (by three-step reaction). Subsequently, representative dehydrated heterocyclic derivatives were obtained from the respective 5-hydroxy-2-pyrazoline moieties by classical dehydration reactions, which resulted in the corresponding (5-(trifluoromethyl)-1H-pyrazol-1-yl)(quinolin-4-yl)methanones (three examples) at yields of 69–82%. The subsequent cytotoxicity evaluation showed that compounds with aromatic groups at the 2-position of the quinoline and a methyl moiety at the 3-position of the pyrazole have significant cytotoxicity in human leukocytes at high concentrations (200 μM).

Figure optionsDownload as PowerPoint slideConvergent synthesis and cytotoxicity of a series of 16 new polysubstituted (5-hydroxy-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl)(quinolin-4-yl)methanones, starting from isatin and alky(aryl/heteroaryl) ketones, is reported.