Synthesis and evaluation of biological activity of rhodaninepyrazoline hybrid molecules with a 2-(2,6-dichlorophenylamino)- phenylacetamide fragment

Abstract

Synthesis of new rhodanine-pyrazoline hybrid molecules with a diclofenac fragment in position 3 using the reactions of heterocyclization and aminolysis with potential antitumor and antitrypanosomal activities. Methods. Organic synthesis, NMR spectroscopy, pharmacological screening. Results. The reaction between 2-(2,6-dichloro-phenyl-amino)-phenylacetic acid hydrazide and thiocarbonyl-bis-thioglycolic acid in ethanol medium providing rhodanine derivative with fragment of the anti-inflammatory drug diclofenac in position 3 was performed. The presence of an active methylene group in position 5 and its subsequent modification providing 5-ethoxymethylenerhodanine and further aminolysis reaction with various 3,5-diaryl-4,5-dihydro-1H-pyrazoles allowed to produce of a series of 5-(3,5-diaryl-4,5-dihydropyrazol-1-ylmethylene)-2-thioxothiazolidin-4-ones. The antitumor activity screening allowed to identify a highly active compound 9 with a mean GI50 = 0.71/1.09 and TGI = 82.95/28.46 μM towards 60 cancer lines (DTP NCI program). The synthesized pyrazoline-thiazolidine hybrid molecules with the diclofenac fragment in the structure did not show significant antitrypanosomal activity against Trypanosoma brucei brucei (Tbb). Conclusions. The synthesized 5-(3,5-diaryl-4,5-dihydropyrazol-1-ylmethylene)-2-thioxothiazolidin-4-ones with a diclofenac fragment in the structure are a promising molecular platform for creation of new highly active potential drugs with a low toxicity.