3-methyl-2-(4-substituted phenyl)-4,5-dihydronaphtho[1,2-c]-pyrazoles: synthesis and in-vitro biological evaluation as antitumour agents

The synthetic strategies and characterization of some novel derivatives of 3-methyl-2-(4-substituted phenyl)-4,5-dihydronaphtho1,2-c]pyrazoles carrying different pharmacophores and heterocyclic rings that are relevant to potential antitumour and cytotoxic activities are described. The antitumour activities of the newly synthesized compounds were evaluated according to the protocol of the National Cancer Institute (NCI) in-vitro disease-oriented human cells screening panel assay. The results revealed that six compounds, namely 6, 8, 11, 15, 17 and 18; displayed promising in-vitro antitumour activity in the 60-cell lines assay. The sulfonylthioureido group emerged as the most favourable pharmacophore. Incorporating such thioureido counterpart into the 6-membered 1,3-thiazinan-5-one resulted in better antitumour activities than those displayed by the 5-membered thiazoles and the 6-membered 1,3-thiazinan-4-one ring systems. Further ring expansion led to a total loss of the antitumour activity. The analog 18, 3-benzyl-2-4-(3-methyl-4,5-dihydronaphtho-1,2-c]pyrazol-2-yl)-benzenesulfonylimino]-1,3-thiazinan-5-one, proved to be the most active member identified in this series of compounds (GI(50), TGI, and LC(50) MG-MID values of 34.7, 85.1 and 97.7 microM, respectively). The differential cytotoxicity of the six active compounds to cancer and normal cells was studied utilizing the standard MTT cell viability assay. Compounds 17 and 18 were totally selective for the breast cancer cell line MCF7 (IC(50 )8.5 and 4.7 microM), without exerting any inhibitory effect on the normal breast cell line MCF-10A at the concentration level used (25 microM).