Design, synthesis and cytotoxic properties of novel 1-[4-(2-alkylaminoethoxy)phenylcarbonyl]-3,5-bis(arylidene)-4-piperidones and related compounds

The 3,5-bis(arylidene)-4-piperidones 1 contain the 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore which is considered to interact at a complementary binding site in susceptible neoplasms. The hypothesis was formulated that the presence of an acyl group attached to the piperidyl nitrogen atom in series 1 may interact with an additional binding site thereby enhancing cytotoxic potencies. This concept led to the synthesis of various N-acyl-3,5-bis(arylidene)-4-piperidones 3-7 many of which displayed significant cytotoxicity towards a variety of Cancer cell lines. A comparison of the potencies between the compounds in series 1 and the related nonquaternary analogues 3-6 revealed that in approximately half of the comparisons made, the N-acyl analogues had increased potencies.