A series of 1-[3-(2-hydroxyethylsulfanyl)propanoyl]-3,5-bis(benzylidene)-4-piperidones 4a-e display promising P-glycoprotein dependent multidrug resistance (MDR) revertant properties and are significantly more potent than a reference drug verapamil when evaluated against L-5178Y MDR lymphoma cells. These dienones may be referred to as dual agents having both MDR revertant properties and tumour-selective cytotoxicity. In particular, 3,5-bis(4-chlorobenzylidene)-1-[3-(2-hydroxyethylsulfanyl]propanoyl-4-piperidone 4d emerged as a lead molecule for further development based on its MDR revertant properties, cytotoxic potencies and tumour-selective toxicity. The structure-activity relationships reveal important structural requirements for further designing of potent MDR revertants.