Abstract: AIM: To study the structure-activity relationship of phenothiazines(PTZs) for inhibition of protein kinase C (PKC) and reversal of multidrug resistance (MDR) in vitro. METHODS and RESULTS: The possible binding model of PTZs to PKC based upon the X-ray structure of PMA(phorbol myristic acetate) in complex with PKC Cys 2 with DOCK program was explored. The results showed that the order of potency of reversal effect of PTZs on MDR is as follows: 2-COC₃H₇>2-CF₃>2-COCH₃>H. The type of piperazinyl substitution also significantly affected potency against MDR. The result showed the order: CH₃>COOC₂H₅>C₂H₄OH. CONCLUSION: Some derivatives of PTZ was tested for inhibition of PKC. The observation indicates that PTZs inhibit PKC in a manner related to specific structural feature. Our molecular-modeling study suggests preliminarily how these PTZs bind to PKC and provide a structural basis for the design of high affinity PKC-modulator. Our structure-activity studies offer a way to understand which molecular structure affects activity, and this information may be used in the rational design of more effective drugs.