Phenothiazines and Related Drugs as Multi Drug Resistance Reversal Agents in Cancer Chemotherapy Mediated by p-glycoprotein

Background: Multi Drug Resistance (MDR) is one of the main hindrances in the successful treatment of cancer by natural agents. Most of the natural anticancer drugs are effluxed by the P-glycoprotein resulting in the failure of cancer chemotherapy. Phenothiazines and related drugs are one of the first drugs investigated for the reversal of MDR. Exhaustive studies have been done to develop potent phenothiazines analogues for MDR reversal activity. Materials and Methods: Quantitative Structural Activity Relationship (QSAR) and Structural Activity Relationship (SAR) studies of phenothiazines have provided some fruitful results in order to develop potent anti-MDR phenothiazine drugs but no success has been achieved yet. The main mechanism through which phenothiazines act on the Pglycoprotein includes the same binding site of vinblastine drug and it inhibits the efflux of such drugs. To develop a potent anti-MDR agent, it is indispensable to study the mechanism of efflux of anticancer drugs by P-gp, SAR and QSAR studies of phenothiazines as anti-MDR agents and mechanism of phenothiazines as anti-MDR agents simultaneously. Conclusion: This review will discuss the work done on the SAR and QSAR of phenothiazines as anti-MDR agents along with their putative mechanism of action as MDR reversal agents.