aLipophilicity is one of the major determining physicochemical descriptors for P-glycoprotein (P-gp) inhibitory activity. Recently, Pajeva and Wiese showed a Department of that in case of P-gp interaction, lipophilicity may be regarded as space-directed Pharmaceutical Chemistry, property. In the present study, a series of propafenone-type P-gp inhibitors with University of Vienna, systematically varying hydrophobicity distribution within the molecules were synWien, Austria thesised and pharmacologically tested. QSAR studies on the basis of multiple b Department of Medical linear regression analysis showed that with increasing lipophilicity of the Chemistry, University of substituents on the amine moiety, the statistical significance of the indicator variVienna, ables, denoting the substitution pattern on the central aromatic ring system, also Wien, Austria increases. This indicates that the distribution of hydrophobicity within the molecules influences the mode of interaction with P-gp.Keywords: Multidrug resistance; P-Glycoprotein, Propafenone; Hydrophobicity distribution IntroductionThe phenomenon of multidrug resistance (MDR) has become a major obstacle in the treatment of cancer with chemotherapeutic drugs. The development of broad specificity mechanisms of resistance to multiple classes of drugs is strongly associated with the overexpression of membrane-bound drug efflux pumps such as P-glycoprotein (P-gp) [1]. P-gp is a 170-kDa membrane protein that belongs to the family of ABC (ATP-Binding Cassette) transporters and functions as an ATP-dependent efflux protein for a large variety of structurally and functionally diverse drugs and natural products. These include anthracyclines, epipodophyllotoxines, actinomycin D, vinca alkaloids, colchicine and taxol [2]. All ABC transporters share a common architecture consisting of four domains. Two transmembrane domains form a pathway across the membrane through which solutes can move. . The low-resolution three-dimensional structure of P-gp in the presence and absence of ATP has recently been resolved at 10-Å resolution by electron cryomicroscopy of negatively stained crystals [12]. Very recently, two protein homology models of P-gp on the basis of the X-ray structure of MsbA were published [13,14]. However, both the detailed mechanism of transport and the ligand/protein interaction remain unresolved up to now.It has been shown that drugs with the ability to inhibit P-gp lead to resensitisation of resistant tumour cells. Among them are numerous structurally and functionally diverse drugs, such as verapamil, dihydropyridines, phenothiazines, thioxanthenes, amiodarone, and even flavonoids, steroids and detergents. In an attempt to systematically explore structure-activity relationships within the class of P-gp inhibitors, we used the class Ic anti-arrhythmic agent propafenone as template ( Figure 1A).Our results obtained so far show that pharmacophoric substructures such as H-bond acceptors and one or more aromatic rings seem to be important for the biological activity....