Antimicrobial Activity of N-Acylphenothiazines and Their Influence on Lipid Model Membranes and Erythrocyte Membranes

Abstract

The antibacterial activity and influence on lipid model membranes and erythrocyte membranes of 24 N-acylphenothiazines and trifluoperazine were studied. (1) Among 24 phenothiazines, the antimicrobial activity of amino maleates was the highest. (2) The influence of phenothiazines on model liposome and erythrocyte membranes was studied using N-phenyl-1-naphthylamine (NPN) as fluorescence probe. From the three types of phenothiazine substitution (H, Cl, CF3) at position 2, CF3-phenothiazines were the most effective in the interaction with liposomal membranes. (3) As measured by the polarization degree of 1,6-diphenyl-1,3,5-hexatriene (DPH) fluorescence, the alteration of membrane fluidity induced by CF3-phenothiazines was the biggest. Surprisingly, phenothiazines induced stomatocytic shape alterations (invaginations) in erythrocytes and at higher concentrations, also hemolysis of erythrocytes was observed. (4) The microcalorimetic measurements of influence of phenothiazines on thermal behaviour of synthetic lipid systems confirmed the previously obtained results. The main transition temperature and enthalpy of transition of 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC) were significantly modified by CF3-phenothiazines, suggesting their penetration of the lipid bilayer. Above results show that phenothiazine maleates were generally more effective than other phenothiazines used in this study.

The Role of the Membrane Actions of Phenothiazines and Flavonoids as Functional Modulators

“…Similar localization of both drugs inside anionic detergent sodium dodecyl sulfate (SDS) micelles was also postulated [23]. In this system the pK values of CPZ (9) and TFP (5) were increased in the presence of detergent. The process of phenothiazine association with SDS micelles was much more complex than in the case of neutral and cationic detergents, being biphasic and dependent on drug and surfactant concentrations.…”

“…The authors also pointed out the fact that only taking into account two protonation states (two pK values) of TFP (5) could correctly explain the data obtained for this drug. In conclusion it was proposed that TFP (5) was able to penetrate deeper into the micelle interior than CPZ (9). Similar localization of both drugs inside anionic detergent sodium dodecyl sulfate (SDS) micelles was also postulated [23].…”

“…The critical micelle concentrations (cmc) for phenothiazines in water were reported to range from 10 -5 M for trifluoperazine (TFP) (5) and 10 -3 M for thioridazine (TDZ) (6) up to 10 -2 M for chlorpromazine (CPZ) (9), promazine (8), and promethazine (1) [20]. Phenothiazines formed roughly spherical micelles consisting of 6-15 molecules, which underwent spherical-to-rod transition at higher salt concentrations.…”

“…The interaction of two phenothiazines, TFP (5) and CPZ (9), with detergent micelles of different character was thoroughly investigated [22][23][24][25][26]. First, the binding of 5 and 9 to cationic, zwitterionic, and neutral detergent micelles was studied by means of absorption spectroscopy [22].…”

“…An important feature of phenothiazine drugs is also their activity against Mycobacterium tuberculosis (for a review see Amaral et al [7]) and Staphylococcus aureus [8]. Apart from effects on bacteria phenothiazines could also act as antifungal agents, as was shown with respect to Saccaromyces cerevisiae [9] and Candida albicans [10]. In many studies on cancer cells, various phenothiazine derivatives were proved to act as antitumor [11,12], antimutagenic, chemopreventive [13][14][15], antiproliferative, or pro-apoptotic agents [16][17][18].…”