Halogenation of Drugs Enhances Membrane Binding and Permeation

Halogenation of drugs is commonly used to enhance membrane binding and permeation. We quantify the effect of replacing a hydrogen residue by a chlorine or a trifluoromethyl residue in position C-2 of promazine, perazine, and perphenazine analogues. Moreover, we investigate the influence of the position (C-6 and C-7) of residue CF₃ in benzopyranols. The twelve drugs are characterized by surface activity measurements, which yield the cross-sectional area, the air-water partition coefficient, and the critical micelle concentration. By using the first two parameters (AD and Kaw) and the appropriate membrane packing density, the lipid-water partition coefficients, are calculated in excellent agreement with the lipid-water partition coefficients measured by means of isothermal titration calorimetry for small unilamellar vesicles of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine. Replacement of a hydrogen residue by a chlorine and a trifluoromethyl residue enhances the free energy of partitioning into the lipid membrane, on average by ΔGlw≈−1.3 or −4.5 kJ mol⁻¹, respectively, and the permeability coefficient by a factor of ∼2 or ∼9, respectively. Despite exhibiting practically identical hydrophobicities, the two benzopyranol analogues differ in their permeability coefficients by almost an order of magnitude; this is due to their different cross-sectional areas at the air-water and lipid-water interfaces.